Conditions: Locally Advanced or Metastatic and Unresectable HCC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 543
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, international, multi-center, phase III trial to evaluate the efficacy and safety of SHR-1210 plus apatinib mesylate versus sorafenib as first-line therapy in patients with advanced HCC.

Detailed description:

Arms:
arm 1: SHR-1210+Apatinib arm 2: Sorafenib

Interventions: intervention 1: SHR-1210 intervention 2: Apatinib intervention 3: Sorafenib
Intervention descriptions: intervention 1: Subjects receive SHR-1210 intravenously, Dosage form: lyophilised powder, Strength: 200 mg /vial intervention 2: Subjects receive Apatinib orally, Dosage form: tablet, Strength: 250 mg/tablet intervention 3: Subjects receive Sorafenib orally, Dosage form: tablet, Strength: 0.2 g/tablet

Protocol document:
Prot_000.pdf: 
Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
 
A Randomized, Open-Label, International, Multi-
Center, Phase 3 Clinical Study of PD-1 Antibody 
SHR-1210 Plus Apatinib (Rivoceranib) Mesylate 
Versus Sorafenib as First-Line Therapy in Subjects 
with Advanced Hepatocellular Carcinoma (HCC) 
Who Have Not Previously Received Systemic Therapy 
 
Protocol number: 
SHR-1210-III-310 
Trial phase: 
Phase 3 
Compound name: 
Camrelizumab for Injection (SHR-1210 for Injection), 
Rivoceranib Mesylate 
Person liable for protocol: 
 
 
 
Principal investigator: 
 
 
 
Version No.: 
6.0 
Version date: 
21 Sep 2022 
 
Sponsor:  Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
Confidentiality Statement 
The information contained in this protocol is confidential, only for use by clinical 
investigators and must not be revealed unless required by current law or regulations. The 
copyright of this protocol is owned by Jiangsu Hengrui Pharmaceuticals Co., Ltd. or its 
subsidiaries. It must not be replicated or distributed to any person who is not involved in this 
clinical study unless he/she has signed a non-disclosure agreement with Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. or its subsidiaries. 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version History / Amendment History 
Version 
No. 
Version 
Date 
Summary of Major Changes 
1.0 
10 Sep 
2018 
NA 
2.0 
12 Nov 
2018 
Primary Study Objective: 
• Updated from “To compare the overall survival (OS) of SHR-
1210 combined with apatinib mesylate (experimental arm) with 
sorafenib (control arm) as first-line therapy for subjects with 
advanced HCC who have not previously received systemic 
therapy” to “To compare the overall survival (OS) and 
progression-free survival (PFS) of SHR-1210 combined with 
apatinib mesylate (experimental arm) with sorafenib (control 
arm) as first-line therapy for subjects with advanced HCC who 
have not previously received systemic therapy”; 
Secondary Study Objective: 
• Updated from “To evaluate the immunogenicity of SHR-1210 
and analyze it in combination with the concentration of SHR-
1210” to “To evaluate pharmacokinetics (PK) of SHR-1210 
and apatinib and immunogenicity of SHR-1210, and to analyze 
the immunogenicity of SHR-1210 in combination with the 
concentration of SHR-1210”; 
Exploratory Study Objectives: 
• Added the following 2 exploratory study objectives: 
To compare the efficacy of SHR-1210 combined with apatinib 
mesylate (experimental arm) versus sorafenib (control arm) as 
first-line therapy in subjects with advanced HCC through 
evaluations of PFS, TTP, ORR, DCR and DoR based on immune-
modiﬁed Response Evaluation Criteria in Solid Tumors 
(imRECIST); 
To explore the correlation between biomarkers and the efficacy 
of combined therapeutic regimen; 
Primary Study Endpoints: 
• Updated from “overall survival (OS)” to “OS and PFS 
evaluated by the blinded independent review committee 
(BIRC) based on Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST v1.1)” as the co-primary study 
endpoints; 
Secondary Study Endpoints: 
• Secondary efficacy endpoint evaluated by BIRC updated from 
based on “imRECIST” to base on “RECIST v1.1 and 
mRECIST”; secondary efficacy endpoints evaluated by 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
investigator updated from based on “RECIST v1.1 and 
imRECIST” to base on “RECIST v1.1”; 
• Added PK endpoint “serum concentration of SHR-1210 and 
plasma concentration of apatinib”; 
Exploratory Study Endpoints: 
• Added exploratory study endpoint “PFS, TTP, ORR, DCR and 
DoR evaluated by investigator based on imRECIST”; 
• Added exploratory study endpoint “The expression level of PD-
L1, proportion of strong expression of PD-L1 in tumor tissue and 
tumor mutation burden (TMB) as well as their correlation with 
the efficacy of SHR-1210 combined with apatinib mesylate 
(including but not limited to ORR, OS)”; 
Other Changes:  
• The statistical hypothesis determined sample size and statistical 
analysis method were updated along with the change of primary 
study endpoints;  
• “Etiology (hepatitis B vs. hepatitis C vs. other)” was removed 
from the stratification factors;  
• Inclusion criteria: Child-Pugh hepatic function score was 
updated from “≤7” to “Grade A”;  
• The administration method of sorafenib is unified in accordance 
with the package insert approved by the FDA. Dose adjustment 
of sorafenib is supplemented in accordance with the package 
insert approved by the FDA; 
• Drugs used cautiously for subjects given sorafenib were 
supplemented;  
• Section of collection of tumor tissue sample and biomarker test 
added (exploratory study objective, study endpoint, inclusion 
criteria, study flow chart, evaluation and analysis of exploratory 
tumor markers); 
• Criteria on tumor evaluation updated to RECIST v1.1 
(investigator and BIRC evaluated), mRECIST (only BIRC 
evaluated) and imRECIST (only investigator evaluated);  
• The AE/SAE collection period was updated;  
• The safety follow-up period was updated;  
• The concomitant therapy collection period was updated;  
• “≥ grade 2 capillary endothelial proliferation with hemorrhage or 
≥ grade 3 capillary endothelial proliferation” was removed from 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
the adverse events of special interest;  
• Day 60 and Day 90 were deleted from the time of collection of 
immunogenicity samples. The collection method and volume of 
blood for immunogenicity and PK sampling were updated;  
• The definition of end of study was updated from “338 OS events 
obtained from LSLV” to “354 OS events obtained from LSLV”; 
• The coordinating investigator was updated to Professor Andrew 
ZHU;  
• In Appendix 2, expanded subsection “Comparison of imRECIST 
with RECIST v1.1”, and added subsection “Comparison of 
mRECIST with Conventional RECIST”.  
Detailed changes will be provided in a separate document: 
Description of Amendment to SHR-1210-III-310 Study Protocol 
v2.0. 
3.0 
17 Dec 
2018 
 
Cover page: Updated the compound name from “Camrelizumab” 
to “Camrelizumab for Injection”; 
 
Updated wording for exploratory study objectives, i.e., 
“experimental arm vs control arm” was clarified as “SHR-1210 
combined with rivoceranib mesylate vs sorafenib”; 
 
Updated the “utility score for economic assessment” in an 
exploratory study objective to the “utility score for health 
economic assessment”; 
 
Updated the CTCAE version from 5.0 to 4.03; 
 
Removed the detection of tumor mutation burden (TMB) 
throughout the protocol, revised its pertinent exploratory study 
endpoint, and reduced the number of unstained FFPE slides to 5; 
 
Included “rivoceranib”, the international nonproprietary name 
[INN] for apatinib;  
 
Increased the sample size to 510 subjects, added the interim OS 
analysis, and updated efficacy analyses accordingly; 
 
Modified the dose of SHR-1210 to 200 mg, added the rationale 
for dose selection of the combination therapy, updated the 
administration route of SHR-1210 from “IV” to the more specific 
term “intravenous infusion”; 
 
In the inclusion criteria, the antiviral therapy guideline for 
subjects with positive HCV-RNA was clarified as the “local 
standard treatment guideline”; 
 
Added strong inducers and strong inhibitors of CYP2C19 as 
prohibited medications in the exclusion criteria and in the section 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
regarding prohibited medications; 
 
In sections regarding PK and immunogenicity sampling, added 
“When SHR-1210 is interrupted for longer than 30 days and 
finally is confirmed to be unable to resume, for this situation, the 
subject is required to come for a site visit and collect blood 
sample immediately when investigator confirms the subject is 
permanently terminated SHR-1210 treatment”. The volume of 
blood to be collected was updated to “approximately 8 mL” for 
detection of immunogenicity and drug concentrations and to 
“approximately 6 mL” for detection of SHR-1210. Removed 
details on aliquots in blood sample handling and processing, and 
stated that detailed procedures are described in the laboratory 
manual; 
 
Set back study milestones by 1 month; 
 
Updated the initiation date of the screening period from Day -3 
to Day -7; 
 
Added Child-Pugh class in the schedule of activities and study 
procedures; 
 
Added “physical examination of reactive capillary endothelial 
proliferation needs to be performed on the experimental arm”; 
 
Added “γ-glutamyl transferase, direct bilirubin and indirect 
bilirubin” in blood biochemistry; 
 
Updated known potential risks of SHR-1210 and rivoceranib 
based on the most recent clinical study results; 
 
Added criteria of abnormal liver function tests for SHR-1210 
dose delay; updated criteria for permanent discontinuation of 
SHR-1210; 
 
Updated rules for safety management of immuno-oncology 
drugs; 
 
Added liver function test abnormalities to the list of special 
interest AEs; 
 
Updated the section of pregnancy; 
 
Updated treatment procedures for common immune-related AEs 
in Appendix 6 based on ESMO guidelines in combination with 
this protocol to make these procedures more practical.  
Detailed changes will be provided in a separate document: 
Description of Amendment to SHR-1210-III-310 Study Protocol 
v3.0. 
3.1 
26 Mar 
2019 
Administrative: 
 
Cover page: Corrected title for Andrew ZHU, MD to Co-


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
investigator 
Schedule of Events: 
 
ECG and PK Timepoints 
 
Footnotes 2, 5, and 32 PK collection and language added 
 
Footnote 4: ECG and PK added to C1D1 
 
Footnote 25: ECG and PK additional verbiage added 
Protocol Sections: 
 
Section 5.3.1.1: Drugs and Therapies Prohibited for all subjects 
during the study.  
 
Section 6.1: PK collection added  
 
Section 6.2.1: ECG assessment added to C1D1 study procedures 
 
Section 6.2.1: PK language added 
 
Sections 6.2.2; 6.2.3; 6.3; and 6.4: PK language added 
Appendix: 
 
Appendix 11: Additional information regarding Concomitant use 
of drugs effecting CYP enzymes, acid reducing agents or QT 
interval 
3.2 
27 Mar 
2019 
Protocol Section: 
• 5.1.6.1.5: changed verbiage (language) 
3.3 
28 Mar 
2019 
Protocol Section: 
• 5.3.1: Concomitant Therapy 
• Table 12 - removed 
• Appendix 11 - updated 
4.0 
16 Apr 
2019 
• Subject contraception requirements revised; 
• Inclusion and exclusion criteria updated; 
• The requirements of order of administration for SHR-1210 and 
rivoceranib with meal; 
• The study design schematic diagram adjusted; 
• The end time of study drug treatment clarified: Study treatment 
will continue until the subject develops intolerable toxicity, 
withdrawal of informed consent, or disease progression 
confirmed by BIRC in accordance with RECIST v1.1 and after 
comprehensive assessment investigator considers the subject no 
longer has clinical benefit based on radiological, laboratory data, 
and clinical status (e.g., tumor-related symptoms worsen), or 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
other criteria for discontinuation of treatment as specified in the 
protocol, whichever occurs first. When the subject develops 
disease progression that conforms to the definition by RECIST 
v1.1 according to the investigator's assessment, and BIRC also 
confirms the disease progression (according to RECIST v1.1), if 
the investigator assesses that the subject still has clinical benefit 
and is tolerated to study treatment, subject will continue SHR-
1210 alone or in combination with rivoceranib (experimental 
arm) or sorafenib (control arm) (see Section 6.6 of the main text 
for continued treatment after progression);  
• Specific timing of tumor assessment clarified: Tumor radiological 
assessment will continue until the occurrence of disease 
progression confirmed by BIRC according to RECIST v1.1 
criteria or study treatment termination, whichever occurs later. 
Subjects who discontinues treatment for other reasons than 
BIRC-confirmed disease progression (according to RECIST 
v1.1) will also continue with regular follow-up by tumor 
radiological assessments after treatment is completed. If the 
subject withdraws the informed consent before BIRC confirms 
the disease progression according to the RECIST v1.1 criteria or 
the treatment is discontinued, other anti-tumor treatment has 
begun (except for traditional Chinese medicine), or the subject 
dies, there is no need to continue the radiological evaluation. If 
the subject does not meet the above criteria for stopping 
radiological assessment, the efficacy evaluation of the three 
efficacy 
evaluation 
criteria 
(RECIST 
v1.1, 
mRECIST, 
imRECIST) needs to continue even if disease progression under 
a certain efficacy evaluation criterion occurs; 
• Flow chart for disease progression added;  
• The specific procedures of immunogenicity and PK blood 
collection in the experimental arm were clarified; and the blood 
sample collection table was added; 
• Safety visits schedule adjusted; 
• The survival follow-up was defined to start from the last safety 
visit; 
• The description of the sample size calculation section clarifies 
that the expected mOS of the experimental arm will be14.6 
months and the mPFS will be 6 months; 
• Updated assessment of subject self-reported outcomes: EORTC 
QLQ-C30 (version 3.0), EORTC QLQ-HCC18 and EQ-5D-5L 
questionnaire will be completed by all subjects from the first 
cycle, on the first day of each cycle prior to study drug 
administration and prior to any other study evaluation at the 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
clinical site. In addition, all subjects will be required to conduct 
the above questionnaire assessment at the end-of-treatment visit 
and during the first safety follow-up period. Before the subject 
leaves the site, the study staff should review all the questionnaires 
for completeness; 
• The handling method of a missed dose added; 
• Revision to the dose adjustment of rivoceranib; 
• Suggestions on management of immune related AEs in Table 10 
was deleted; 
• Deleted the treatment recommendations for immune-related 
adverse reactions in Table 10; 
• Revised description of each efficacy endpoint; 
• The efficacy analysis population was updated from FAS to ITT; 
• Updated efficacy endpoint analysis, interim analysis, multiple 
comparisons/multiplicity; 
• Deleted the estimated time of the study progress; 
• Clarify the storage of trial data: The sponsor should maintain 
clinical trial data for at least 15 years after the study medication 
is approved for marketing in the last country or region or after 
this clinical study is early terminated;  
• References updated; 
• PFS event definition and BOR definition under the imRECIST 
criteria added; 
• The classification and management of reactive capillary 
proliferation updated. 
5.0 
1 May 
2020 
• Co-investigator and relevant content removed; 
• Abbreviation table updated; 
• Background updated, include the description of the most recent 
data from previously conducted studies and most recent newly 
initiated studies. 
• Scientific rationale for antibody affinity study data updated. 
• SHR-1210 clinical studies progress updated. 
• Clarified that “vascular invasion” was “macrovascular invasion” 
in the randomization stratification factors.  
• Inclusion/exclusion criteria modified. 
• Removed “subject death” from the criteria of withdrawal from 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
study. 
• Improved the storage conditions of rivoceranib.  
• Removed “subsequent dosing time is calculated based on the 
actual date of previous administration” from dosing regimen; 
added missed dose rules. 
• Modified the description of the management of reactive capillary 
endothelial proliferation in the SHR-1210 dose delay criteria.  
• The description which interval of test frequency cannot exceed 6 
weeks for the safety visit and laboratory examination when dose 
delay occurs was modified to be “the required examinations 
during study treatment need to be performed as planned or more 
frequently when clinically indicated”. 
• Modified table of dosage adjustment plan of rivoceranib.  
• Modified table of dosage adjustment plan of sorafenib. 
• The requirement for daily blood pressure in both rivoceranib and 
sorafenib adverse reaction management was modified to 
recommended daily monitoring of blood pressure.  
• Modified the use of systemic corticosteroids in the prohibited 
medication for subjects given SHR-1210 during the study. 
• Modified the prohibited and cautiously used medication of 
rivoceranib.  
• Modified the description of antiviral therapy during study 
treatment.  
• Added “tumor tissue collection” in the screening period.  
• Among tumor image evaluation, “enhanced CT of chest, 
abdomen, pelvic cavity and lesion site” was modified to be 
“enhanced CT/MRI of chest, abdomen, pelvic cavity and lesion 
site”. 
• Serum biochemistry and serum HCG tests were modified to be 
blood biochemistry and blood HCG tests.  
• Added TT3 tests as the alternative test in the thyroid function 
examination.  
• Removed the “indirect bilirubin” in the blood biochemistry test. 
• Clarified the immunogenicity blood samples and PK blood 
samples collection rules. 
• Modified the definition of efficacy endpoints based on 
imRECIST. 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Version 
No. 
Version 
Date 
Summary of Major Changes 
• Modified the viral tests requirement (include HBV and HCV). 
• Modified the definition of TTD. 
• Modified the reporting requirement of Grade 5 SAE term caused 
by disease progression. 
• Delete duplicated descriptions regarding the use of the 
independent nominal alpha of 0.001% for OS at the time of the 
planned PFS analysis when OS events < 251 and that the study 
will not stop based on this result. The study will continue to the 
next planned OS interim analysis (70%) and could continue to 
final analysis after ~251 OS events and ~359 OS events are 
observed, respectively, according to the efficacy boundaries as 
described. Other minor changes such as typographical error were 
also made. 
• Improved the Data Monitoring Committee Part. 
• Reference updated. 
• Modified BCLC stage in appendix 1.  
5.1 
10 
March 
2021 
• Additional information about risk of Stevens-Johnson Syndrome 
(SJS) and toxic epidermal necrolysis (TEN) management 
guidelines for these events has been provided.  
• Removed “PK collection” on C1D15 in Section 6.2.1 to 
consistent with SCHEDULE OF ACTIVITIES. 
• Revised PPI drugs in APPENDIX 11 due to typo error.  
• Changed the emailbox for Sponsor receiving safety report to 
hengrui_drug_safety@hengrui.com 
6.0 
21 
Sep 
2022 
• Disease progression will only be confirmed by investigator 
instead of BIRC upon protocol v6.0 approval.  
• Definition of end of study was updated. 
• Added extension phase to provide study drug for subjects who 
still continue on treatment at the time of study closure.  


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
HENGRUI CONFIDENTIAL 
Signature Page of Sponsor 
I have read and confirmed this protocol (protocol number: SHR-1210-III-310; version 
number: 6.0; version date: 21 Sep 2022). I agree that relevant responsibilities must be 
fulfilled in accordance with ICH-GCP, any appropriate laws and regulations and this 
study protocol. 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
HENGRUI CONFIDENTIAL 
Signature Page of Principal Investigator (Lead Institution) 
I will fulfill investigator’s responsibilities carefully in accordance with ICH-GCP 
provisions, and will personally conduct or supervise this clinical study. I have received 
the investigator’s brochure of the investigational product for this clinical study; I have 
read and understood the preclinical data of the investigational product and the protocol 
of this clinical study. I agree that relevant responsibilities must be conducted in 
accordance with ICH-GCP, Declaration of Helsinki, applicable laws and regulations 
and this study protocol. Unless for the purpose of protection of subject’s safety, rights 
and benefits, I will amend the protocol only after informing the sponsor and obtaining 
consent and put into effect upon agreement by the ethics committee. I am responsible 
for making medical decisions related with clinical practice, as to ensure prompt and 
appropriate treatment for subjects when any adverse event occurs during the study, and 
record and report these adverse events in accordance with national relevant regulations. 
I will ensure the authentic, accurate, complete and prompt entry of the data into the 
study medical record. I will accept the monitoring and auditing by monitors and auditors 
appointed by the sponsor, and inspection by the drug regulatory authority, to ensure the 
quality of the clinical trial. I commit keeping confidential on subject’s personal 
information and relevant affairs. I agree to publicize my full name and occupation to 
the sponsor as well as the expenditure related with the clinical study as requested and 
prohibit any commercial or economic behavior related with the study. I agree upon the 
use of the study results for the drug registration and publication. I will provide one 
curriculum vitae of the principal investigator to the ethics committee and submit to the 
drug regulatory agency for a record prior to the start of the study. 
Study Center: 
 
 
 
 
 
 
 
屯


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
Signature Page of Principal Investigator (Participating Institution) 
 
I will fulfill investigator’s responsibilities carefully in accordance with ICH-GCP 
provisions, and will personally conduct or supervise this clinical study. I have received 
the investigator’s brochure of the investigational product for this clinical study; I have 
read and understood the preclinical data of the investigational product and the protocol 
of this clinical study. I agree that relevant responsibilities must be conducted in 
accordance with ICH-GCP, Declaration of Helsinki, applicable laws and regulations 
and this study protocol. Unless for the purpose of protection of subject’s safety, rights 
and benefits, I will amend the protocol only after informing the sponsor and obtaining 
consent and put into effect upon agreement by the ethics committee. I am responsible 
for making medical decisions related with clinical practice, as to ensure prompt and 
appropriate treatment for subjects when any adverse event occurs during the study, and 
record and report these adverse events in accordance with national relevant regulations. 
I will ensure the authentic, accurate, complete and prompt entry of the data into the 
study medical record. I will accept the monitoring and auditing by monitors and auditors 
appointed by the sponsor, and inspection by the drug regulatory authority, to ensure the 
quality of the clinical trial. I commit keeping confidential on subject’s personal 
information and relevant affairs. I agree to publicize my full name and occupation to 
the sponsor as well as the expenditure related with the clinical study as requested and 
prohibit any commercial or economic behavior related with the study. I agree upon the 
use of the study results for the drug registration and publication. I will provide one 
curriculum vitae of the principal investigator to the ethics committee and submit to the 
drug regulatory agency for a record prior to the start of the study. 
 
Study Center: ___________________________________________ 
 
 
 
 
 
 
 
Principal Investigator  
(Print Name) 
Principal Investigator 
(Signature) 
Signature Date 
(Day/Month/Year) 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
 
1 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................... 1 
LIST OF TABLES…………… ..................................................................... …………5 
LIST OF FIGURES….. ................................................................................................. 5 
SYNOPSIS OF PROTOCOL ........................................................................................ 6 
SCHEDULE OF ACTIVITIES .................................................................................... 24 
ABBREVIATIONS 
36 
1. 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE ....... 39 
1.1. 
Study Background .................................................................................... 39 
1.1.1. 
Epidemiology and Current Treatment Status of Hepatocellular 
Carcinoma ................................................................................. 39 
1.1.2. 
Advances in the Treatment of Advanced Hepatocellular 
Carcinoma ................................................................................. 40 
1.1.3. 
Development of PD-1/PD-L1 Monoclonal Antibody in 
Advanced Tumors ..................................................................... 41 
1.2. 
Scientific Rationale .................................................................................. 45 
1.2.1. 
Preclinical Studies with SHR-1210 .......................................... 45 
1.2.2. 
Clinical Studies with SHR-1210 ............................................... 48 
1.2.3. 
Progress in Clinical Research of Rivoceranib Monotherapy for 
Advanced HCC ......................................................................... 50 
1.2.4. 
Preliminary Data of SHR-1210 Combined with Rivoceranib .. 51 
1.2.5. 
Selection Rationale of Control Arm ......................................... 57 
1.3. 
Potential Risks and Benefits .................................................................... 57 
1.3.1. 
Known Potential Risks ............................................................. 58 
1.3.2. 
Known Possible Benefits .......................................................... 59 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................... 60 
3. 
STUDY DESIGN ............................................................................................... 62 
3.1. 
Overall Design ......................................................................................... 62 
3.2. 
Measures to Minimize Bias ..................................................................... 64 
3.2.1. 
Randomization .......................................................................... 64 
3.2.2. 
Evaluation of Success of Blinding ............................................ 64 
3.2.3. 
Breaking the Study Blind/Participant Code .............................. 64 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................... 64 
4.1. 
Inclusion Criteria ..................................................................................... 64 
4.2. 
Exclusion Criteria .................................................................................... 66 
4.3. 
Randomization Criteria ............................................................................ 69 
4.4. 
Lifestyle Requirements ............................................................................ 69 
4.4.1. 
Contraception ............................................................................ 69 
4.5. 
Subjects’ Withdrawal from the Study or Discontinuation of Study 
Treatment ................................................................................................. 71 
4.5.1. 
Criteria for Discontinuation of Study Treatment ...................... 71 
4.5.2. 
Criteria for Withdrawal from the Study .................................... 71 
4.5.3. 
The Procedures of Withdrawal from the Study or 
Discontinuation of Study Treatment ......................................... 72 
4.5.4. 
Lost to Follow-Up..................................................................... 72 
4.6. 
Early Termination or Suspension of Study .............................................. 72 
4.7. 
Definition of End of Study ....................................................................... 73 
5. 
STUDY TREATMENT ..................................................................................... 73 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
 
2 
 
5.1. 
Description of the Investigational Product .............................................. 73 
5.1.1. 
Acquisition and Accountability ................................................ 73 
5.1.2. 
Formulation, Appearance, Packaging and Storage of Drug ..... 73 
5.1.3. 
Storage and Stability ................................................................. 74 
5.1.4. 
Preparation ................................................................................ 75 
5.1.5. 
Dose Regimen ........................................................................... 75 
5.1.6. 
Dose Adjustment and Safety Management............................... 76 
5.2. 
Management, Distribution and Recovery of Drugs ................................. 91 
5.2.1. 
Drug Preparation ....................................................................... 91 
5.2.2. 
The Disposal of Remaining Drugs ........................................... 91 
5.3. 
Concomitant Therapy ............................................................................... 91 
5.3.1. 
Prohibited or Cautiously Used Medications and Treatments 
During the Study ....................................................................... 92 
5.3.2. 
Permitted Concomitant Medications and Treatments During the 
Study ......................................................................................... 94 
5.3.3. 
Surgery or Palliative Radiotherapy ........................................... 95 
6. 
STUDY PROCEDURES ................................................................................... 95 
6.1. 
Screening Period ...................................................................................... 96 
6.2. 
Treatment Period ...................................................................................... 98 
6.2.1. 
Cycle 1 ...................................................................................... 99 
6.2.2. 
Cycles 2 and 3 ......................................................................... 101 
6.2.3. 
Cycle 4 and Onwards .............................................................. 103 
6.3. 
End of Treatment Visit ........................................................................... 105 
6.4. 
Follow-up Period ................................................................................... 107 
6.5. 
Unscheduled Visits ................................................................................ 109 
6.6. 
Treatment Beyond Progression .............................................................. 109 
6.6.1. 
Criteria on Post-Progression Continuation of SHR-1210 Alone 
or Combined with Rivoceranib in Subjects in Experimental 
Arm ......................................................................................... 110 
6.6.2. 
Criteria on Post-Progression Continuation of Sorafenib 
Treatment in Subjects in Control Arm .................................... 110 
6.6.3. 
Other Precautions for Post-Progression Continuation of 
Treatment ................................................................................ 111 
6.7. 
Study Extension Phase ........................................................................... 111 
7. 
EVALUATION 112 
7.1. 
Efficacy Evaluation ................................................................................ 112 
7.2. 
Tumor Radiological Evaluation ............................................................. 113 
7.2.1. 
Tumor Evaluation Based on RECIST v1.1, mRECIST and 
imRECIST .............................................................................. 113 
7.2.2. 
Determination Process for Disease Progression (PD) ............ 115 
7.3. 
Safety Evaluation ................................................................................... 116 
7.3.1. 
Pregnancy Testing .................................................................. 116 
7.3.2. 
Adverse Events ....................................................................... 116 
7.3.3. 
Laboratory Safety Evaluation ................................................. 116 
7.3.4. 
Physical Examination and Vital Signs .................................... 117 
7.3.5. 
12-lead ECG ........................................................................... 117 
7.3.6. 
Echocardiography ................................................................... 117 
7.3.7. 
ECOG-PS Scores .................................................................... 117 
7.4. 
Pharmacokinetics and Immunogenicity Evaluation ............................... 117 


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7.4.1. 
Collection Time of Blood Samples ......................................... 117 
7.4.2. 
Processing and Storing of Blood Samples .............................. 118 
7.4.3. 
Delivery of Blood Samples ..................................................... 118 
7.5. 
Patient Reported Outcomes (PRO) ........................................................ 118 
7.5.1. 
EORTC QLQ-C30 and EORTC QLQ-HCC18 ...................... 119 
7.5.2. 
EQ-5D-5L ............................................................................... 119 
7.6. 
Evaluation of Exploratory Tumor Markers ............................................ 120 
8. 
ADVERSE EVENT REPORTING .................................................................. 120 
8.1. 
Adverse Events ...................................................................................... 120 
8.1.1. 
Definition ................................................................................ 120 
8.1.2. 
The Judgment Standard on Severity of AE ............................ 121 
8.1.3. 
Causality Assessment ............................................................. 121 
8.2. 
Serious Adverse Events ......................................................................... 122 
8.2.1. 
Definition of SAE ................................................................... 122 
8.2.2. 
Hospitalization ........................................................................ 122 
8.2.3. 
Disease Progression and Death ............................................... 123 
8.2.4. 
Reporting Procedures of SAE ................................................. 123 
8.3. 
Collection and Follow-Up of AE/SAE .................................................. 124 
8.4. 
AEs of Special Interest ........................................................................... 125 
8.4.1. 
Liver Function Test (LFT) Abnormalities .............................. 125 
8.5. 
Pregnancy ............................................................................................... 126 
9. 
CLINICAL MONITORING ............................................................................ 126 
10. 
STATISTICAL ANALYSIS ........................................................................... 126 
10.1. Sample Size Determination .................................................................... 126 
10.2. Objectives and Statistical Hypotheses ................................................... 127 
10.2.1. Primary Objectives and Statistical Hypotheses ...................... 127 
10.2.2. Key Secondary Objectives and Statistical Hypotheses .......... 127 
10.3. Analysis Populations .............................................................................. 127 
10.4. Statistical Analysis Methods .................................................................. 127 
10.4.1. General Method ...................................................................... 127 
10.4.2. Subject Disposition ................................................................. 128 
10.4.3. Demographics and Baseline Characteristics ........................... 128 
10.4.4. Prior and Concomitant Medications ....................................... 128 
10.4.5. Primary Efficacy Endpoints Analyses .................................... 128 
10.4.6. Secondary Efficacy Endpoints Analyses ................................ 129 
10.4.7. Pharmacokinetics and Immunogenicity .................................. 129 
10.4.8. Exploratory Endpoints Analyses ............................................ 129 
10.4.9. Handling of Missing Data ....................................................... 130 
10.4.10. Safety Analyses ...................................................................... 130 
10.4.11. Interim Analyses ..................................................................... 131 
10.4.12. Multiplicity ............................................................................. 132 
10.4.13. Subgroup Analyses ................................................................. 133 
10.5. Blinded Independent Review Committee .............................................. 134 
10.6. Data Monitoring Committee .................................................................. 134 
11. 
DATA MANAGEMENT METHODS ............................................................ 135 
11.1. Recording of Data .................................................................................. 135 
11.1.1. Recording of Source Document .............................................. 135 
11.1.2. Filling of eCRF ....................................................................... 135 
11.1.3. eCRF Review .......................................................................... 135 


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11.2. Data Management .................................................................................. 136 
11.2.1. Establishment of EDC Database ............................................. 136 
11.2.2. Data Review and Database Lock ............................................ 136 
11.2.3. Data Archiving ........................................................................ 136 
12. 
SOURCE DATA AND SOURCE DOCUMENT............................................ 136 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL ............................... 137 
14. 
REGULATIONS, ETHICS, INFORMED CONSENT AND PROTECTION OF 
SUBJECTS 
137 
14.1. Considerations on Regulations .............................................................. 137 
14.2. Ethics ...................................................................................................... 138 
14.3. Independent Ethics Committee .............................................................. 138 
14.4. Informed Consent ................................................................................... 138 
14.4.1. Written Information Required for Informed Consent Form and 
Subjects ................................................................................... 138 
14.4.2. Course and Record of Informed Consent ............................... 139 
14.5. Confidentiality of Subject’s Information ............................................... 139 
15. 
PUBLICATION OF STUDY RESULTS ........................................................ 139 
16. 
REFERENCES 141 
APPENDIX 1. 
Barcelona Clinic Liver Cancer (BCLC) Classification ........ 144 
APPENDIX 2. 
Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1) and Its Comparison with Immune-Modified RECIST 
(imRECIST) and Modified RECIST (mRECIST) ........................................... 145 
APPENDIX 3. 
Child-Pugh Classification Criteria for Liver Function ......... 161 
APPENDIX 4. 
Criteria for Eastern Cooperative Oncology Group - 
Performance Status (ECOG-PS) Score ............................................................ 162 
APPENDIX 5. 
New York Heart Association (NYHA) Cardiac Function 
Classification 
163 
APPENDIX 6. 
Recommended Treatment Procedures for Common Immune-
Related Adverse Events ................................................................................... 164 
APPENDIX 7. 
Grade and Management of Reactive Capillary Endothelial 
Proliferation (RCEP) ........................................................................................ 176 
APPENDIX 8. 
EORTC QLQ-C30 (Version 3.0) ......................................... 177 
APPENDIX 9. 
EORTC QLQ-HCC18 .......................................................... 179 
APPENDIX 10. 
EQ-5D-5L ............................................................................ 180 
APPENDIX 11. 
Information Regarding Concomitant Use of Drugs Effecting 
CYP Enzymes and Acid Reducing Agents ...................................................... 183 
APPENDIX 12. 
Schedule of Activities: Extension Phase .............................. 189 
 


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LIST OF TABLES 
Table 1 
Binding Affinity of Antibody SHR-1210 to Human and Cynomolgus and 
Rhesus Monkey PD-1 .............................................................................. 46 
Table 2 
Binding Affinity of Antibody SHR-1210, Nivolumab and MK3475 to 
Human PD-1 Antigen ............................................................................... 46 
Table 3 
Pharmacokinetic Parameters of Cynomolgus Monkeys After Single 
Intravenous Infusion of SHR-1210 at Different Doses ............................ 47 
Table 4 
Occurrence of DLT in Each Dose Group in the Studies on SHR-1210 
Combined with Rivoceranib in Treatment of Advanced Hepatocellular 
Carcinoma and Gastric Cancer ................................................................ 54 
Table 5 
Occurrence of Clinically Significant Toxicity in Each Dose Group in the 
Study on SHR-1210 Combined with Rivoceranib in Treatment of 
Advanced Non-Small Cell Lung Cancer ................................................. 55 
Table 6 
Phase 3 Clinical Trial on Sorafenib in Advanced Hepatocellular 
Carcinoma ................................................................................................ 57 
Table 7 
Dosing Regimens for Each Treatment Cycle ........................................... 75 
Table 8 
Dose Adjustment Plan of Rivoceranib ..................................................... 81 
Table 9 
Dose Adjustment of Sorafenib When Dermatologic Toxicities Occur .... 83 
Table 10 
Recommendations for the Treatment of Infusion Reactions .................... 87 
Table 11 
Items of Laboratory Tests ...................................................................... 116 
Table 12 
The Judgment Standard on Severity of AE ............................................ 121 
Table 13 
AE/SAE Collection Period .................................................................... 124 
Table 14 
SAE Collection During Extension Phase ............................................... 125 
Table 15 
Boundary Properties for Planned Analyses of OS ................................. 132 
Table 16 
SJS/TEN management and treatment .................................................... 172 
 
LIST OF FIGURES 
Figure 1. 
SHR-1210 and Pembrolizumab Blocking the Binding of PD-1/PD-L1 .. 46 
Figure 2. 
SHR-1210 and Nivolumab Blocking the Binding of PD-1 / PD-L1 ....... 47 
Figure 3. 
Evaluation of the Effect of SHR-1210 Combined with Rivoceranib on 
MC38 Colorectal Cancer in Tg Mice Expressing Human PD-1 .............. 52 
Figure 4. 
Relationship of Efficacy and Safety Indexes with Doses ........................ 54 
Figure 5. 
The Best Response of SHR-1210 Combined with Rivoceranib in 
Advanced Hepatocellular Carcinoma and Change in the Diameter of 
Target Lesions After Administration ........................................................ 56 
Figure 6. 
Study Design Chart .................................................................................. 63 
Figure 7. 
Disease Progression Confirmation Process ........................................... 115 
Figure 8. 
Type I error reallocation strategy for endpoints PFS and OS. ............... 133 


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SYNOPSIS OF PROTOCOL 
Study Title 
A Randomized, Open-Label, International, Multi-Center, Phase 
3 Clinical Study of PD-1 Antibody SHR-1210 Plus Apatinib 
(Rivoceranib) Mesylate Versus Sorafenib as First-Line 
Therapy in Subjects with Advanced Hepatocellular Carcinoma 
(HCC) Who Have Not Previously Received Systemic Therapy 
Protocol Number 
SHR-1210-III-310 
Version Number 
6.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Principle 
Investigator 
 
Study Centers 
Approximately 140 centers globally 
Study Objectives 
Primary Objective: 
• 
To compare the overall survival (OS) and progression-free 
survival (PFS) of SHR-1210 combined with apatinib 
(hereafter referred to as “rivoceranib”, its international 
nonproprietary name [INN]) mesylate (experimental arm) 
with sorafenib (control arm) as first-line therapy for 
subjects with advanced HCC who have not previously 
received systemic therapy. 
Secondary Objectives: 
• 
To compare the efficacy of SHR-1210 combined with 
rivoceranib versus sorafenib as first-line therapy in 
subjects with advanced HCC, who have not previously 
received systemic therapy, through evaluations of PFS, 
time to progression (TTP), objective response rate (ORR), 
disease control rate (DCR), and duration of response 
(DoR);  
• 
To evaluate the safety of SHR-1210 combined with 
rivoceranib versus sorafenib as a first-line therapy in 
subjects with advanced HCC; 
• 
To evaluate the pharmacokinetics (PK) of SHR-1210 and 
rivoceranib and the immunogenicity of SHR-1210, and to 
analyze the immunogenicity combined with the 
concentration of SHR-1210.  
Exploratory Objectives: 
• 
To evaluate the quality of life (QoL), including health 
related quality of life (HRQOL) / general health status 
(GHS), physical functioning and role functioning, of 
subjects with advanced HCC who receive SHR-1210 
combined with rivoceranib mesylate as first-line therapy 
versus those who receive sorafenib as first-line therapy; 
• 
To evaluate the health status of subjects with advanced 


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HCC who receive SHR-1210 combined with rivoceranib 
as first-line therapy versus those who receive sorafenib as 
a first-line therapy, so as to generate a utility score for 
health economic assessment; 
• 
To compare the efficacy of SHR-1210 combined with 
rivoceranib versus sorafenib as first-line therapy in 
subjects with advanced HCC through evaluations of PFS, 
TTP, ORR, DCR and DoR based on immune-modiﬁed 
Response 
Evaluation 
Criteria 
in 
Solid 
Tumors 
(imRECIST)； 
• 
To explore the correlation between biomarkers and the 
efficacy of combined therapeutic regimen; 
• 
To evaluate the potential effect of immunogenicity of 
SHR-1210 on the efficacy and safety of SHR-1210 
combined with rivoceranib as a first-line therapy in 
subjects with advanced HCC. 
Study Endpoints 
Primary Endpoints: 
• 
OS; 
• 
PFS evaluated by the blinded independent review 
committee (BIRC) based on Response Evaluation Criteria 
in Solid Tumors Version 1.1 (RECIST v1.1). 
Secondary Endpoints: 
Efficacy: 
• 
TTP, ORR, DCR and DoR evaluated by the BIRC based on 
RECIST v1.1; 
• 
PFS, TTP, ORR, DCR and DoR evaluated by investigator 
based on RECIST v1.1; 
• 
PFS, TTP, ORR, DCR and DoR evaluated by the BIRC 
based on modiﬁed RECIST (mRECIST). 
Safety: 
• 
Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs) judged in accordance with NCI-
CTCAE v4.03; vital signs, ECG and abnormal laboratory 
examinations.  
PK and Immunogenicity parameters:  
• 
Serum 
concentration 
of 
SHR-1210 
and 
plasma 
concentration of rivoceranib; proportion of anti-SHR-1210 
antibody (ADA) and neutralizing antibody (Nab) formed 
during the study from baseline; and analysis of the 
immunogenicity of SHR-1210 combined with the 
concentration of SHR-1210. 
Exploratory Endpoints: 
• 
Time to deterioration (TTD): defined as time from 
randomization to first deterioration (a score decrease of 


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≥10 from baseline) maintained for two consecutive time 
points, or one time-point followed by death (from any 
cause] within 4 weeks, as determined by following 
subscales of European Organization for Research and 
Treatment of Cancer (EORTC) Quality 
of 
Life 
Questionnaire-Core 30 (QLQ-C30):  
- 
HRQoL/Global health status 
- 
Physical Functioning 
- 
Role Functioning 
• 
Average score and its change in the score from baseline in 
all the subscales of EORTC QLQ-C30 and EORTC QLQ-
HCC18 (by cycle);  
• 
Health utility index and VAS score of EQ-5D-5L 
questionnaire; 
• 
PFS, TTP, ORR, DCR and DoR evaluated by investigator 
based on imRECIST; 
• 
The correlation of the expression level of PD-L1 and 
proportion of strong expression of PD-L1 in tumor tissue 
with the efficacy of SHR-1210 combined with rivoceranib 
mesylate (including but not limited to ORR, OS); 
• 
Efficacy endpoints (e.g., best overall response (BOR), 
ORR, etc.), and safety endpoint (e.g., immune-related 
adverse events [irAEs], ≥ Grade 3 treatment-related 
adverse events, treatment-related SAEs, etc.) listed 
according to the ADA / Nab status of SHR-1210 in the 
experimental arm. 
Study Subjects 
Subjects with incurable, locally advanced or metastatic HCC 
who have not received previous systematic treatment  
Study Design 
This is a randomized, open-label, international, multi-center, 
phase 3 trial to evaluate the efficacy and safety of PD-1 
antibody SHR-1210 plus rivoceranib mesylate versus sorafenib 
as first-line therapy in subjects with incurable advanced HCC.  
The study will be conducted in subjects with incurable, locally 
advanced or metastatic HCC who have not received previous 
systematic treatment. Primary efficacy endpoints include both 
OS and PFS evaluated by the BIRC based on RECIST v1.1, and 
approximately 510 subjects will be enrolled. Eligible subjects 
will be randomized to receive either SHR-1210 combined with 
rivoceranib mesylate (experimental arm) or sorafenib (control 
arm) in a 1:1 ratio.  
The stratification factors for randomization include:  
1. Macrovascular invasion and/or extrahepatic metastasis 
(presence vs. absence) 
2. Geographical region (Asia vs. countries outside of Asia) 
3. Baseline AFP (AFP < 400 ng/mL vs. AFP ≥ 400 ng/mL) 


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Subjects will receive study treatment after being informed of 
all pertinent aspects of the study, signing the informed consent 
form and passing the screening for eligibility. Experimental 
arm: SHR-1210, 200 mg, via intravenous infusion, once every 
two weeks (Q2W) + rivoceranib 250 mg, p.o., once per day 
(QD), continuously, 4 weeks (28 days) per cycle of therapy. 
Control arm: sorafenib, 400 mg, p.o., twice per day (BID), 
4 weeks (28 days) per cycle of therapy. Study treatment will 
continue until the subject develops an intolerable toxicity, 
withdrawing informed consent, disease progression confirmed 
by BIRC according to RECIST v1.1 (when the subject has 
disease progression assessed by the investigator according to 
RECIST v1.1, the investigator must submit the radiological 
data to BIRC immediately. If BIRC evaluates it as non-disease 
progression according to RECIST v1.1, the subject should 
continue to receive the study drug treatment and continue the 
tumor radiological evaluation; if BIRC confirms it as disease 
progression based on RECIST v1.1, the investigator needs to 
assess whether the subject still has clinical benefit. If the 
subject is considered to still have clinical benefit and meets the 
criteria for continuing treatment beyond the disease progresses 
[see Section 6.6 for details], the subject may continue to receive 
study treatment; if the subject is no longer considered to have 
clinical benefit, the treatment should be discontinued) or other 
discontinuation criteria specified in the protocol, whichever 
occurs first. Upon approval of Protocol v6.0, disease 
progression will not be evaluated by BIRC anymore, and will 
only be confirmed by the investigator per RECIST v1.1.  
Subjects will have safety visits on D1 and D15 of each cycle of 
therapy within the first 3 cycles for both arms. From Cycle 4 
onwards, subjects will have safety visits on D1 and D15 of each 
cycle in the experimental arm, and on D1 of each cycle in the 
control arm; refer to the SCHEDULE OF ACTIVITIES for 
details. Subjects will continue to have safety follow-up and 
survival follow-up after the study treatment discontinuation. 
Tumor radiological examination will be performed once every 
8 weeks to evaluate efficacy for the first 48 weeks from 
randomization, and once every 12 weeks thereafter. During the 
study period, radiological examination and evaluation can be 
added at any time if clinically indicated. Tumor radiological 
assessment will continue until the occurrence of disease 
progression confirmed by BIRC according to RECIST v1.1 
criteria or treatment discontinuation, whichever occurs later. 
Subjects who discontinue treatment for reasons other than 
BIRC-confirmed disease progression (according to RECIST 
v1.1) will also continue with regular follow-up by tumor 
radiological assessments after study treatment is discontinued. 


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Before BIRC confirms the disease progression according to the 
RECIST v1.1 criteria or the study treatment is discontinued, if 
the subject withdraws the informed consent, other anti-tumor 
treatment has begun (except for traditional Chinese medicine), 
or the subject dies, there is no need to continue the radiological 
evaluation. If the subject does not meet the above criteria for 
stopping radiological assessment, the efficacy evaluation of the 
three efficacy evaluation criteria (RECIST v1.1, mRECIST, 
imRECIST) needs to continue even if the disease progression 
under certain efficacy evaluation criteria occurs.  
The study extension phase will be initiated when sufficient 
follow up is completed and the study is ended (at least 2 years 
follow up of the last subject randomized). The purpose of the 
extension phase is to continue to provide access to study drugs 
for subjects who are still on study treatment and still derive 
clinical benefit at the time of study closure. Upon initiation of 
the extension phase, the Sponsor considers the safety and 
efficacy profile of the experimental treatment regimen within 
this study to have been sufficiently established and data 
analysis required for regulatory purposes have been completed. 
The study will establish a Data Monitoring Committee (DMC) 
to regularly monitor safety of the subjects on a periodic basis 
and evaluate efficacy and safety data at the time of PFS 
analysis and OS interim analysis. The DMC will make 
recommendations for continuing, revising or terminating the 
study based on observed safety or efficacy data. The 
composition, responsibilities, operation and management of 
the DMC will be detailed in a separate DMC charter. 
Study Drug 
SHR-1210 for Injection (Generic Name: Camrelizumab for 
Injection) 
(Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., 
Ltd.) 
Rivoceranib Mesylate Tablet 
(Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd.) 
Sorafenib Tosylate Tablet 
(Manufacturer: Bayer AG) 
Route of 
Administration 
Experimental Arm: 
Rivoceranib 250 mg will be administered orally within 
30 minutes after meals, once per day, continuously. 
One treatment cycle is 4 weeks (28 days). 
SHR-1210 200 mg will be infused intravenously. Each 
infusion will be administered over 30 minutes (no less 
than 20 minutes, no more than 60 minutes) once every 
two weeks. One treatment cycle is 4 weeks (28 days). 
Where possible, completion of the administration 


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should be done prior to ECG assessment. 
On days of rivoceranib PK blood collection (Day 1 of 
Cycle 1-4: C1D1, C2D1, C3D1 and C4D1), it is 
necessary to administer rivoceranib first at the study 
center, followed by SHR-1210 administration. For 
specific information, refer to the SCHEDULE OF 
ACTIVITIES and BLOOD SAMPLE COLLECTION 
TABLE. 
Control Arm: 
Sorafenib 400 mg is administered orally under fasted 
state (at least 1 hour prior to meal or 2 hours after meal), 
twice per day, continuously.  
One treatment cycle is 4 weeks (28 days). 
If a subject in the experimental arm (SHR-1210 in combination 
with rivoceranib) develops a treatment-related AE that leads to 
permanent discontinuation of rivoceranib and the investigator 
determines that the subject can benefit from SHR-1210 as 
monotherapy, the subject is allowed to continue to receive 
SHR-1210 monotherapy until the criteria for study treatment 
discontinuation as specified in the protocol has been met, and 
vice versa. In addition, during the study treatment period, if a 
subject in the experimental arm develops a treatment-related 
AE that leads to temporary discontinuation of SHR-1210 or 
rivoceranib, the subject may continue to receive monotherapy. 
The combination therapy can be resumed only after the 
treatment-related toxicity resolves. 
Subjects continue to receive study treatment until intolerable 
toxicity occurs, withdrawal of informed consent, disease 
progression confirmed by BIRC according to RECIST v1.1 and 
lack of clinical benefits as determined by investigator after 
comprehensive evaluation of radiological and laboratory 
examination data as well as the subject’s clinical condition 
(e.g., 
tumor 
symptomatic 
exacerbation) 
or 
other 
discontinuation criteria specified in the protocol, whichever 
comes first. Upon approval of protocol V6.0, disease 
progression will only need to be confirmed by investigator per 
RECIST v1.1. 
When a subject develops disease progression that conforms to 
the definition of RECIST v1.1 according to the investigator's 
assessment, and BIRC also confirms that disease progression 
(according to RECIST v1.1), subject may continue treatment 
with SHR-1210 monotherapy or in combination with 
rivoceranib (experimental arm) or sorafenib (control arm), if 
the subject still has clinical benefit and can tolerate study 
treatment as determined by investigator (see Section 6.6 for 
treatment criteria after disease progression). 


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Inclusion Criteria 
Subjects can be enrolled in this study only when they meet all 
the inclusion criteria:  
1. Provided informed consent and sign the informed 
consent form;  
2. Male or female, ≥ 18 years old;  
3. Histopathologically or cytologically confirmed HCC; 
4. Subjects must be able to provide fresh or archived 
tumor tissue (formalin-fixed, paraffin-embedded 
[FFPE] tissue block or at least 5 unstained FFPE slides) 
as well as corresponding pathological report. If less 
than 5 unstained slides are available or tumor tissue is 
not available (e.g., used up due to previous diagnostic 
tests), subjects may be permitted to enroll on a case-by-
case basis after discussion with the medical monitor; 
5. Barcelona Clinic Liver Cancer (BCLC) stage B or C 
(see APPENDIX 1 for BCLC classification), and not 
suitable for surgical or local therapy, or has progressed 
following surgical and/or local therapy;  
6. Local regional therapy (including but not limited to 
surgery, radiotherapy, hepatic artery embolization, 
TACE, hepatic arterial infusion, radiofrequency 
ablation, 
cryoablation 
or 
percutaneous 
ethanol 
injection) must have been completed at least 4 weeks 
(subjects received palliative radiotherapy at least 2 
weeks) prior to baseline radiological scanning, and any 
toxicity (except alopecia) induced by local regional 
therapy must have resolved to ≤ Grade 1 in accordance 
with National Cancer Institute – Common Terminology 
Criteria for Adverse Event version 4.03 (NCI-CTCAE 
v4.03);  
7. No previous systematic treatment for advanced HCC; 
8. Have at least one measurable lesion (in accordance 
with RECIST v1.1, major diameter ≥ 10 mm of the 
measurable lesion in spiral CT scan or short diameter 
of swollen lymph node ≥ 15 mm; the lesion with 
previous local therapy can be used as target lesion after 
the progression is confirmed in accordance with 
RECIST v1.1);  
9. Child-Pugh class (see APPENDIX 3 for Child-Pugh 
classification criteria): Grade A;  
10. ECOG-PS score (See APPENDIX 4 for ECOG-PS 
scoring criteria): 0-1; 
11. With a life expectancy of ≥ 12 weeks;  
12. Have the required screening laboratory values 
including the following parameters (within 7 days prior 
to the start of study treatment):  


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(1) Hematology: (except for hemoglobin, no blood 
transfusion or use of granulocyte colony-
stimulating factor [G-CSF] or use of drugs for 
correction within 14 days prior to screening);  
 
Absolute neutrophil count ≥ 1.5×109/L; 
 
Platelet count ≥ 75×109/L; 
 
Hemoglobin ≥ 90 g/L; 
(2) Blood biochemistry: (no infusion of albumin 
within 14 days):  
 
Albumin ≥ 29 g/L； 
 
Total bilirubin ≤1.5×upper limit of normal 
(ULN);  
 
Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and alkaline 
phosphatase (ALP)≤5×ULN;  
 
Creatinine (Cr) ≤1.5×ULN or Cr 
clearance >50 mL/min (Cockcroft-Gault 
formula as below) 
Male: Cr clearance =((140-age) ×weight)/ 
(72×blood Cr) 
Female: Cr clearance =((140-age) ×weight)/ 
(72×blood Cr) × 0.85 
Weight unit: kg; Blood Cr unit: mg/mL;  
(3) International normalized ratio (INR) ≤2.3 or 
prothrombin time (PT) ≤6s beyond normal range;  
(4) urine protein <2+ (subjects with urine protein ≥ 2+ 
may 
undergo 
24-hour 
(h) 
urine 
protein 
quantification and those with 24-h urine protein 
quantity of <1.0 g can be enrolled);  
13. If subjects have active hepatitis B (HBV) infection: 
HBV- deoxyribonucleic acid (DNA) must be < 500 
IU/mL(or must be < 2500 copy/mL if copy/mL is the 
only unit available in the study site) and are willing to 
receive antiviral therapy throughout the study 
(treatment in accordance with local standard of care, 
e.g., entecavir); subjects with positive hepatitis C 
(HCV) ribonucleic acid (RNA) must receive antiviral 
therapy in accordance with the local standard treatment 
guideline and have ≤ CTCAE Grade 1 elevated hepatic 
function;  
14. Women of childbearing potential(WOCBP): must 
agree to use a reliable and valid contraception methods 
(refer to Section 4.4.1) following the date of signed 
informed consent form until at least 120 days after the 
last dose of study drug. The blood human chorionic 
gonadotropin (HCG) test must be negative within 7 


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Version 6.0, 21 Sep 2022 
 
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14 
 
days prior to enrollment in the study; and the subject 
must not be in lactating period.  
If a female subject has menses, has not reached 
postmenopausal state (absence of menses for ≥ 
consecutive 12 months, with no other reason found 
except menopause) and has not received sterilization 
operation (e.g., hysterectomy, bilateral tubal ligation or 
bilateral ovariectomy), she would be considered to 
have childbearing potential.  
15. Male subjects, whose partner are women of 
childbearing potential, must agree to use reliable and 
valid contraception method (Section 4.4.1) following 
the date of signed informed consent form until at least 
120 days after last dose of study drug. Male subjects 
must also abstain from donation of sperm in the same 
period. Male subjects whose partners are pregnant 
must use a condom but other contraceptive method is 
not required. 
Exclusion Criteria Subjects who meet any one of the following criteria must be 
excluded from the study:  
1. Known hepatocholangiocarcinoma, sarcomatoid HCC, 
mixed cell carcinoma and lamellar cell carcinoma; 
other active malignant tumor except HCC within 5 
years or simultaneously. Cured localized tumor, for 
example, basal cell carcinoma of skin, squamous cell 
carcinoma of skin, superficial bladder cancer, 
carcinoma in situ of prostate, carcinoma in situs of 
cervix, breast cancer in situ may be enrolled;  
2. Planning to or previously received organ or allogenic 
bone marrow transplantation;  
3. Moderate-to-severe ascites with clinical symptoms, 
i.e., requiring therapeutic puncture or drainage, or 
Child-Pugh score >2, except the subjects with small 
amount of ascites in radiological examination but free 
from clinical symptoms; uncontrolled or moderate to 
severe pleural effusion, pericardial effusion.  
4. History of gastrointestinal bleeding within 6 months 
prior to the start of study treatment or clear tendency of 
gastrointestinal bleeding, for example, at risk of 
bleeding or severe esophagogastric varices , locally 
active peptic ulcer, persistent fecal occult blood (+) (the 
fecal occult blood test should be repeated if it is 
positive at baseline, and gastroduodenoscopy [EGD] 
would be needed if it is still positive in repeated test; 
the subject can not be enrolled if the EGD shows 
esophageal and fundal varices with hemorrhagic risk 
or other gastrointestinal disorder with risk of bleeding); 


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15 
 
5. Abdominal fistula, gastrointestinal perforation or 
intraperitoneal abscess within 6 months prior to the 
start of study treatment;  
6. Known genetic or acquired hemorrhage (e.g., 
coagulation dysfunction) or thrombotic tendency, for 
example, subject with hemophilia; current or recent 
(within 10 days prior to the start of study treatment) use 
of full-dose of oral or intravenous anticoagulant or 
thrombolytic drug for the purpose of treatment 
(preventive use of low-dose aspirin or low molecular 
weight heparin is allowed); 
7. Current or recent (within 10 days prior to the start of 
study treatment) use of aspirin (> 325 mg/day, 
maximum dose for antiplatelet) or dipyridamole, 
ticlopidine, clopidogrel and cilostazol;  
8. Thrombosis or thromboembolic event within 6 months 
prior to the start of study treatment, for example, 
cerebrovascular accident (including transient ischemic 
attack, cerebral hemorrhage, cerebral infarction), 
pulmonary embolism;  
9. Cardiac clinical symptom or disease that is not well 
controlled, for example, (1) > Grade II cardiac 
insufficiency in accordance with New York Heart 
Association (NYHA) criteria (see APPENDIX 5) or 
color 
Doppler 
echocardiography: 
LVEF 
(left 
ventricular ejection fraction) <50%; (2) unstable 
angina pectoris; (3) myocardial infarction within one 
year prior to the start of study treatment; (4) clinically 
significant supraventricular or ventricular arrhythmia 
requiring treatment or intervention; (5) QTc > 450 ms 
(males) or QTc > 470ms (females) (QTc interval is 
calculated by Fridericia formula; In case QTc value is 
abnormal, it can be evaluated for three times at an 
interval of 2 minutes and the average value will be 
used);  
10. Hypertension that can not be well controlled through 
antihypertensive drugs (systolic blood pressure ≥ 140 
mmHg or diastolic blood pressure ≥ 90 mmHg) (based 
on the average of BP readings acquired from ≥ 2 
measurements), 
allowing 
to 
reach 
the 
above 
parameters by the use of antihypertensive therapy; 
previous 
hypertensive 
crisis 
or 
hypertensive 
encephalopathy;  
11. Major vascular disease within 6 months prior to the 
start of study treatment (for example, aortic aneurysm 
requiring surgical repair or peripheral arterial 
thrombosis in recent days);  
12. Serious, unhealed or splitting wound and active ulcer 


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or untreated bone fracture;  
13. Major surgical therapy within 4 weeks prior to the start 
of study treatment (except diagnosis), or planned major 
surgery during the study;  
14. Inability to swallow tablets, malabsorption syndrome 
or any condition affecting gastrointestinal absorption;  
15. Intestinal obstruction and/or clinical signs or 
symptoms of gastrointestinal obstruction within 6 
months prior to the start of study treatment, including 
incomplete obstruction that is related with the original 
disease or needs routine parenteral hydration, 
parenteral nutrition or tube feeding;  
 
If the subject has signs/symptoms of incomplete 
obstruction/ 
obstructive 
syndrome/intestinal 
obstruction at the initial diagnosis receives clear 
(surgical) therapy to resolve symptoms, the 
subject may be enrolled;  
16. Evidence on intraperitoneal pneumatosis that can not 
be explained by puncture or recent surgery;  
17. Previous or current presence of metastasis to central 
nervous system;  
18. Metastatic disease involving main airway or blood 
vessels (e.g. Vena cava tumor invasion or complete 
occlusion of the major portal vein due to HCC, the 
major portal vein is defined as the part of portal vein 
between the union of the splenic and superior 
mesenteric veins and the first bifurcation into the left 
and right vein) or high-volume mediastinal tumor mass 
located in the center (distance from carina <30 mm);  
19. History of hepatic encephalopathy;  
20. Current interstitial pneumonia or interstitial lung 
disease, or history of interstitial pneumonia or 
interstitial lung disease which required hormonal 
therapy, or other pulmonary fibrosis that may interfere 
with the judgement and treatment of immune-related 
pulmonary toxicity; organizing pneumonia (e.g., 
obliterative bronchiolitis), pneumoconiosis, drug 
related pneumonitis, idiopathic pneumonia, subjects 
with evidence on active pneumonia or serious 
pulmonary function impairment on thoracic computed 
tomography (CT) in screening period (previous 
radiation pneumonitis in the radiation area will be 
allowed); active tuberculosis;  
21. Active autoimmune disease or history of autoimmune 
disease and may relapse (including but not limited to 
autoimmune hepatitis, interstitial pneumonia, uveitis, 
enteritis, 
hypophysitis, 
vasculitis, 
nephritis, 


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hyperthyroidism, hypothyroidism [with the exception 
that it can be controlled by hormone replacement 
therapy]). Subjects with skin disease that do not require 
systemic 
treatment 
are 
eligible, 
for 
example, 
leukoderma, 
psoriasis, 
alopecia; 
subjects 
with 
controlled type 1 diabetes by insulin are eligible; 
subjects with asthma that has been completely resolved 
in childhood and don’t need any treatment are eligible, 
but subjects with asthma that require a bronchodilator 
as medical intervention are not eligible;  
22. Use of immunosuppressive medication within 14 days 
prior to the start of study treatment, or systemic 
corticosteroid therapy to achieve the objective of 
immunosuppression 
(Prednisone 
at 
the 
dose 
of >10mg/day or equivalent);  
23. Use of strong CYP3A4/CYP2C19 inducers, including 
rifampicin (and its analogues) and St. John’s Wort, or 
strong CYP3A4/CYP2C19 inhibitors within 14 days 
prior to the start of study treatment;  
24. Known history of hypersensitivity to the active 
substance or to any other components of each 
investigational medicinal product as SHR-1210, 
rivoceranib, sorafenib or other monoclonal antibody or 
targeted anti-angiogenic drug;  
25. Severe infection within 4 weeks prior to the start of 
study treatment, including but not limited to 
hospitalization 
for 
infection, 
bacteremia 
or 
complications 
of 
severe 
pneumonia; 
oral 
or 
intravenous therapeutic antibiotics within 2 weeks 
prior to the start of study treatment (subjects who are 
treated with antibiotics for prevention, e.g., preventive 
urinary tract infection or exacerbation of chronic 
obstructive pulmonary disease are eligible for 
participation in the study);  
26. Congenital or acquired immunodeficiency (e.g., HIV 
infection); 
27. Hepatitis B and hepatitis C co-infection;  
28. Previous treatment with other PD-1 antibody or other 
immunotherapy against PD-1/PD-L1, or previous use 
of rivoceranib or sorafenib;  
29. Attenuated live vaccine therapy administered within 28 
days prior to the start of study treatment, or are 
expected to receive such vaccines during SHR-1210 
treatment or within 60 days after the last dose of SHR-
1210;  
30. Treatment of other investigational product(s) within 28 
days or 5 half-lives (whichever is longer) prior to the 


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start of study treatment;  
31. Other factors that may affect the study results or lead 
to early study termination as judged by investigators, 
such as alcoholism, drug abuse, other serious diseases 
(including mental disorders) requiring concomitant 
therapy, 
with 
serious 
laboratory 
examination 
abnormality, with family or social factors, that may 
affect subject’s safety.  
PK And 
Immunogenicity 
Sampling  
Immunogenicity and PK measurement will be assessed in the 
experimental arm only. 
Pre-dose sampling: blood samples will be collected once within 
0.5 hours prior to rivoceranib administration on Day 1 from 
Cycle 1 to Cycle 4 (C1D1, C2D1, C3D1, C4D1); and collected 
once within 0.5 hours prior to rivoceranib administration on 
Day 1 of every 3 cycles afterwards. A blood sample will be 
collected 30 days (±7 days) after the last administration of 
SHR-1210. When SHR-1210 is interrupted for longer than 30 
days and finally is confirmed to be unable to resume, subjects 
are required to return for a site visit as early as possible for a 
blood sample to be collected. If the subject has started other 
anti-tumor therapy, it’s not necessary to collect the 
immunogenicity blood sample at 30 days (±7 days) after the 
last administration of SHR-1210. If SHR-1210 and/or 
rivoceranib 
is 
temporarily 
interrupted, 
pre-dose 
immunogenicity and PK sample will be collected on schedule. 
If only rivoceranib is temporarily interrupted at the sampling 
time above, and the blood sample should be collected within 
0.5 hours before the administration of SHR-1210. The above 
samples will be used to measure the blood concentration and 
immunogenicity of SHR-1210, and the plasma concentration of 
rivoceranib in the C2D1-C4D1 samples. The exact time of the 
previous administration of rivoceranib (as provided by the 
subject) will be collected for C2D1, C3D1 and C4D1. 
ECG blood sampling: ECG examination will be performed 2.5 
hours (±1 hour) after the end of the rivoceranib administration, 
and blood will be collected within 15 minutes after the ECG 
examination on the first day from C1 to C4. If rivoceranib is 
interrupted, blood samples within 15 minutes of ECG will not 
be collected. The samples above will be detected for the 
concentrations of rivoceranib only. 
The actual sampling time, the actual administration time of 
SHR-1210 and rivoceranib will be recorded on the day of 
sampling. Pre-dose sampling and ECG blood sampling will not 
be performed in the extension phase (refer to BLOOD 
SAMPLE COLLECTION TABLE). 
Criteria for Study 
Discontinuation from study treatment does not represent 


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Treatment 
Discontinuation 
subject withdrawal from the study. Subjects who discontinue 
the study treatment should complete the remaining study visits 
as required in the protocol. Subjects should discontinue study 
treatment when any of the following conditions occurs:  
 Subject requests discontinuation of study treatment;  
 Efficacy evaluation meets disease progression criteria 
confirmed by BIRC (according to RECIST v1.1) 
(disease progression will be confirmed by the 
investigator per RECIST v1.1 upon approval of 
Protocol v6.0) unless investigator judges that the 
subject will continue to benefit from the treatment and 
the criteria for treatment beyond progression is met 
(see Section 6.6 of the protocol); 
 Pregnancy in female subject occurs during the study; 
 Unacceptable toxicity despite dose modification, or 
occurrence of adverse event, abnormal laboratory 
examination, or concomitant diseases, then it is no 
longer in the best interests of the subjects to continue 
study treatment according to the judgment of the 
investigator; 
 Overall deterioration of health status, inability to 
continue participation in the trial;  
 Significant protocol deviation or violations confirmed 
by sponsor, e.g., ineligibility of subjects after 
enrollment;  
 Termination of study by the sponsor; 
 Other reasons for inability to continue study treatment 
as considered by investigators.  
Criteria for 
Withdrawal from 
the Study 
The reasons for withdrawal from the study may include:  
 Withdrawal of the informed consent upon participation 
in the study, and refusal of further follow-up;  
 Other conditions that necessitate the withdrawal from 
the study, as considered by investigators, for example, 
loss of the ability to express his/her wishes freely due 
to imprisonment or segregation;  
 Lost to follow-up;  
 Termination of study by the sponsor. 
Criteria for Study 
Termination 
The criteria for termination of this study include but not 
limited to the following:  
 Discovery of unexpected, significant or unacceptable 
risk;  
 The efficacy data support early termination of the 
study; 
 Low compliance with study requirements. 


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Safety Evaluation 
The severity of adverse events will be judged in accordance 
with CTCAE v4.03. Adverse event (AE) record forms should 
be filled out during the trial, including the occurrence time, 
severity, relationship with the study drug, duration, measures 
taken and outcome of the AE.  
Efficacy 
Evaluation 
To evaluate OS (co-primary efficacy endpoint), subjects after 
study treatment discontinued will have their survival status 
collected through site visits or telephone follow-up on a regular 
basis until death. Subject who died during the trial, their actual 
time of death will be recorded. 
PFS: defined as the time from the date of randomization to the 
first occurrence of radiological progression or death, whichever 
comes first. Evaluations of PFS (another primary efficacy 
endpoint) as well as TTP, ORR, DCR and DoR (secondary or 
exploratory efficacy endpoints) will be performed based on 
RECIST v1.1, mRECIST and imRECIST: From randomization 
to 48 weeks, the radiological evaluation will be performed once 
every 8 weeks; once every 12 weeks thereafter; and can be 
performed in a real-time manner if new lesion is suspected; the 
tumor response must be confirmed in 4 weeks or at next 
scheduled timepoint for the subjects who are initially evaluated 
as PR/CR. When suspected clinical progression occurs, 
physical examination and confirmation by radiological 
evaluation should be performed as soon as possible, rather than 
waiting until the next scheduled imaging examination. 
When progression of disease is confirmed by investigator 
according to RECIST v1.1, the investigator must submit the 
radiological data to BIRC immediately for evaluation of 
disease progression. If BIRC confirms non disease progression 
according to RECIST v1.1, the subject should continue with 
study treatment and tumor radiological evaluation; if BIRC 
confirms as disease progression according to RECIST V1.1, the 
investigator should evaluate whether the subject still has 
clinical benefit, if the subject is considered to have clinical 
benefit from study treatment and meet criteria for continuation 
of treatment after the disease progresses (see Section 6.6 for 
details), the subject may continue study treatment and efficacy 
assessment as originally scheduled. 
Tumor radiological assessment should continue until disease 
progression confirmed by BIRC according to RECIST v1.1 or 
treatment discontinuation, whichever occurs later. Subjects 
who discontinue study treatment for reasons other than BIRC-
confirmed disease progression (according to RECIST v1.1) 
must continue with their regular follow-up tumor radiological 
assessments. Prior to BIRC confirmed disease progression 
according to the RECIST v1.1 or discontinuation of study 
treatment, if the subject has withdrawn informed consent, 


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Protocol Number: SHR-1210-III-310 
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HENGRUI CONFIDENTIAL 
 
21 
 
started other anti-tumor treatment (except for traditional 
Chinese medicine), or subject died, no further imaging 
assessment is required. If subject does not meet the above 
criteria for stopping radiological assessment, tumor efficacy 
evaluation of the three efficacy evaluation criteria (RECIST 
v1.1, mRECIST, imRECIST) needs to continue even if the 
disease progression under certain efficacy evaluation criteria 
occurs.  
Upon approval of Protocol v6.0, disease progression will be 
confirmed by the investigator per RECIST v1.1, and tumor 
assessments evaluated by BIRC per mRECIST will not be 
performed afterwards. If the investigator confirms non-disease 
progression, the subject should continue on study treatment and 
tumor radiological evaluation as required; if the investigator 
confirms as disease progression, the subject may continue to 
receive study treatment after disease progression at the 
investigator’s discretion (see Section 6.6). 
Sample Size 
Determination 
Assuming a 1:1 randomization between sorafenib and SHR-
1210+rivoceranib, and a median PFS time of 3.6 months for 
subjects in the sorafenib group and a median PFS of 6 months 
for a subject in the combination group, 332 PFS events will be 
sufficient to detect a hazard ratio (HR) of 0.60 with 98% power 
based on Log-rank test at significance level of 0.005 one-sided. 
Similarly, assuming a median survival time of 10.5 months for 
subjects in the sorafenib group and a median time of 14.6 
months for subjects in combination group, 359 OS events will 
be sufficient to detect a hazard ratio (HR) of 0.72 with 85% 
power based on Log-rank test at significance level of 0.020 
one-sided. Assuming an accrual period of 18 months, total 
duration of 36 months and 19 months for the OS and PFS, 
respectively, and probability of subject loss at approximately 
10% per 12 months and per 6 months for the OS and PFS 
respectively, a sample size of 510 subjects will be enrolled for 
the study. Power and sample calculations were performed using 
EAST® 6.4.1. software package. 
Data Analysis / 
Statistical 
Methods 
Efficacy Analyses 
The two primary endpoints for the study are OS and PFS 
(assessed by BIRC based on RECIST v1.1). For the PFS, there 
is one planned analysis, which is expected to occur when 332 
PFS events are observed at ~19 months after first subject 
enrolled. The OS will be evaluated in the following time points: 
when PFS is analyzed; when 251 OS events are observed (70% 
at ~ 23 months after first subject enrolled) and when 359 OS 
events are observed at 36 months after first subject enrolled. 
The hypothesis testing of OS and PFS will be evaluated by 
comparing SHR-1210 plus rivoceranib to sorafenib on events 


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in the ITT using a stratified Log-rank test (based on 
randomization stratification factors). The hazard ratio 
(HR=SHR-1210 plus rivoceranib / sorafenib) and the 
corresponding 95% confidence interval (CI) will be estimated 
in a stratified Cox proportional hazard model with treatment 
group and randomization stratification factors included in the 
model. The survival curve for each treatment group will be 
estimated using the Kaplan-Meier (KM) product-limit method. 
A 95% CI for median survival time will be estimated by 
Brookmeyer-Crowley method.  
Objective response rate (ORR) assessed by BIRC according to 
RECIST v1.1 will be analyzed as a key secondary endpoint and 
will be analyzed when 70% OS events are observed. If both 
PFS and OS primary endpoints are positive, comparison 
between treatment groups in ORR by BIRC according to 
RECIST v1.1 will be performed using stratified Cochran-
Mantel-Haenszel (CMH) test. Difference in proportions for 
ORR and its 95% CI using normal approximation will be 
provided. Overall response rates and their corresponding 95% 
exact CIs will be calculated by Clopper-Pearson method for 
each treatment group.  
The other time-to-event endpoints will be estimated using the 
Kaplan-Meier (KM) product-limit method, unless specified. A 
95% CI for median survival time will be estimated by 
Brookmeyer-Crowley method, if necessary.  
For other binary variables, stratified CMH test will be used and 
two-sided 95% CI for treatment difference will be calculated 
using normal approximation. 
Safety Analyses 
Safety data including AEs and laboratory results will be 
summarized descriptively using summary statistics. 
Other Analyses: 
Exploratory endpoints including average scores and its change 
from baseline obtained from EORTC QLQ-C30 and EORTC 
QLQ-HCC18 will be summarized descriptively using summary 
statistics. 
Biomarkers (e.g. the expression level of PD-L1 and proportion 
of strong expression of PD-L1 in tumor tissue) will be 
summarized using descriptive statistics, and an ad hoc analysis 
will be performed if required.  
Population pharmacokinetics, drug exposure-QTc analysis and 
drug exposure-response relation will be analyzed and reported 
separately. 
End of Study 
For this study, end of study is defined as the date when the last 
subject randomized has been followed for at least 2 years.  
Subject who are still on treatment at the time of study closure 


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Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
 
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will join study extension phase to continue study treatment 
(Section 6.7).  


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24 
SCHEDULE OF ACTIVITIES 
Item/evaluation time 
(window period) 
Screening period 
Treatment period [4] 
One treatment cycle is 28 days 
End-of-
Treatment 
Visit [5] 
Follow-up period 
Screening 
Period [1] 
(Day -28) 
Screening 
Period [2] 
(Day -14) 
Screening 
Period [3] 
(Day -7) 
Cycle 1 
Cycle 2, 3 
Cycle 4 and 
onwards 
Safety 
follow-up 
[6] 
Once every 
30 days 
(±7 days) 
Survival 
follow-up [7] 
Once every 
30 days 
(±7 days) 
 
 
 
 
D1 
D15 
D1 
D15 
D1 
D15 
 
 
 
 
 
 
 
 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
 
 
 
Baseline data 
 
Signature of informed 
consent form [8] 
√ 
 
 
 
 
 
 
 
 
 
 
 
Determination of 
inclusion / exclusion 
criteria 
√ 
√ 
√ 
 
 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
 
 
 
Tumor History [9] 
√ 
 
 
 
 
 
 
 
 
 
 
 
Other past medical 
history [10] 
√ 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
examination, clinical 
examination/evaluatio
n 
 


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Item/evaluation time 
(window period) 
Screening period 
Treatment period [4] 
One treatment cycle is 28 days 
End-of-
Treatment 
Visit [5] 
Follow-up period 
Screening 
Period [1] 
(Day -28) 
Screening 
Period [2] 
(Day -14) 
Screening 
Period [3] 
(Day -7) 
Cycle 1 
Cycle 2, 3 
Cycle 4 and 
onwards 
Safety 
follow-up 
[6] 
Once every 
30 days 
(±7 days) 
Survival 
follow-up [7] 
Once every 
30 days 
(±7 days) 
 
 
 
 
D1 
D15 
D1 
D15 
D1 
D15 
 
 
 
 
 
 
 
 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
 
 
 
Child-Pugh class [11] 
 
 
√ 
 
 
√ 
 
√ 
 
√ 
√ 
 
ECOG-PS score [12] 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
Physical examination 
[13] 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Vital signs [14] 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Virology [15] 
 
√ 
 
 
 
√ 
 
√ 
 
√ 
 
 
Hematology [16] 
 
 
√ 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
 
Urinalysis [17] 
 
 
√ 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
 
Fecal occult blood [18] 
 
√ 
 
 
 
√ 
 
√ 
 
√ 
 
 
Blood biochemistry 
[19] 
 
 
√ 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
 
Blood electrolytes [20] 
 
 
√ 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
 
Archive tumor tissue 
sample (or fresh 
biopsy sample) [21] 
√ 
 
 
 
 
 
 
 
 
 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
26 
Item/evaluation time 
(window period) 
Screening period 
Treatment period [4] 
One treatment cycle is 28 days 
End-of-
Treatment 
Visit [5] 
Follow-up period 
Screening 
Period [1] 
(Day -28) 
Screening 
Period [2] 
(Day -14) 
Screening 
Period [3] 
(Day -7) 
Cycle 1 
Cycle 2, 3 
Cycle 4 and 
onwards 
Safety 
follow-up 
[6] 
Once every 
30 days 
(±7 days) 
Survival 
follow-up [7] 
Once every 
30 days 
(±7 days) 
 
 
 
 
D1 
D15 
D1 
D15 
D1 
D15 
 
 
 
 
 
 
 
 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
 
 
 
Coagulation 
parameters [22] 
 
 
√ 
 
 
√ 
 
√ 
 
√ 
√ 
 
AFP [23] 
 
√ 
 
 
 
√ 
 
√ 
 
√ 
√ 
 
Thyroid function [24] 
 
√ 
 
 
 
√ 
 
√ 
 
√ 
√ 
 
12-lead ECG [25] 
 
√ 
 
√ 
√ 
√ 
 
√ 
 
√ 
√ 
 
Echocardiography [26] 
 
√ 
 
If required by clinical judgement 
 
Blood HCG test [27] 
 
 
√ 
If required by clinical judgement 
√ 
√ 
 
Concomitant 
medications / therapy 
[28] 
√ 
√ 
√ 
√ 
 
Collection of AE [29] 
√ 
√ 
√ 
√ 
 
Radiological 
assessment, PK and 
immunogenicity 
 
Tumor imaging 
evaluation [30] 
√ 
 
 
√ 
√ 
√ 
√ 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
27 
Item/evaluation time 
(window period) 
Screening period 
Treatment period [4] 
One treatment cycle is 28 days 
End-of-
Treatment 
Visit [5] 
Follow-up period 
Screening 
Period [1] 
(Day -28) 
Screening 
Period [2] 
(Day -14) 
Screening 
Period [3] 
(Day -7) 
Cycle 1 
Cycle 2, 3 
Cycle 4 and 
onwards 
Safety 
follow-up 
[6] 
Once every 
30 days 
(±7 days) 
Survival 
follow-up [7] 
Once every 
30 days 
(±7 days) 
 
 
 
 
D1 
D15 
D1 
D15 
D1 
D15 
 
 
 
 
 
 
 
 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
 
 
 
Pre-dose sampling [31] 
 
 
 
√ 
 
 
√ 
 
 
√ 
 
 
√ 
 
ECG blood 
sampling [32] 
 
 
 
 
√ 
 
√ 
 
√* 
 
 
 
 
Study treatment 
 
Randomization [33] 
 
 
 
√ 
 
 
 
 
 
 
 
 
Intravenous infusion 
of SHR-1210 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Oral administration of 
rivoceranib 
 
 
 
√ continuous oral administration 
 
 
 
Oral administration of 
sorafenib 
 
 
 
√ continuous oral administration 
 
 
 
Other 
 
Distribution, 
verification and return 
of subject’s diary [34] 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
28 
Item/evaluation time 
(window period) 
Screening period 
Treatment period [4] 
One treatment cycle is 28 days 
End-of-
Treatment 
Visit [5] 
Follow-up period 
Screening 
Period [1] 
(Day -28) 
Screening 
Period [2] 
(Day -14) 
Screening 
Period [3] 
(Day -7) 
Cycle 1 
Cycle 2, 3 
Cycle 4 and 
onwards 
Safety 
follow-up 
[6] 
Once every 
30 days 
(±7 days) 
Survival 
follow-up [7] 
Once every 
30 days 
(±7 days) 
 
 
 
 
D1 
D15 
D1 
D15 
D1 
D15 
 
 
 
 
 
 
 
 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
(±3 
days) 
 
 
 
Subject’s self-
evaluation results [35] 
 
 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
Survival follow-up  
 
 
 
 
 
 
 
 
 
 
√ 
√ 
Subsequent antitumor 
therapy 
 
 
 
 
 
 
 
 
 
 
√ 
√ 


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Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
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Note: Except the test items and time points listed in the table, the investigator may add necessary examinations at any time. The test results will be filled in the section of 
“Examinations at Unscheduled Visits” in the CRF.  
[1] 
Screening period (Day -28): baseline data will be collected after signature of informed consent form and no longer than 28 days before start of study drug; if routine 
radiological evaluation of tumor has been performed prior to signature of the informed consent, it is unnecessary to repeat these scans during screening period in cases 
where these enhanced CTs or MRIs are completed within 28 days prior to the start of study drug (bone scan within 42 days prior to the start of study drug is acceptable). 
All baseline evaluations will be based on the results collected closest to the start of study drug.  
[2] 
Screening period (Day -14): physical examination, vital signs, ECOG-PS score and laboratory examinations (including fecal occult blood, thyroid function, 
alpha- fetoprotein, and virology), 12-lead ECG and echocardiography (including LVEF) to be collected within 14 days prior to the first dose, following the signature of 
informed consent form. All baseline evaluations will be based on the results collected closest to the start of study drug. 
[3] 
Screening period (Day -7): following the signature of informed consent form, data on hematology, urinalysis, blood chemistry, blood electrolytes, coagulation parameters, 
blood HCG (for women of childbearing potential) and Child-Pugh class must be collected within 7 days prior to the first dose. All baseline evaluations will be based on 
the results collected closest to the start of study drug. Subjects with screening failure can be re-screened. They must sign the informed consent form again, re-register and 
obtain a new subject number at the re-screening. Subjects can only be re-screened once.  
[4] 
Treatment period: data on hematology, urinalysis, blood chemistry and blood electrolytes will be evaluated within 72h prior to administration of study drug during the 
scheduled visit; ECOG-PS score, physical examination and vital signs will be evaluated within 24h prior to administration of study drug during the scheduled visit (they 
are not needed on C1D1 in cases where they are completed within 24h prior to the first dose during the screening period). In the event of a dose delay, the required 
examinations at each corresponding visit during study treatment should be scheduled as planned or more frequently if clinically indicated (Immunogenicity, concentrations 
of SHR-1210 and rivoceranib, and patient reported outcomes should be collected at respective treatment cycles as specified in Footnotes [31] [32] [35]).  
[5] 
End-of-treatment visit: Only after permanent discontinuation of both drugs (SHR-1210 and rivoceranib), the end-of-treatment visit shall start. End-of-treatment visit 
includes ECOG performance, C-P score, vital sign, physical examination, 12-lead ECG, hematology, urinalysis, blood biochemistry, blood electrolytes, coagulation, 
thyroid function, fecal occult blood test, virology, APF, HCG, subject’s self-evaluation and tumor imaging evaluation. If tumor imaging evaluation completed within 4 
weeks prior to end-of-treatment visit, or the other examinations of end-of-treatment visit completed within 7 days, then these study procedures would not be necessary to 
be repeated. For subjects who enter the extension phase after the end of study, all of the subject’s data occurring prior to extension phase need to be captured into CRFs 
and EOT visit needs to be performed even the subjects continue on study treatment (detailed instruction for data entering, refer to CRF completion guideline), the EOS 
page in CRFs for extension subjects should be collected as well before entering the extension phase. If planned schedule visit occurred within 7 days before the time of 
extension phase initiation or the relevant examinations for end of treatment visit completed within 7 days, these study procedures would not be necessary to be repeated 
on EOT. 
[6] 
Safety follow-up: Subject who completed end-of-treatment visit (after permanent discontinuation of both drugs) will have safety follow-up after last dose. It will end 90 
days after the last dose of SHR-1210 (non-serious AE unrelated to study drug will only be collected for 30 days after the last dose) or 30 days after the last dose of 
rivoceranib in experimental arm (whichever comes later); and 30 days after the last dose of study drug in sorafenib (control) arm. The first safety follow-up should start 
30 days (±7 days) after the last dose of study drug and must be performed at the study center, regardless of initiation of new antitumor therapy. A telephone visit will be 
performed 60 days (±7 days) and 90 days (±7 days) after the last dose of study drug in the experimental arm for survival status, subsequent antitumor therapy, concomitant 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
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medications/therapy and AEs/SAEs collection (see Section 8.3 for details). When developing a safety follow-up plan, ensure that a visit is scheduled at this point in the 
safety follow-up period. If the date of the previously completed end-of-treatment visit has exceeded the safety follow-up period, there is no need to schedule a safety 
follow-up. For the subjects in experimental arm, if the date of completed end-of-treatment visit has exceeded the first safety follow-up (30 days after the last dose), but 
the safety follow-up period has not been reached, the subject does not need to go to the site for safety follow-up, and 1-2 telephone visits can be scheduled during the 
safety follow-up period. At this time, ensure that the interval between visits should not exceed 44 days, and a telephone visit should be conducted at this time point of the 
safety follow-up period. 
[7] 
Survival follow-up: the subject will enter survival follow-up period after the end of safety follow-up period. the telephone follow-up will be performed 30 days (±7 days) 
after last safety follow-up for the first survival follow-up, after that, the frequency was once every 30 days (±7 days), collecting of data on survival and subsequent 
antitumor treatment.  
[8] 
Signature of informed consent form: the informed consent on enrollment into this study needs to be completed during screening period. Prior to acquisition of the written 
informed consent form, no screening procedures specified in the study can be performed; there are special provisions on the baseline radiological examination of tumor, 
please refer to the note in radiological evaluation for tumors in this flow chart for details. Subjects with screening failure prior to treatment are allowed to have another 
opportunity for screening in this study and must repeat the informed consent and register again for a new subject number at re-screening.  
[9] 
Tumor history: including previous history of HCC, history of present illness, initial diagnosis, pathological diagnosis, data on radiological examination, course of treatment 
(e.g., surgery, interventional therapy, local ablation, and radiotherapy).  
[10] Other medical history: including history of drug allergy, history of diagnosis and treatment for other significant concomitant disease, history of tumors except 
hepatocellular carcinoma, and history of alcohol consumption etc.  
[11] Child-Pugh class: will be performed within 7 days prior to the first dose during the screening period, on Day 1 of each cycle in Cycles ≥ 2 during the treatment period, at 
end-of-treatment visit and safety follow-up. 
[12] ECOG-PS score: will be performed within 14 days prior to the first dose during the screening period, prior to administration on Day 1 of the subsequent cycles of therapy, 
at end-of-treatment visit and safety follow-up.  
[13] Physical examination: including height (only for initial examination), body weight, head and face, skin system, lymph nodes, eyes (sclera, pupil), otolaryngology, mouth, 
respiratory system, cardiovascular system, abdomen, genitourinary system, musculoskeletal system, neurological and mental status. A full physical examination will be 
performed in the screening period, and only body weight and important sites (including skin, respiratory system, cardiovascular system, abdomen and mental state) will 
be examined during the study. Physical examination will be performed within 14 days prior to first dose during the treatment period (experimental arm: prior to 
administration on Day 1 and 15 of each cycle of therapy; control arm: prior to administration on Day 1 and 15 of each cycle in Cycle 1-3, prior to administration only on 
Day 1 from Cycle 4), at end-of-treatment visit and safety follow-up. Note: except for the physical examination during the screening period and end-of-treatment visit, it 
is not necessary to record complete results of physical examination in the eCRF during the trial, and only weight and abnormal results need to be recorded. In addition, 
physical examination of reactive capillary endothelial proliferation needs to be performed in the experimental arm, occurrence sites, such as the skin, oral mucosa, nasal 
mucosa, etc., should be recorded in the eCRF in detail. Reactive capillary endothelial proliferation will be followed up until it is resolved, other reasonable time points 
(e.g., loss of follow-up, death), or reached to a stable state without any expectation of recovery.  


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
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[14] Vital signs (5 minutes after resting state/sitting still): including temperature (whenever possible, the same method of measurement should be used throughout), blood 
pressure (which needs to be measured and recorded at least twice to get the mean value as the blood pressure value), pulse rate and respiratory frequency. Vital signs will 
be performed within 14 days prior to first dose, during the treatment period (experimental arm: prior to administration on Day 1 and 15 of each cycle of therapy; control 
arm: prior to administration on Day 1 and 15 of each cycle in Cycle 1-3, prior to administration only on Day 1 from Cycle 4), at end-of-treatment visit and safety follow-
up.  
[15] Virology: HIV-Ab (screening period only), HBV and HCV test should be included. Screening period: all subjects will be required for HBV serology test by five hepatitis 
B markers (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb), HBV-DNA will be quantified if the HBsAg or HBcAb test is positive. All subjects will be required for HCV-Ab 
test, and HCV-RNA will be quantified if the HCV-Ab test is positive. Treatment period and end-of-treatment visit: Five hepatitis B markers (HBsAg, HBsAb, HBcAb, 
HBeAg, HBeAb) and HBV-DNA needs to be detected every two cycles of therapy (starting C3D1, C5D1, C7D1, etc.) for subjects with positive HBsAg or HBcAb at 
screening; HCV-RNA needs to be detected every two cycles of therapy (starting C3D1, C5D1, C7D1, etc.) for subjects with positive HCV-Ab at screening .   
[16] Hematology: including complete blood count and category (white blood cell, red blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, platelet 
count. CBC will be performed within 7 days prior to first dose, during the treatment period (prior to study drug administration on Day 1 of each cycle in Cycles 2-3 and 
on Day 15 of each cycle in Cycles 1-3, prior to administration only on Day 1 of each cycle in Cycles ≥ 4), at end-of-treatment visit and safety follow-up.  
[17] Urinalysis: white blood cell, red blood cell, urine protein should be included. If urine protein level ≥ 2＋ is detected, 24h urine protein quantification must be added. 
Urinalysis will be performed within 7 days prior to first dose, during the treatment period (prior to study drug administration on Day 1 of each cycle in Cycles 2-3 and on 
Day 15 of each cycle in Cycles 1-3, prior to administration only on Day 1 of each cycle in Cycles ≥ 4), at end-of-treatment visit and safety follow-up.  
[18] Fecal occult blood: If fecal occult blood test is positive during the trial, the result must be evaluated by investigators, and gastroscopy will be performed if necessary. 
Fecal occult blood will be performed within 14 days prior to first dose, on Day 1 of each cycle in Cycles ≥ 2 and at the end of study.  
[19] Blood biochemistry: hepatic function (ALT, AST, total bilirubin, ALP, γ-glutamyl transferase [GGT], direct bilirubin), renal function (blood urea nitrogen [BUN] or urea, 
creatinine), albumin, amylase (lipase must be detected additionally if amylase is abnormal and clinically significant), blood glucose, LDH should be included. Blood 
chemistry will be performed within 7 days prior to first dose, during the treatment period (prior to study drug administration on Day 1 of each cycle in Cycles 2-3 and on 
Day 15 of each cycle in Cycles 1-3, prior to administration only on Day 1 of each cycle in Cycles ≥ 4), at end-of-treatment visit and safety follow-up.  
[20] Blood electrolytes: potassium, sodium, calcium, phosphorus, magnesium, chlorine should be included. Blood electrolytes will be detected within 7 days prior to first dose, 
during the treatment period (prior to study drug administration on Day 1 of each cycle in Cycles 2-3 and on Day 15 of each cycle in Cycles 1-3, prior to administration 
only on Day 1 of each cycle in Cycles ≥ 4), at end-of-treatment visit and safety follow-up.  
[21] If archived tumor tissue samples were collected at different time points, the sample collected just prior to participation on this study should be provided. The specific 
guidance on collection and shipment of tumor tissue is provided in the Laboratory Manual.  
[22] Coagulation parameters: INR and/or PT (if INR can not be collected, PT will be used as judgment basis). Coagulation parameters will be performed within 7 days prior 
to first dose, on Day 1 of each cycle in Cycles ≥ 2 during the treatment period, at end-of-treatment visit and safety follow-up.  
[23] AFP will be evaluated within 14 days prior to the first dose, on Day 1 of each cycle in Cycles ≥ 2 during the treatment period, at end-of-treatment visit and safety follow-


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up.  
[24] Thyroid function: TSH, FT3 or TT3, FT4 should be included. Thyroid function will be performed within 14 days prior to the first dose, once every two cycles during the 
treatment period, at end-of-treatment visit and safety follow-up.  
[25] 12-lead ECG (following resting state/sitting still for at least 5 minutes): heart rate and QTc interval (calculated by Fridericia formula: QTcF = QT/(RR^0.33), RR is the 
normalized heart rate and is calculated as 60 divided by heart rate). If QTc interval is abnormal, QTc needs to be measured for three consecutive times at an interval of 
approximately two minutes apart;  
QTc needs to be re-tested if: 
  - at baseline: male > 450 ms, female > 470 ms, retest 2 times and take the mean value;  
  - after enrollment: same as baseline, or longer than the baseline average ≥ 30 ms.  
 Experimental arm: The 12-lead ECG will be performed within 14 days prior to first dose in screening period, 2.5 (±1) hours post dose at each of the following days: 
C1D1, C1D15, D1 of Cycles 2 and afterwards, and at end-of-treatment visit and safety follow-up. When the ECG collection day is coincident with the PK collection day, 
time matched ECG and PK samples (within 15 minutes apart, ECG collection first) will be collected. Control arm:14 days prior to first dose in screening period, C1D1, 
C1D15, D1 of Cycles 2 and afterwards, and at end-of-treatment visit and safety follow-up. 
[26] Echocardiography must include LVEF and can be scheduled at the investigator’s discretion during the study.  
[27] Blood HCG test: only for women of childbearing potential (WOCBP, any woman who has experienced menarche, has not undergone a hysterectomy, ligation of bilateral 
fallopian tubes or bilateral oophorectomy, and is not post-menopausal). (See definition of menopausal in Section 4.4.1) Blood HCG will be performed within 7 days prior 
to the first dose, at end-of-treatment visit and safety follow-up.  
[28] Collection of concomitant medication/therapy: collect concomitant medication/therapy information (drugs excluding solvents) from 28 days prior to the signing of the 
informed consent form to the end of safety follow-up: record drug names, drug dosage, route of administration, frequency of administration, purpose of administration, 
and date of start and end. After the safety follow-up period, only record medication/therapy that is used to manage the study drugs related AE/SAE. Please refer to 
Section 5.3 (Concomitant therapy) of the protocol for details. 
[29] Collection of AE: in accordance with NCI-CTCAE v4.03, AEs are observed and recorded from the signature of informed consent form, until 90 days after the last dose 
of SHR-1210, or 30 days after the last dose of anti-angiogenesis targeted therapy, whichever comes later. For specific AE collection periods, please refer to Section 8.3, 
Table of AE/SAE Collection Period. An AE/SAE will be followed up until it is resolved, returns to the baseline level or ≤ Grade 1, or reaches a stable state, or until other 
reasonable time points (e.g., loss of follow-up, death). Every effort should be made to ensure that the subject achieves the final outcome and definite causality assessment 
is obtained. 
[30] Tumor radiological evaluation: all the evaluable tumor lesions should be evaluated and recorded based on RECIST v1.1 (evaluated by investigator and BIRC), mRECIST 
(evaluated by BIRC only) and imRECIST (evaluated by investigator only). The baseline evaluation includes the enhanced CT/MRI scan of chest, abdomen, pelvis and 
sites of lesions, brain enhanced MRI or enhanced CT scan (to exclude intracranial metastasis). Thoracic plain CT scan + abdominal, pelvic and brain MRI can be 
performed in case of allergy to the contrast agent for enhanced CT; bone scan will be performed only when clinically indicated. Tumor radiological evaluation during 
treatment period will be performed once every 8 weeks (56±7 days) within the first 48 weeks from randomization and once every 12 weeks (84±7 days) thereafter and 
can be additionally performed when clinically indicated. When there is no clear disease progression, tumor evaluation should be continued regardless of discontinuation 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
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of study treatment, unless death, withdrawal of informed consent, start of subsequent anticancer therapy or termination of study by the sponsor, whichever comes first; 
the evaluation includes the enhanced CT/MRI scan of chest, abdomen, pelvis and sites of lesions. Thoracic plain CT scan + abdominal and pelvic MRI can be performed 
in case of allergy to the contrast agent for enhanced CT; cranial CT/MRI and bone scan will be performed only when clinically indicated. The same radiological technique 
should be used in each subject throughout the study. Investigators must review the results prior to administration in the next cycle. After first documentation of response 
(CR or PR), confirmation of tumor response should occur at 4 weeks after the first response or at the next scheduled assessment time point. When a subject develops a 
disease progression as assessed by the investigator according to RECIST v1.1, the investigator is required to submit radiological data immediately to BIRC. If BIRC 
confirms non-disease progression according to RECIST v1.1, the subject should continue to receive study drug therapy and continue to perform tumor radiological 
assessment; if BIRC confirms disease progression according to RECIST v1.1, then the investigator needs to assess whether the subject still has clinical benefit, and if the 
subject is still considered to have clinical benefit and meets the criteria for continued treatment after progression of the disease (see Section 6.6 for details), the subject 
may continue to receive study medication and continue the efficacy assessment at the scheduled frequency. Tumor radiological assessment will continue until the 
occurrence of disease progression confirmed by BIRC according to RECIST v1.1 criteria or study treatment discontinuation, whichever occurs later. Before BIRC 
confirms the disease progression according to the RECIST v1.1 criteria or the treatment is discontinued, if the subject withdraws the informed consent, other anti-tumor 
treatment has begun (except for traditional Chinese medicine), or the subject dies, there is no need to continue the radiological evaluation. If the subject does not meet 
the above criteria for stop radiological assessment, the efficacy evaluation of the three efficacy evaluation criteria (RECIST v1.1, mRECIST, imRECIST) needs to 
continue even if the disease progression under certain efficacy evaluation criteria occurs. If there has not been any disease progression confirmed by a radiological 
examination when the subject is about to withdraw from the study, it is recommended that a radiological examination be performed in time before the withdrawal (if the 
time from the last radiological examination to the withdrawal is ≤ 4 weeks, additional radiological examination will not be required at the time of withdrawal). Detailed 
requirements for image collection will be described in image acquisition guideline. Disease progression will rely on the investigator’s confirmation per RECIST v1.1 
upon approval of protocol v6.0, and radiological data will not be submitted to BIRC anymore, tumor assessment evaluated by BIRC per mRECIST will not be performed 
afterwards. If the investigator confirms non-disease progression, the subject should continue on study treatment and tumor radiological evaluation as required; if the 
investigator confirms as disease progression, the subject may continue to receive study treatment after disease progression at the investigator’s discretion (see Section 
6.6). 
[31] Pre-dose sampling: only the blood sample in the experimental arm will be collected (including SHR-1210 combined with rivoceranib, SHR-1210 monotherapy or 
rivoceranib monotherapy) on Day 1 of Cycle 1-4 (C1D1, C2D1, C3D1 and C4D1) and once on Day 1 of every three cycles thereafter (The time point for sample collection 
will be within 0.5 hours prior to administration of rivoceranib); on 30 days (±7 days) after the last dose of SHR-1210. When SHR-1210 is interrupted for longer than 30 
days and is confirmed to be unable to resume, the subject is required to come for a site visit and collect blood sample. If the subject has started other anti-tumor therapy, 
it’s not necessary to collect the immunogenicity blood sample at 30 days (±7 days) after the last administration of SHR-1210. If SHR-1210 and/or rivoceranib is 
temporarily interrupted, pre-dose immunogenicity and PK sample will be collected on schedule. If only rivoceranib is interrupted, the time of sampling is 0.5 hours prior 
to SHR-1210 administration. On C1D1 approximately 6 mL venous blood will be collected for detection of the serum concentration and immunogenicity of SHR1210; 
On C2D1, C3D1 and C4D1 approximately 8mL venous blood will be collected, 6 mL will be used for detection of the serum concentration and immunogenicity of SHR-
1210, and 2 mL will be used for detection of plasma concentration of rivoceranib. The exact time of the previous administration of rivoceranib concentration will be 
collected (provided by the subject). Approximately 6 mL venous blood will be collected for detection of the serum concentration and immunogenicity of SHR1210 at the 
later time points (e.g., C7D1, C10D1 etc.). Pre-dose sampling will not be performed in the extension phase. [See BLOOD SAMPLE COLLECTION TABLE for details] 
[32] ECG blood sampling: ECG examination will be performed 2.5 hours (±1 hour) after the end of the rivoceranib administration, and blood will be collected within 15 
minutes after the ECG examination on the first day from Cycle 1 to Cycle 4. If the rivoceranib is temporarily interrupted, a blood sample within 15 minutes after ECG 


Study Drug Number: SHR-1210 
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Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
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will not be collected. 2 mL venous blood will be collected at each time point for the concentration of rivoceranib. ECG blood sampling will not be performed in the 
extension phase. [See BLOOD SAMPLE COLLECTION TABLE for details]. 
[33] Randomization: subjects will be randomized into either the experimental arm or control arm after their data are reviewed and determined to be in accordance with the 
inclusion/exclusion criteria, and the first dose should be given within 24 hours following randomization (on Day 1 of Cycle 1).  
[34] Distribution, verification and return of subject’s medication diary: in the experimental arm at D1 and D15 of each cycle, in the control arm, at D1 and D15 of Cycles 1-
3, and D1 for every cycle thereafter. On C1D1, only distribution is needed. At the end-of-treatment visit, distribution of diary is not needed but verification and return are 
required.  
[35] Subject’s self-evaluation results: all subjects will complete EORTC QLQ-C30 (version 3.0), EORTC QLQ-HCC18 and EQ-5D-5L questionnaires prior to administration 
of study drug and any study procedure at the clinical center, starting from C1D1 and on D1 of each cycle onward. In addition, all subjects are required to complete the 
questionnaires at the end-of-treatment visit and during the first safety follow-up visit. Before the subject leaves the site, the study staff should review all the questionnaires 
for completeness. 
BLOOD SAMPLE COLLECTION TABLE 
 
Visit period 
Day 
Pre-dose sampling 
ECG blood sampling 
 
 
 
Blood sample for detection of 
immunogenicity and serum 
concentration of SHR-1210（6 
mL）[6] 
Blood sample for detection of 
concentration of rivoceranib (2 
mL) [1] 
Blood sample for detection of 
concentration of rivoceranib
（2 mL） 
 
Before rivoceranib administration [2] 
Within 15 minutes after ECG 
and 2.5 hours (±1 hour) after 
rivoceranib administration [3] 
Treatment period
（28 days for 1 
cycle） 
Cycle 1 
C1D1 
√ 
 
√ 
Cycle 2-4 
D1（±3 
days） 
√ 
√  
√ 
Every 3 cycles after Cycle 4 
（e.g. Cycle7, Cycle 10 etc.）[4] 
D1（±3 
days） 
√ 
 
 


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30 days after last 
dose of SHR-1210 
（±7 days） [5] 
 
 
√ 
 
 
[1] To collect the dose time and sampling time of rivoceranib on the sampling day. It is necessary to collect the exact time of previous administration of rivoceranib, i.e. the 
day before the blood collection (the subject is required to provide it). If rivoceranib is temporarily interrupted on the day before the blood collection, it is necessary to collect 
the exact time of the dose of rivoceranib closest from this blood collection (the subject is required to provide it). 
[2] If SHR-1210 and/or rivoceranib is temporarily interrupted, pre-dose immunogenicity and PK sample will be collected on schedule. If only rivoceranib is temporarily 
interrupted, the time point for collection is within 0.5 hours before the administration of SHR-1210. 
[3] If rivoceranib is temporarily interrupted, blood samples within 15 minutes of ECG will not be collected. To collect the dose time and sampling time of rivoceranib on the 
sampling day. 
[4] Collection on Day 1 of every 3 cycles (within 0.5 hours before the administration of rivoceranib). If rivoceranib is temporarily interrupted, the time point for collection is 
within 0.5 hours before the administration of SHR-1210. Blood sampling will not be performed in the extension phase. 
[5] Collected once 30 days (±7 days) after the last SHR-1210 administration; If SHR-1210 is temporarily interrupted, and it is subsequently confirmed that the subject is unable 
to continue treatment, and it is more than 30 days since the last dose, the subject is required to return for site visit as soon as possible and collect blood samples at the same 
time. If the subject has started other anti-tumor therapy, it’s not necessary to collect the immunogenicity blood sample at 30 days (±7 days) after the last administration of SHR-
1210. Blood sampling will not be performed in the extension phase. 
[6] To collect the dose time and sampling time of SHR-1210 on the sampling day. 
 


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ABBREVIATIONS 
Abbreviations 
Definition 
5 on 2 off 
5 days on 2 days off 
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
ADA 
antidrug antibody 
AFP 
alpha-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ARB 
Angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
BCLC 
Barcelona Clinic Liver Cancer 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BIRC 
Blinded Independent Review Committee 
BOR 
best overall response 
BUN 
blood urea nitrogen 
CCR 
Clinical Cancer Research 
CI 
Confidence interval 
CK 
creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
Cmax 
maximum concentration 
Cr 
creatinine 
CT 
computed tomography 
CTLA4 
cytotoxic T lymphocyte antigen 4 
CYP 
Cytochrome P450 
D 
Day 
DCR 
disease control rate 
DMC 
Data monitoring committee 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
ECOG-PS 
Eastern Cooperative Oncology Group- Performance Status 
EDC 
electronic data capture 
EORTC 
European Organization for the Research and Treatment of 
Cancer 
EQ-5D-5L 
five-level of EuroQol-5D version 
ESMO 
European Society for Medical Oncology 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
GHS 
general health status 


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Abbreviations 
Definition 
h 
hour 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDL-C 
high-density lipoproteincholesterol 
HIV 
human immunodeficiency virus 
HR 
Hazard ratio 
ICC 
intrahepatic cholangiocarcinoma 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
imRECIST 
immune-modified RECIST 
INN 
international nonproprietary name (for pharmaceutical 
substances) 
INR 
international normalized ratio 
ITT 
Intent-to-treat 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LEU 
leukocytes in urine 
LVEF 
left ventricular ejection fraction 
IU 
international unit 
LDH 
lactate dehydrogenase 
LSLV 
last subject last visit 
LYMPH 
lymphocyte 
MATE 
multidrug and toxin extrusion protein  
MFD 
maximum feasible dose 
mRECIST 
modified RECIST 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI-CTCAE v4.03 
National Cancer Institute - Common Terminology Criteria 
for Adverse Events Version 4.03 
NMPA 
National Medical Products Administration 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed death-l 
PFS 
progression-free survival 
P-gp 
P-glycoprotein  
PPI 
proton pump inhibitor 
PT 
prothrombin time 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
QLQ-HCC 
Quality of Life Questionnaire-Supplement Module for 
HCC 


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Abbreviations 
Definition 
RCEP 
Reactive Capillary Endothelial Proliferation 
RCCEP 
Reactive Cutaneous Capillary Endothelial Proliferation 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors 
RO 
receptor occupancy 
SAE 
serious adverse event 
SIE 
AE of special interest 
SRO 
subject reported outcome 
SS 
safety set 
TBIL 
total bilirubin 
TEAE 
Treatment Emergent Adverse Events 
TTD 
time to deterioration 
TTP 
time to progression 
ULN 
Upper limit of normal 
VAS 
visual analogue scale 
WOCBP 
women of childbearing potential 
 
 


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1. 
INTRODUCTION: BACKGROUND AND SCIENTIFIC 
RATIONALE 
1.1. 
Study Background 
1.1.1. 
Epidemiology and Current Treatment Status of Hepatocellular 
Carcinoma 
Primary Carcinoma of the Liver is referred to as liver carcinoma. Primary Carcinomas 
of the Liver mainly include three different pathological types of Hepatocellular 
Carcinoma (HCC), Intrahepatic Cholangiocarcinoma (ICC), and the mixed HCC-ICC, 
in which HCC accounts for 90% [1 ]. According to data from GLOBOCAN 2012, liver 
carcinoma is the sixth most common cancer, with about 782,500 new cases of liver 
carcinoma and 745,500 deaths worldwide annually, ranking it second in the cause of 
death amongst male tumors worldwide [2]. 
The majority of HCC cases (> 80%) occur in Eastern Asia and sub-Saharan Africa, with 
incidence rates of > 20 per 100,000 individuals, followed by Southern European 
countries, such as Spain, Italy and Greece, with an incidence of 10 to 20 cases per 
100,000 populations. HCC incidence is relatively lower in North America, South 
America, Northern Europe and Oceania (< 5 / 100,000) [3]. 
China is a high-risk area for liver carcinoma, with morbidity and death accounting for 
about 50% of the world [2]. In 2015, there were 466,100 new subjects with liver 
carcinoma, the fourth most common tumor, and 422,100 deaths in China. Liver 
carcinoma ranks the third as cause of death in China, and it ranks third in males (12.72%) 
and seventh in females (5.68%) [4]. 
The main risk factors for HCC are infection with HBV and hepatitis C virus (HCV), 
vinyl chloride, alcohol abuse, and nonalcoholic fatty liver; in addition, the rare causes 
include hereditary hemochromatosis, α-antitrypsin deficiency and autoimmune 
hepatitis [5]. HBV and HCV infection account for 80%~90% of total HCC cases 
worldwide. Chronic HBV infection is a major risk factor for HCC in most Asian regions 
except Japan[3],while chronic HCV infection is a major risk factor for HCC in Japan[6]. 
In China, up to 80% of HCC is hepatitis B virus (HBV)-related HCC [7]. A considerable 
proportion of subjects are already in advanced stage at diagnosis or cannot undergo 
surgery or local treatment due to underlying liver diseases such as combined cirrhosis. 
The different treatments of HCC are selected according to disease staging, which is 
mainly based on BCLC staging system, Child-Pugh liver function classification system 
and disease degree. About 30% of HCC cases are diagnosed at an early stage (that is, 
BCLC stage 0 or A), and the main treatments include surgical resection, ablation 
technique and liver transplantation. But the 5-year recurrence rate is still as high as 70% 
[8]. 
The recommended treatment for mid-stage HCC (BCLC stage B) is hepatic artery 
interventional therapy, that is, transcatheter arterial chemoembolization (TACE), but 
the application scope is limited due to concomitant disease and liver function damage, 
and the subject will eventually experience progression after treatment and is no longer 
suitable for further TACE treatment. 


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The treatment options available for advanced HCC (also known as BCLC stage C) are 
very limited, and sorafenib, an oral multi-target inhibitor, is the first targeted drug 
approved globally for HCC first-line systemic treatment. Recently, the FDA approved 
the second oral multi-kinase inhibitor lenvatinib for the first-line treatment of advanced 
HCC, which has not been widely used. In addition to the above two types of targeted 
therapy, the first-line standard of care of HCC also includes oxaliplatin-based 
chemotherapy, which is also used as the first-line treatment in some regions. 
1.1.2. 
Advances in the Treatment of Advanced Hepatocellular Carcinoma 
For advanced hepatocellular carcinoma, the available treatment options are very limited. 
Sorafenib is an oral multi-target inhibitor (VEGFR-1, -2, -3, PDGFR, c-KIT, etc.) that 
directly blocks the formation of neovascularization and inhibits tumor growth. It is the 
first FDA-approved targeted drug for HCC first-line systemic treatment. This approval 
was based on the positive results from the SHARP and ORIENTAL trials. The efficacy 
and safety of sorafenib and placebo were compared in the treatment of advanced HCC. 
The results showed that the survival and safety of subjects in the sorafenib group were 
significantly improved compared with those in the placebo group. 
The SHARP study was a randomized, phase 3 study in western populations, in which 
sorafenib increased progression free survival (PFS) (median: 5.5 months and 2.8 
months, respectively) by 73% and overall survival (OS) (median: 10.7 months and 7.9 
months, respectively) by 44% compared with placebo. ORIENTAL, another 
randomized phase 3 study conducted in Asian populations similar to the SHARP study 
in design, had the same results, increasing overall survival (OS) by 2.3 months (median 
OS: 6.5 months and 4.2 months, respectively)[9, 10]. 
In addition, the results of the phase 3 non-inferiority study on the efficacy and safety of 
lenvatinib (developed by Eisai) versus sorafenib in the first-line treatment of subjects 
with unresectable HCC (REFLECT trial [11]) showed, lenvatinib achieved the primary 
endpoint, demonstrating that the median OS with lenvatinib was non-inferior to that 
with sorafenib. Subjects treated with lenvatinib experienced a median OS of 13.6 
months compared to 12.3 months with sorafenib (Hazard Ratio [HR]: 0.92); In terms 
of secondary endpoints, lenvatinib seemed significantly superior to sorafenib in median 
PFS (7.4 months vs 3.7 months), median TTP (8.9 months vs 3.7 months) and ORR 
(24% vs 9%). In terms of safety, the incidence of adverse events (AE) was similar in 
the two groups. At the 2017 CSCO Annual Meeting, Professor Qin Shukui published 
the data analysis results of the Asian subgroup of the trial. A total of 288 subjects were 
enrolled. The lenvatinib and the sorafenib groups were compared in the median PFS 
(9.2 months vs 3.6 months), median TTP (11 months vs 3.7 months), and ORR (21.5% 
vs 8.3%), showing that lenvatinib was more effective for subgroups of subjects in 
China's mainland, Taiwan and Hong Kong and will become a new treatment option for 
subjects with unresectable advanced HCC worldwide. Based on REFLECT study, 
lenvatinib was approved by FDA as the second first-line treatment for advanced HCC 
following sorafenib. 
In addition to the two approved targeted therapies, Oxaliplatin-based chemotherapy is 
also the standard first-line treatment in some areas. The EACH study was a prospective, 
randomized, controlled phase 3 international clinical study of Oxaliplatin-containing 
FOLFOX4 chemotherapy and Doxorubicin for palliative chemotherapy in Asian 


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subjects with advanced hepatocellular carcinoma who are not suitable for surgery or 
local treatment. The study had the largest number of enrolled subjects (371 cases) in the 
field of systemic chemotherapy for liver carcinoma, with Chinese subjects accounting 
for 75%. The study confirmed for the first time that compared with doxorubicin, the 
regimen with Oxaliplatin-containing FOLFOX4 prolonged the median OS of subjects 
with advanced liver cancer from 4.97 months to 6.40 months, reduced the risk of death 
by 20%, improved the median PFS (2.93 months vs. 1.77 months), reduced the risk of 
recurrence and metastasis, and significantly increased the ORR to 8.2%, meanwhile the 
adverse reactions could be tolerated [12]. 
Regorafenib, another oral multi-kinase inhibitor, was approved by the FDA in 2017 for 
the second-line treatment of subjects with HCC who received previous treatment with 
sorafenib, based on an international multicenter, placebo-controlled phase 3 clinical 
study (RESORCE study [13]). The data showed a significant improvement in OS in the 
Regorafenib group compared with placebo (median: 10.6 months vs. 7.8 months, 
HR=0.62, 95% CI 0.50-0.79, P<0.001), and the risk of death was reduced by 37%. The 
most common adverse reactions in the Regorafenib and placebo groups were pain (55% 
vs. 44%), hand-foot skin reaction/palmar-plantar erythrodysesthesia (51% vs. 7%), and 
weakness/fatigue (42% vs. 33%), diarrhea (41% vs. 15%), hypertension (31% vs. 6%), 
infection (31% vs. 18%), anorexia (31% vs. 15%). It is currently approved only for 
second-line treatment after the progression with sorafenib treatment; the registered 
clinical trials do not include subjects with post-chemotherapy progression/sorafenib 
intolerance, and there is no data on the efficacy of second-line and later-line therapies. 
At the same time, the incidence of treatment-related adverse events for Regorafenib is 
relatively high, limiting its clinical use. 
1.1.3. 
Development of PD-1/PD-L1 Monoclonal Antibody in Advanced Tumors 
Programmed cell death protein 1 (PD-1) is the first immune checkpoint molecule to be 
discovered, expressed in stimulated B cells, T cells, and myeloid cells. It is initially 
described as "a brake on the immune response" for its role in inhibiting the immune 
response by binding to the ligand PD-L1. PD-1/PD-L1 immunological checkpoint 
inhibitor is currently the most attractive tumor immunotherapy drug, which can regulate 
the anti-tumor activity of T lymphocytes by blocking PD-1/PD-L1 signaling pathway, 
and improve the subject's own immune response to tumor, thus achieving the purpose 
of killing tumor cells. 
Since 2014, the U.S. FDA has approved anti-PD-1 monoclonal antibodies, Bristol-
Myers Squibb's nivolumab and Merck's pembrolizumab, based on outstanding efficacy, 
for the treatment of subjects with advanced melanoma, non-small cell lung cancer, renal 
cell carcinoma, head and neck cancer, Hodgkin's lymphoma, urothelial carcinoma, 
MSI-H or dMMR malignant tumor, gastric cancer and gastroesophageal junction 
adenocarcinoma, and cervical cancer as well as subjects with hepatocellular carcinoma 
(HCC) who have received sorafenib, including advanced subjects who have failed 
standard treatment without effective treatment and are advanced to first- and second-
line treatments. In addition, due to the long-lasting efficacy and mild adverse reactions, 
hundreds of clinical trials on anti-PD-1 monoclonal antibodies (including monotherapy 
and combined therapy) have been conducted internationally for advanced solid tumor 
and haematological malignancy. The preliminary results of trials have shown greater 
efficacy and long-term survival compared with existing therapies. At the same time, in 


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terms of safety, drug-related toxicity was controllable, and the toxicity of Grade 3 and 
above was lower than that of traditional chemotherapy drugs [14 ]. 
1.1.3.1. PD-1/PD-L1 Monotherapy and Hepatocellular Carcinoma 
In advanced HCC, PD-1/PD-L1 antibody also showed significant initial efficacy: the 
Checkmate-040 study was a single-arm, open-label, dose escalation and expansion, 
phase I/II clinical study evaluating nivolumab monotherapy for advanced 
hepatocellular carcinoma: a total of 262 subjects (48 for dose escalation and 214 for 
expansion) were enrolled to evaluate the efficacy and safety of nivolumab. The results 
of this study indicate that the initial efficacy of nivolumab monotherapy for advanced 
hepatocellular carcinoma was significant. For the subjects with advanced HCC (N=154) 
who have been treated with sorafenib, the objective response rate (ORR) of nivolumab 
was 14.3%, and 91% of subjects had a duration of response (DoR) of 6 months or more. 
55% of subjects had a DoR of 12 months or more [15]. Based on this study, in September 
2017, the FDA approved nivolumab for subjects with advanced hepatocellular 
carcinoma (HCC) who had previously received sorafenib, marking the official entry 
into the era of immunotherapy for HCC. 
In addition, the KEYNOTE 224 study also confirmed the significant efficacy of PD-1 
monoclonal antibody in HCC. This study was a one-arm, open-label, phase II clinical 
trial of pembrolizumab monotherapy for subjects with advanced HCC who had failed 
or were intolerant to sorafenib alone. A total of 104 subjects with advanced HCC were 
enrolled in the study. The results showed that the ORR of pembrolizumab was 17%, the 
DCR was 62%, the median PFS was 4.9 months, and the median OS was 12.9 months 
[16]. Based on this study, in November 2018, the FDA approved pembrolizumab 
indicated for the treatment of subjects with advanced HCC who have previously failed 
sorafenib treatment. Because of the prominent efficacy of PD - 1 antibodies in liver 
carcinoma, the domestic and foreign companies have carried out a number of 
randomized, controlled phase 3 studies of PD-1 antibody monotherapy for advanced 
hepatocellular carcinoma. 
Despite the unprecedented success of PD-1/PD-L1 antibodies, it should not be 
overlooked that nearly 50% of solid tumor subjects do not benefit from this therapy. 
Taking advanced hepatocellular carcinoma accompanied with HBV infection as an 
example (about 90% of subjects with hepatocellular carcinoma in China are 
accompanied by HBV infection), the ORR of nivolumab was only 14%, and the DCR 
was only 55%. Nearly half of the subjects developed disease progression after 8 weeks 
of treatment. How to optimize the efficacy of anti-PD-1 antibody in advanced HCC on 
the basis of monotherapy effectiveness has become an urgent problem to be solved. 
1.1.3.2. PD-1/PD-L1 Combined with Anti-angiogenic Targeted Drugs 
At present, there are two methods for improving the efficacy of PD-1/PD-L1 
immunotherapy. Firstly, molecular markers that predict efficacy have been explored. In 
this direction, the therapeutic effect of PD-1/PD-L1 is improved by detecting and 
enriching subjects with molecular markers such as the expression level of PD-L1 in 
tumor tissue, the level of tumor mutational burden (TMB), high microsatellite 
instability (MSI-H) and dMMR. Secondly, a suitable combination regimen for 
immunological combination therapy are being sought. At present, a large number of 


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clinical studies have been carried out on the combination of PD-1/PD-L1 inhibitors with 
other immunological checkpoint inhibitors, traditional chemotherapeutic drugs or 
targeted anti-tumor drugs. 
Among them, PD-1/PD-L1 inhibitors combined with anti-angiogenic targeted drugs 
have a significant synergistic effect on efficacy. Currently, the FDA has granted 
breakthrough therapy designation for the multiple PD-1/PD-L1 inhibitors combined 
with anti-angiogenic targeted drugs. In a phase Ib clinical study of pembrolizumab 
combined with Axitinib for the treatment of advanced renal cell carcinoma, a total of 
52 subjects with advanced renal cell carcinoma who had not received systemic 
treatment were recruited in the study. The optimal dose of the combination was taken 
as the primary endpoint, and the efficacy endpoints such as ORR, DoR, and PFS were 
also assessed. The observation results of tolerance showed that the combination of 
Axitinib standard dose (5 mg, BID) and pembrolizumab, 2 mg/kg Q3W was well 
tolerated. The efficacy results showed that the anti-tumor effect of combined therapy 
was far superior to that of Axitinib or anti-PD-1 monotherapy, and ORR reached 73%, 
among which 8% achieved complete response. More than 90% of subjects showed 
tumor shrinkage and mPFS was over 20 months, far exceeding Axitinib monotherapy 
for control of disease progression (mPFS = 10-15 months). While there are still no data 
on pembrolizumab monotherapy for renal cell carcinoma, the synergistic effect of 
Axitinib and pembrolizumab in the treatment of renal cell carcinoma is superior to that 
of nivolumab (ORR = 13%) and atezolizumab (untreated: ORR = 25%, mPFS = 6 
months; treated: ORR = 15%, mPFS = 6 months) monotherapy[17]. In addition, based 
on excellent efficacy data, pembrolizumab combined with lenvatinib in the treatment 
of advanced renal cell carcinoma and advanced endometrial cancer, as well as PD-L1 
monoclonal antibody Avelumab combined with Axitinib in the treatment of advanced 
renal cell carcinoma has been granted breakthrough therapy designation by the FDA. 
In addition to renal cell carcinoma, combinations of anti-PD-1/PD-L1 inhibitors and 
VEGFR inhibitors have shown good efficacy in many solid tumors such as non-small 
cell lung cancer, hepatocellular carcinoma, and endometrioid carcinoma. A number of 
phase 3 studies are ongoing. 
In the combination therapy of advanced hepatocellular carcinoma, anti-angiogenic 
targeted drugs have also achieved breakthroughs in combination with PD-1/PD-L1 
antibodies. Several studies have confirmed that PD-1/PD-L1 antibodies and anti-
angiogenic targeted drugs, including small molecule VEGFR inhibitors and 
VEGF/VEGFR antibodies, are safe and well tolerated, and can achieve synergistic 
effects. 
In 2019, the updated efficacy of atezolizumab in combination with bevacizumab in the 
treatment of advanced hepatocellular carcinoma was reported in ESMO. This study was 
performed with atezolizumab in combination with bevacizumab in subjects with 
advanced hepatocellular carcinoma who had not received systemic therapy. Of the 104 
evaluable cases, a total of 37 cases of response were observed, with an confirmed ORR 
of 36%, DCR was 71%, mPFS was 7.3 months (95%CI: 5.4, 9.9), mOS was 17.1months 
(95%CI:13.8, NE) [18]. A randomized, controlled phase 3 clinical study of atezolizumab 
in combination with bevacizumab versus sorafenib in the treatment of unresectable 
locally advanced or metastatic hepatocellular carcinoma had been initiated since 2018 
(IMbrave150, NCT03434379), of which primary endpoints were OS and BIRC 


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evaluated PFS per RECIST v1.1, and the positive result was reported during the ESMO-
Asia 2019. A total of 501 advanced HCC subjects were randomized at 2:1 to receive 
atezolizumab combined with bevacizumab (336 subjects) or sorafenib (165 subjects). 
The mOS in the experimental arm has not reached, the mOS in the control arm was 13.2 
months, HR=0.58. The mPFS was 6.8 months (95%CI: 5.7, 8.3) and 4.3 months 
(95%CI: 4.0, 5.6) in experimental arm and control arm respectively [19]. The Chinese 
subgroup data was released in the following EASL 2020, a total of 194 Chinese subjects 
(137 of them were from the study of IMbrave 150, and 57 of them were from the 
extended enrollment in China；experimental arm 133 subjects, control arm 61 subjects) 
were enrolled in this study. The mOS in the experimental arm has not reached, the 
control arm mOS was 11.4 months, HR=0.44. The mPFS was 5.7 months (95%CI: 4.2, 
8.3) and 3.2 months (95%CI: 2.6, 4.8) in experimental arm and control arm respectively, 
HR=0.60 [20].  
In another phase Ib study of pembrolizumab combined with lenvatinib for unresectable 
hepatocellular carcinoma which was reported during ESMO 2019, all 67 subjects with 
hepatocellular carcinoma who were enrolled in efficacy expansion stage of the study 
had never received sorafenib treatment. Based on IRC assessment according to RECIST 
v1.1, the ORR and DCR was 32.8% (95% CI: 21.8, 45.4) and 85.1% (95% CI: 74.3, 
92.6), mPFS was 9.5 months (95%CI: 5.6, 11.8) and mOS was 20.4 months (95%CI: 
11.0, NE) [21]. Based on above phase Ib data, a phase III, randomized, double-blind 
study of pembrolizumab combined with lenvatinib versus lenvatinib as the first-line 
treatment for advanced HCC is ongoing. 
The preliminary results of an exploratory clinical study of SHR-1210 combined with 
the VEGFR inhibitor rivoceranib in hepatocellular carcinoma and gastric cancer were 
also published in 2018. For the dose group of SHR-1210 200 mg, Q2W combined with 
rivoceranib 125 mg, 250 mg or 500 mg, QD. Total 18 subjects with HCC enrolled, 16 
were evaluable (all HBV-positive, 15 of which failed after sorafenib), 8 of which were 
evaluated as disease remission, the objective response rate (ORR) was 50% (95%CI: 
24.7, 75.4), DCR was 93.8% (95% CI: 69.8, 99.8), median time to response was 3.4 
months (range, 1.4, 9.7), mPFS was 5.8 months (95% CI: 2.6, NR), and the initial effect 
was significant[22]. 
It can be seen that sorafenib is still a widely recognized first-line treatment for advanced 
hepatocellular carcinoma after 10 years on the market. However, the overall efficacy of 
sorafenib for hepatocellular carcinoma is relatively poor. A number of studies have 
confirmed that the ORR of sorafenib in the treatment of advanced liver carcinoma is 
<10%, with mOS <10 months [ 9, 10, 11]. At present, the first-line systemic treatment of 
Chinese subjects with advanced HCC is mainly based on sorafenib and Oxaliplatin-
containing systemic chemotherapy, but the ORR is low and the survival benefit is 
limited [10, 12]. Another first-line treatment of lenvatinib has not been widely used yet. 
Therefore, there is an urgent need to develop a new and effective treatment regimen for 
advanced HCC. 
Multiple studies of immunological checkpoint inhibitors, such as PD-1/PD-L1 
monoclonal antibody, have shown good efficacy in the treatment of HCC. Compared 
with other systemic therapies, they have the features of high ORR, long response time 
and prolonged survival [15-16]. 


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Therefore, this study is a registration study of PD-1 monoclonal antibody SHR-1210 
combined with rivoceranib in the treatment of advanced primary hepatocellular 
carcinoma and hopes to provide guidance and experience for the new combination 
therapy of immunotherapy combined with targeted therapy in the future, so as to 
improve the anti-tumor effect of monotherapy, minimize toxic side effects, and 
ultimately bring better survival benefits to the majority of subjects. 
1.2. 
Scientific Rationale 
1.2.1. 
Preclinical Studies with SHR-1210 
1.2.1.1. Drug Name and Physicochemical Properties 
[Generic name]: Camrelizumab for Injection 
[English name]: Camrelizumab 
[Drug number]: SHR-1210 
[Molecular weight]: about 146.3 kDa 
1.2.1.2. Pharmacological Class and Mechanism of Action 
Programmed death-1 (PD-1) is a protein receptor expressed on the T cell surface that 
was discovered in 1992 [23] and involved in the process of apoptosis. PD-1 belongs to 
the CD28 family, possessing 23% amino acid homology with cytotoxic T lymphocyte 
antigen 4 (CTLA-4), but its expression is mainly on activated T cells, B cells and 
myeloid cells, which is different from that of CTLA-4. PD-1 has two ligands, PD-L1 
and PD-L2, respectively. PD-L1 is mainly expressed on T cells, B cells, macrophages 
and dendritic cells, and can be up-regulated on activated cells [24]. The expression of 
PD-L2 is relatively limited, mainly on antigen-presenting cells, such as activated 
macrophages and dendritic cells. The humanized anti-PD-1 monoclonal antibody 
specifically binds to PD-1 and blocks the interaction of PD-1 with its ligand, allowing 
T cells to recover immune response against the tumor cells. 
1.2.1.3. Pharmacodynamic Studies 
1) Affinity of antibody 
The affinity of SHR-1210 for human, mouse, and cynomolgus and rhesus monkey PD-
1 was determined using Surface Plasmon Resonance (SPR) technology. The Kd values 
for human and cynomolgus and rhesus monkey PD-1 are shown in Table 1. The binding 
affinity of SHR-1210 to mouse PD-1 was also measured; however, no binding was 
detected at the highest concentration tested (400 nM).  


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Table 1 
Binding Affinity of Antibody SHR-1210 to Human and Cynomolgus 
and Rhesus Monkey PD-1  
 
Human Kd (nM) 
Cynomolgus Kd (nM) 
Rhesus Kd (nM) 
SHR-1210 
2 
8 
4 
 
Binding of SHR-1210 to human and cynomolgus monkey neonatal Fc receptor (FcRn) 
was investigated. SHR-1210 binds to human and cynomolgus monkey FcRns with 
similar Kd values. 
The binding of SHR-1210 to different FcγR proteins was also evaluated using SPR 
technology. The data indicate that the binding of SHR-1210 to different FcγR proteins 
is consistent with an IgG4 antibody isotype. 
From the detection of the binding affinity, the affinity of SHR-1210 to antigen (human 
PD-1) was 3.0 nM, which was comparable to that of control antibodies nivolumab and 
MK3475 (pembrolizumab). The results are shown in Table 2. 
Table 2 
Binding Affinity of Antibody SHR-1210, Nivolumab and MK3475 to 
Human PD-1 Antigen 
Antibody 
Antigen 
Binding Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
MK3475 
Human PD-1 antigen 
3.2 
 
2) Experiment on antibody SHR-1210 blocking the binding of PD-1/PD-L1 
The experimental results (see Figure 1 and Figure 2) showed that the antibody SHR-
1210, nivolumab and pembrolizumab were comparable in blocking the binding of PD-
1 / PD-L1 in vitro. The blocking activity of the antibodies SHR-1210, nivolumab and 
pembrolizumab was 0.70 nM / 0.79 nM, 0.79 nM / 0.77 nM, respectively. 
PD1 antibody blocking
-2
-1
0
1
2
3
0.0
0.5
1.0
1.5
2.0
2.5
HR301210
lambrolizumab
IC50
HR301210
0.7007
lambrolizumab
0.7864
negative control
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 1. 
SHR-1210 and Pembrolizumab Blocking the Binding of PD-1/PD-L1 


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HENGRUI CONFIDENTIAL 
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PD1 antibody blocking
-2
-1
0
1
2
3
0
1
2
3
4
HR301210
Nivolumab
IC50
HR301210
0.7913
Nivolumab
0.7745
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 2. 
SHR-1210 and Nivolumab Blocking the Binding of PD-1 / PD-L1 
1.2.1.4. Toxicology Studies 
Eight cynomolgus monkeys (half males and half females) were randomly divided into 
two groups in a pre-clinical study of acute toxicity. SHR-1210 was intravenously 
injected at 200, 400 and 800 mg / kg for animals in Group 2 every other day in a dose 
escalation manner. No changes in clinical signs, weight, food consumption and 
coagulation associated with SHR-1210 were observed. When dose ≥ 200 mg / kg, 
lymphopenia was observed in male and female animals; when dose ≥ 400 mg / kg, 
increased serum globulin and decreased albumin were observed in male and female 
animals. The above changes were small, so it was not considered as harmful effects. 
The maximum tolerated dose (MTD) of SHR-1210 is ≥ 800 mg/kg. 
In the completed pre-clinical study of chronic toxicity in cynomolgus monkeys, male 
and female cynomolgus monkeys SHR-1210 was well tolerated when intravenously 
injected at 20, 50 and 100 mg / kg once weekly for 4 weeks (5 times in total) or 26 
weeks (26 times in total). No changes in clinical signs associated with SHR-1210 were 
observed, including injection site irritation, body weight, food consumption, body 
temperature, 12-lead ECG, blood pressure, heart rate and respiratory parameters; No 
changes in B and T lymphocyte typing, cytokine, immunoglobulin and complement 
parameters were observed; No changes in organ weights, gross lesions and 
histopathological changes associated with SHR-1210 were observed. 
1.2.1.5. Pharmacokinetic Studies 
Pharmacokinetic parameters of cynomolgus monkeys after single intravenous infusion 
of SHR-1210 are shown in Table 3. 
Table 3 
Pharmacokinetic Parameters of Cynomolgus Monkeys After Single 
Intravenous Infusion of SHR-1210 at Different Doses 
Dose 
(mg/kg) Gender 
T1/2 
Tmax 
Cmax 
AUClast 
Vz 
Cl 
MRTlast 
(h) 
(h) 
(μg/mL) (h*μg/mL) (mL/kg) (mL/h/kg) 
(h) 
1 
Female 
76.06 
±32.93 
0.83 
±0.29 
31.16 
±11.25 
1716.12 
±453 
54.09 
±14.85 
0.57 
±0.17 
80.95 
±18.58 
Male 
91.72 
±25.26 
0.83 
±0.29 
35.96 
±13.09 
2359.7 
±684.07 
55.15 
±20.51 
0.37 
±0.06 
102.23 
±38.56 


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Dose 
(mg/kg) Gender 
T1/2 
Tmax 
Cmax 
AUClast 
Vz 
Cl 
MRTlast 
(h) 
(h) 
(μg/mL) (h*μg/mL) (mL/kg) (mL/h/kg) 
(h) 
Total 
83.89 
±27.62 
0.83 
±0.26 
33.56 
±11.23 
2037.91 
± 627.32 
54.62 
±16.02 
0.47 
±0.15 
91.59 
±29.47 
3 
Female 
92.95 
±22.60 
0.83 
±0.29 
81.09 
±12.66 
6896.79 
±1673.36 
40.75 
±12.66 
0.44 
±0.11 
120.92 
±49.96 
Male 
113.54 
±8.26 
1.67 
±0.58 
71.65 
±10.85 
6380.24 
±2062.85 
47.05 
±27.05 
0.47 
±0.12 
127.10 
±59.24 
Total 
103.25 
±18.94 
1.25 
±0.61 
76.37 
 ±11.74 
6638.51 
±1703.60 
43.91 
±19.21 
0.46 
±0.11 
124.01 
±49.13 
10 
Female 
169.70 
±38.96 
2.17 
±1.76 
217.46 
±20.22 
31357.28 
±9338.28 
41.24 
±24.76 
0.33 
±0.1 
179.68 
±73.6 
Male 
128.94 
±35.93 
0.67 
±0.29 
251.88 
±6.49 
26779.98 
±7205.43 
30.9 
±30.2 
0.31 
±0.05 
113.25 
±44.39 
Total 
149.32 
±40.28 
1.42 
±1.39 
234.67 
±23.15 
29068.63 
±7869.83 
36.07 
±25.34 
0.32 
±0.07 
146.46 
±65.42 
1.2.2. 
Clinical Studies with SHR-1210 
1.2.2.1. Safety Summary of SHR-1210 in the Treatment of Advanced Solid 
Tumors 
After obtaining clinical trial approval in 2016, three phase I clinical studies have been 
carried out in China for SHR-1210. They are all safety and tolerability studies in 
subjects with advanced solid tumors. As of February 28, 2018, three phase I studies 
included 258 subjects with advanced solid tumors who have failed standard treatment. 
The safety summary analysis is as follows: 
At least one AE occurred in 258 subjects (100.0%). AEs with an incidence of ≥ 10% 
mainly included: skin and subcutaneous tissue disorders: reactive cutaneous capillary 
endothelial proliferation (81.8%), pruritus (22.5%), rash (16.3%); abnormal liver 
function: elevated asparagine transaminase (22.1%), elevated alanine aminotransferase 
(19.0%), elevated conjugated bilirubin (17.8%), elevated blood bilirubin (13.2%); 
hematologic toxicity: anemia (29.5%), decreased white blood cell count (17.1%), 
decreased neutrophil count (10.5%); general disorders: fatigue (38.4%), fever (22.1%); 
gastrointestinal AE: nausea (12.0%), diarrhea (11.6%); respiratory, thoracic and 
mediastinal disorders: cough (21.3%), upper respiratory tract infection (10.9%); 
metabolism and nutrition disorders: hypoproteinemia (22.1%), decreased serum sodium 
concentration (18.2%), anorexia (12.0%); renal and urinary disorders: proteinuria 
(22.5%); endocrine disorders: hypothyroidism (20.9%). A total of 98 (38.0%) subjects 
experienced at least one AE of Grade 3 or above, and AEs of Grade 3 or above with an 
incidence of ≥ 2% mainly included anemia (7.0%), pulmonary infection (6.6%), 
decreased serum sodium concentration (4.3%), elevated conjugated bilirubin (3.9%), 
progressive tumors (3.5%), death (3.1%), elevated asparagine transaminase (2.7%), 
elevated alanine aminotransferase (2.3%), and elevated blood bilirubin (2.3%). 
In 258 subjects, 256 subjects (99.2%) experienced at least one drug-related AE. Drug-
related AEs with an incidence of ≥ 10% included: skin and subcutaneous tissue 
disorders: reactive cutaneous capillary endothelial proliferation (81.8%), pruritus 


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(22.1%), rash (16.3%); general disorders: fatigue (37.6%) , fever (20.9%); abnormal 
liver function: elevated asparagine transaminase (21.7%), elevated alanine 
aminotransferase (18.6%), elevated conjugated bilirubin (16.7%), elevated blood 
bilirubin (12.0%); hematologic toxicity: anemia (27.5%), decreased white blood cell 
count (14.7%); gastrointestinal disorders: diarrhea (11.2%), nausea (10.5%); respiratory, 
thoracic and mediastinal disorders: cough (19.0%), upper respiratory tract infection 
(10.1%); metabolism and nutrition disorders: hypoproteinemia (19.4%), decreased 
serum sodium concentration (14.3%); renal and urinary disorders: proteinuria (22.1 %); 
endocrine disorders: hypothyroidism (19.8%). 82 (31.8%) subjects had at least one 
drug-related AE of Grade 3 or above, and the drug-related AEs of Grade 3 or above 
with incidence of ≥ 2% mainly included anemia (6.2%), pulmonary infection (5.8%), 
elevated conjugated bilirubin (3.9%), decreased serum sodium concentration (3.5%), 
death 
(3.1%), 
elevated 
asparagine 
transaminase 
(2.7%), 
elevated 
alanine 
aminotransferase (2.3%), and elevated blood bilirubin (2.3%). 
Among 258 subjects, AEs of Grade 3 or above with an incidence of ≥ 2% mainly 
included anemia (7.0%), pulmonary infection (6.6%), decreased serum sodium 
concentration (4.3%), and elevated conjugated bilirubin (3.9%), progressive tumor 
(3.5%), death (3.1%), elevated asparagine transaminase (2.7%), elevated alanine 
aminotransferase (2.3%), elevated blood bilirubin (2.3%). 
Overall, the AEs of SHR-1210 were similar to those of the already marketed same kind 
of drugs in subjects with advanced solid tumors except for reactive cutaneous capillary 
endothelial proliferation (RCCEP). Most of the RCCEP occurred within 1-2 months 
after the start of the study drug. The early ones could appear several days after the 
administration, and the late ones could appear about 5 months after the administration, 
mainly in the trunk or limbs. The vast majority (99.5%) were CTCAE 1-2, and only one 
subject reported Grade 3. The subject was rated as Grade 3 AE due to hospitalization 
from surgical resection, and no subjects discontinued medication due to this AE. A small 
number of subjects with bleeding symptoms received local symptomatic treatment. The 
symptoms usually resolved after stopping SHR-1210 treatment. Overall, SHR-1210 has 
good safety and tolerability. 
1.2.2.2. Preliminary Results of SHR-1210 Monotherapy for HCC Study 
The study was a single-arm study of SHR-1210 in subjects with advanced HCC who 
had undergone systemic therapy (NCT02989922). SHR-1210 was administered at a 
dose of 3 mg/kg once every 2 weeks or every 3 weeks. The enrollment of this study has 
been completed, the data was published in Lancet Oncology [25]. As of November16, 
2018 (data cut-off date), 12 months after last subject received first dose, 217 subjects 
received at least one dose of SHR-1210. 
Of 217 subjects treated, 206 (94.9%) were BCLC stage C subjects; all subjects received 
at least ≥ 1 line systemic therapies, 49 (23%) subjects underwent at least ≥ 2 line 
systemic therapies before enrollment; 177 (82%) subjects had extrahepatic metastasis 
at baseline; 171 (79%) subjects had a baseline ECOG-PS score of 1; 111(51%) subjects 
had baseline AFP ≥ 400 ng/mL, 181 (83%) subjects had HBV infection. 217 subjects 
met the definition of the full analysis set and were included in the full analysis set. 
Efficacy results: based on the judgment of the Independent Imaging Center (IRC) tumor 


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assessment data (as of November 16, 2018, RECIST Version 1.1), overall ORR was 
14.7% (95% CI: 10.3, 20.2). The ORR of the Q2W group was 11.9% (95% CI: 6.5, 
19.5), and the ORR of the Q3W group was 17.6% (95% CI: 10.9, 26.1).  
The 6-month OS rate was 74.7% (95% CI: 68.3, 79.9). The Q2W group was 75.9% (95% 
CI: 66.6, 82.9), and the Q3W group was 73.0% (95% CI: 63.6, 80.4). 
As of data cut-off of November16, 2018, the median follow-up was 12.5 months and 
the observed median OS was 13.8 months (95% CI: 11.5, 16.6).  
Safety results: the category and frequency of common AE were similar to those in phase 
I clinical studies of this study drug. The most common drug-related AEs (incidence of 
any group ≥ 10%) were reactive cutaneous capillary endothelial proliferation, elevated 
transaminases, proteinuria, hyperbilirubinemia, hypothyroidism, thrombocytopenia, 
leukopenia and fatigue. 22% of subjects had at least one drug-related AE of Grade 3 or 
Grade 4. 4% of subjects discontinued experimental drugs due to drug-related AE. At 
least one drug-related SAE occurred in 11% of subjects.  
In this study, 145 (67%) subjects developed reactive capillary endothelial proliferation 
(all in skin, of which three were accompanied in oral mucosa, two cases nasal mucosa, 
two cases palpebral conjunctiva). Except one case was grade 3, others reactive capillary 
endothelial proliferation cases were grade 1-2, mild, self-limiting and clinically 
manageable.  
Clinically significant results in laboratory tests were reported as AE, with no other 
indicators of special attention. Vital signs were stable and there were no extreme values. 
Detailed progress of research on SHR-1210 can be referred to in its investigator’s 
brochure. 
1.2.3. 
Progress in Clinical Research of Rivoceranib Monotherapy for Advanced 
HCC 
This clinical study also involved rivoceranib mesylate tablets (trade name: Aitan), 
which was launched in 2014 by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Rivoceranib 
is a small molecule targeted drug, a vascular endothelial growth factor receptor 
(VEGFR) tyrosine kinase inhibitor, which exerts anti-angiogenic effects on malignant 
tumors mainly through inhibiting VEGFR. Preclinical studies show that its anti-tumor 
effect is superior to similar drugs. In 2014, rivoceranib was approved in China for 
treatment of progression or recurrence of advanced gastric adenocarcinoma or 
adenocarcinoma of gastroesophageal junction after previous use of at least two systemic 
chemotherapies. 
HCC is also a typical tumor with an abundant blood supply, and its occurrence, 
development, metastasis and invasion are closely related to angiogenesis. In 2010-2013, 
the 81st hospital of the Chinese People’s Liberation Army led a randomized, open-label, 
multicenter phase II clinical trial of rivoceranib mesylate tablets in the treatment of 
advanced hepatocellular carcinoma (NCT01192971) [26], and a total of 121 subjects 
received the medication. In the full analysis set, the median time to progression (mTTP) 
and median overall survival (mOS) were 4.21 months and 9.71 months in the 850 mg 
group, and the mTTP and mOS in the 750 mg group were 3.32 months and 9.82 months. 


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There were no statistically significant differences in mTTP and mOS between the 850 
mg and 750 mg groups. The incidence of adverse reactions was 95.71% and 90.20% in 
850 mg and 750 mg groups, respectively; the incidence of severe adverse reactions was 
58.57% and 58.82%, respectively, the difference was not statistically significant. 
Therefore, a well-tolerated 750 mg is recommended as the dose for the phase 3 clinical 
study. The recommended dosing regimen is 750 mg, PO, QD; 28 days is a cycle 
(excluding the time for discontinuance), and continuous administration until the disease 
progression or an intolerable adverse reaction. If a Grade 3/4 hematologic or non-
hematologic adverse reaction occurs, it is recommended to suspend the medication (not 
more than 2 weeks) or to reduce the dose to 500 mg or 250 mg. 
A randomized (2:1), open-label, placebo-controlled, multicenter, phase 3 clinical trial 
of rivoceranib (NCT02329860) is currently ongoing to investigate the efficacy and 
safety of rivoceranib in the second-line treatment of advanced HCC. The trial recruited 
subjects with advanced HCC who have failed, relapsed or are intolerant to side effects 
with sorafenib or systemic chemotherapy. As of December 2017, 400 subjects have 
been enrolled. Adverse events that have been observed include proteinuria, elevated 
blood pressure, thrombocytopenia, hand-foot syndrome, and elevated total bilirubin. 
For more information on the rivoceranib mesylate tablets, please refer to the package 
insert of the rivoceranib mesylate tablets and the investigator's brochure provided by 
the sponsor. 
Based on the above-mentioned large-scale data from these randomized controlled 
clinical studies, the main adverse reactions are hand and foot skin reactions, 
hypertension, 
elevated 
transaminases, 
elevated 
bilirubin, 
leukopenia, 
thrombocytopenia, diarrhea, esophagitis, nausea, and fatigue, most of which are mild 
to moderate reactions. 
Detailed progress of research on rivoceranib can be referred to in its investigator’s 
brochure. 
1.2.4. 
Preliminary Data of SHR-1210 Combined with Rivoceranib 
1.2.4.1. Potential Mechanisms of Combination Administration and Preclinical 
Studies 
The VEGFR signaling pathway plays an important role in mediating tumor immune 
escape, and inhibition of this pathway may enhance the activation of tumor immunity 
by PD-1 antibodies. 
Preclinical data from Jiangsu Hengrui Pharmaceuticals Co., Ltd. suggested that SHR-
1210 combined with rivoceranib could significantly reduce the regulatory T cell (Treg) 
levels in peripheral blood and increase the ratio of effector T cell (Teff) to Treg. 
The results of animal studies showed that SHR-1210 combined with rivoceranib 
significantly enhanced the tumor growth inhibition of SHR-1210 without increasing 
significant toxicity (no significant change in animal body weight): 


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0
4
8
1 2
1 6
2 0
0
3 0 0
6 0 0
9 0 0
1 2 0 0
1 5 0 0
1 8 0 0
h I g G  + 0 . 5 %
 C M
C N a
A p a t i n i b  1 0 0  m
g / k g  Q D x 2 1
S H R 1 2 1 0  3  m
g / k g  Q 2 D x 8
S H R 1 2 1 0  3 m
g / k g + A P 1 0 0 m
g / k g  Q D x 2 1
T u m
o r  V o l u m
e  ( m
m
3 )
m
e a n
±  S E M
D a y s
0
4
8
1 2
1 6
2 0
2 0
2 2
2 4
2 6
2 8
h I g G  + 0 . 5 %
 C M
C N a
A p a t i n i b  1 0 0  m
g / k g  Q D x 2 1
S H R 1 2 1 0  3  m
g / k g  Q 2 D x 8
S H R 1 2 1 0  3 m
g / k g + A P 1 0 0 m
g / k g  Q
D x 2 1
B o d y  w
e i g h t  ( g r a m
)
m
e a n
±  S E M
D a y s
 
Figure 3. 
Evaluation of the Effect of SHR-1210 Combined with Rivoceranib 
on MC38 Colorectal Cancer in Tg Mice Expressing Human PD-1  
Preclinical findings suggest that the use of SHR-1210 in combination with rivoceranib 
may increase the ORR of the tumor while preserving the efficacy and persistence of 
immunotherapy. 
1.2.4.2. Exploration of Combination Administration in Preliminary Clinical 
Studies 
Since October 2016, Jiangsu Hengrui Pharmaceuticals Co., Ltd. has served as a funder 
or sponsor to conduct a number of clinical trials of SHR-1210 combined with 
rivoceranib mesylate, involving a variety of solid tumors such as advanced 
hepatocellular 
carcinoma, 
advanced 
lung 
cancer, 
advanced 
intrahepatic 
cholangiocarcinoma, advanced gastric adenocarcinoma and advanced triple-negative 
breast cancer. These studies explored the safety and tolerance of SHR-1210 combined 
with rivoceranib mesylate and the initial efficacy against a variety of tumors. 
Preliminary results confirm: for SHR-1210 200 mg fixed dose, once every two weeks 
(Q2W) combined with rivoceranib mesylate 250 mg/d, continuous oral dose level is 
tolerable, while the combination regimen for a variety of tumors have shown a 
significant efficacy, significantly increasing the proportion of subjects benefiting from 
treatment. 
Study Title 
Study Design 
First Subject 
Enrolled/Subject 
Number 
Enrolled 
Registration 
Number of 
Clinical Trial 
Exploratory clinical study of PD-1 
antibody SHR-1210 combined with 
rivoceranib mesylate in the treatment 
of advanced gastric cancer and 
hepatocellular carcinoma 
Dose-finding, 
dose expansion, 
phase Ib study 
2016-10/48 
NCT02942329 
Phase II clinical study of PD-1 
antibody SHR-1210 combined with 
rivoceranib mesylate in the treatment 
of advanced non-small cell lung 
cancer 
Dose-finding, 
dose expansion, 
phase II study 
2017-3/201 
NCT03083041 
Phase II clinical study of PD-1 
antibody SHR-1210 combined with 
rivoceranib mesylate or 
Dose-finding, 
dose expansion, 
phase II study 
2017-4/154 
NCT03092895 


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HENGRUI CONFIDENTIAL 
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Study Title 
Study Design 
First Subject 
Enrolled/Subject 
Number 
Enrolled 
Registration 
Number of 
Clinical Trial 
chemotherapy in advanced primary 
liver cancer or extrahepatic 
cholangiocarcinoma 
One-arm, open-label, prospective, 
multicenter clinical study of the 
efficacy and safety of rivoceranib 
mesylate in combination with PD-1 
antibody (SHR-1210) in the 
treatment of progressive 
osteosarcoma with chemotherapy 
failure 
One-arm, open-
label, phase II 
study 
2017-12/43 
NCT03359018 
Two-arm, open-label, investigator-
initiated phase II clinical trial of anti-
PD-1 antibody SHR-1210 in 
combination with rivoceranib 
mesylate in the treatment of recurrent 
metastatic triple-negative breast 
cancer 
Two-arm, open-
label, phase II 
study 
2017-12/40 
NCT03394287 
One-arm, open-label, phase II 
clinical trial of anti-PD-1 antibody 
SHR-1210 combined with 
rivoceranib mesylate in the treatment 
of advanced hepatocellular 
carcinoma 
One-arm, open, 
phase II study 
2018-3/190 
NCT03463876 
Phase II clinical study of SHR-1210 
combined with rivoceranib mesylate 
in the treatment of extensive-stage 
small cell lung cancer with first-line 
standard of care failure 
Dose-finding, 
dose expansion, 
phase II study 
2018-4/59 
NCT03417895 
Cut-off date: 24 Aug. 2019 
1.2.4.3. Selection of Doses for Combined Therapy 
The dose-response relationship analysis was performed on the safety and efficacy data 
of three phase I studies of SHR-1210-101, SHR-1210-102 and SHR-1210-103. This 
analysis defines SHR-1210 (ORR+DCR)/2 as the efficacy index and (number of 
subjects with at least one drug-related AE + skin and subcutaneous tissue disease)/2 as 
the safety index. Figure 4 shows that the efficacy index reaches a steady state at a dose 
of 200 mg Q2W; the safety index increases with the dose. The optimal benefit dose for 
subjects can be defined as the dose with the least severe side effects in the case of 
maximum efficacy. The efficacy index and safety index show that 200 mg Q2W is the 
best benefit dose for subjects.  


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*Efficacy Index = (ORR+DCR)/2; Safety Index = (number of subjects with at least one drug-related 
AE + skin and subcutaneous tissue disease)/2 
Figure 4. 
Relationship of Efficacy and Safety Indexes with Doses 
In one exploratory clinical study on SHR-1210 combined with rivoceranib mesylate in 
treatment of advanced hepatocellular carcinoma and gastric cancer [20.] (NCT02942329), 
the tolerability of SHR-1210 200 mg at the fixed dose of once every two weeks (Q2W) 
combined with rivoceranib mesylate 125 mg/d, 250 mg/d or 500 mg/d for continuous 
administration was observed, and the results showed that rivoceranib 125 mg QD po 
combined with SHR-1210 200 mg Q2W was well tolerated without dose-limiting 
toxicity (DLT); 3/5 subjects given rivoceranib 500 mg QD po combined with SHR-
1210 200 mg Q2W had Grade 3 immune-related pneumonia that could not be tolerated 
during observation of tolerability; 1/5 subject given rivoceranib 250 mg QD po 
combined with SHR-1210 200 mg Q2W had Grade 3 elevated lipase with no clinical 
symptoms during observation of tolerability, the symptoms disappeared after 
symptomatic treatment, see Table 4 for the detail. 
The observation of tolerability showed that rivoceranib 250mg/d po continuously 
combined with SHR-1210 200 mg, Q2W was tolerable in treatment of advanced 
hepatocellular carcinoma, gastric cancer and gastroesophageal junction carcinoma. 
This dose level was selected for efficacy extension in the study subsequently.  
Table 4 
Occurrence of DLT in Each Dose Group in the Studies on SHR-1210 
Combined with Rivoceranib in Treatment of Advanced Hepatocellular 
Carcinoma and Gastric Cancer 
Dose Level of 
Rivoceranib 
Number of Subjects/ 
Number of Subjects 
with Evaluable DLT  
Number / 
Proportion of 
Subjects with DLT 
DLT Details 
0
10
20
30
40
50
60
70
80
90
100
50
150
250
350
450
550
Dose (mg) (dosage per kg of body weight*60)
有效性指标
有效性指标95%置信区间（2.5%至97.5%）
安全性指标
Efficay Index
Efficay Index 95% (2.5%-97.5%)
Safety Index


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125mg/d 
5/5 
0/0 
Not Detected 
250mg/d 
5/5 
1/20.0% 
Grade 3 elevated lipase with no 
clinical symptoms 
500mg/d 
5/5 
3/60.0% 
Grade 3 immune-related 
pneumonia 
 
In one phase II study on SHR-1210 combined with rivoceranib mesylate for treatment 
of advanced non-squamous cell, non-small cell lung cancer (NCT03083041), the 
tolerability of SHR-1210 200 mg fixed dose once every two weeks (Q2W) combined 
with rivoceranib mesylate 250 mg/d, 375mg/d or 500mg/d for continuous 
administration was observed. The preliminary study results during observation of 
tolerability showed that, in the 12 subjects participating in the tolerability observation 
of SHR-1210 200 mg fixed dose once every two weeks (Q2W) combined with 
rivoceranib mesylate 250 mg qd, the clinically significant toxicity was observed in only 
2 subjects during observation of tolerability, which was 1 case of dose interruption of 
rivoceranib for > 7 days caused by increased hydrothorax (suspected pleural fistula) 
and 1 case of dose interruption of rivoceranib for > 7 days caused by anorexia with 
weakness. The incidence of clinically significant toxicity was 16.7% (2/12), the dose 
level was tolerable; in the subsequent observation of the tolerability of SHR-1210 200 
mg fixed dose once every two weeks (Q2W) combined with rivoceranib mesylate 375 
mg QD, a total of 4/12 evaluable subjects had Grade 3 rash during observation of 
tolerability, the incidence of clinically significant toxicity was 33.3%(4/12), the 
proportion of subjects with significant toxicity reached 1/3, and the dose level was 
intolerable.  
Table 5 
Occurrence of Clinically Significant Toxicity in Each Dose Group in 
the Study on SHR-1210 Combined with Rivoceranib in Treatment of Advanced 
Non-Small Cell Lung Cancer 
Dose Level 
of 
Rivoceranib 
Number of 
Subjects/ 
Number of 
Subjects with 
Evaluable DLT 
Number/ 
Proportion of 
Subjects with 
Clinically 
Significant 
Toxicity 
Details 
250mg/d 
12/12 
2/16.7% 
1 case of suspected bronchopleural fistula 
(increased hydrothorax), leading to dose 
interruption of rivoceranib for >7d 
1 case of fatigue with anorexia, leading to 
dose interruption of rivoceranib for >7d 
375mg/d 
12/12 
4/33.3% 
4 cases of Grade 3 rash that could be 
relieved after symptomatic treatment;  
Dose adjustment in 5 subjects in the first 
two cycles, including down-titration of 
rivoceranib to 250mg/d in 3 subjects 
The observation of tolerability showed that rivoceranib 250 mg/d po continuously 
combined with SHR-1210 200 mg, Q2W was tolerable in treatment of advanced non-
squamous cell, non-small cell lung cancer. This dose level was selected for efficacy 
extension in the study subsequently.  
Combined with the analysis results of the pharmacokinetics, efficacy and safety in the 


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above studies, it has been decided that the clinically observed tolerable dose will be 
selected in the upcoming phase 3 studies on SHR-1210 combined with rivoceranib 
mesylate as the first-line therapy for advanced hepatocellular carcinoma: SHR-1210 
200 mg, Q2W combined with rivoceranib 250 mg QD po continuously as combined 
therapy dose.  
1.2.4.4. Preliminary Efficacy of Combined Therapy 
In the exploratory clinical study on SHR-1210 combined with rivoceranib mesylate for 
treatment of advanced hepatocellular carcinoma and gastric cancer, it was found 
through the efficacy extension in SHR-1210 200 mg, Q2W combined with rivoceranib 
250 mg QD continuously that this combined regimen had significant efficacy in 
advanced hepatocellular carcinoma: in the 14 subjects with liver cancer enrolled at this 
dose level, there were 13 evaluable subjects (all positive HBV, including 12 subjects 
with failure of sorafenib), 7 subjects were evaluated as disease remission, the objective 
response rate (ORR) reached 53.8% and the remission was durable, no progression of 
disease was seen in 6 subjects with disease remission after treatment for 18-72 weeks; 
PFS rates of 6-month and 9-month were 51.3% (95% CI: 21.4, 74.9) and 41.0% (95% 
CI:13.8, 66.9) respectively, and the median PFS was 7.2 months (95% CI: 4.1,NR), the 
preliminary efficacy was significant[22]. 
 
Figure 5. 
The Best Response of SHR-1210 Combined with Rivoceranib in 
Advanced Hepatocellular Carcinoma and Change in the Diameter of Target 
Lesions After Administration 
Above preliminary data demonstrated that compared with current therapeutic regimen, 
such as sorafenib, the ORR was <10%; while the ORR of Nivolumab treatment for 
advanced HCC after sorafenib exposure was 14.3%, DCR was 55%. Per above 
preliminary results, SHR-1210 combined with rivoceranib mesylate looks having an 
obvious advantage in treatment of advanced HCC.  
In summary, under the selected dose, SHR-1210 combined with rivoceranib had a good 
tolerability and significant preliminary efficacy observed in advanced hepatocellular 
carcinoma. The randomized, controlled study of SHR-1210 combined with rivoceranib 
versus sorafenib in uncurable HCC is expected to achieve positive outcome and provide 
a more effective therapeutic option for vast subjects with HCC.  
Best response for SHR-1210 combined with 
rivoceranib 
SHR-1210 combined with rivoceranib-change in 
tumor diameter 


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1.2.5. 
Selection Rationale of Control Arm 
Sorafenib was approved by the FDA as a targeted therapy for HCC in 2007. Sorafenib 
is an oral multitarget inhibitor (VEGFR-1, -2, -3, PDGFR and c-KIT) that blocks tumor 
neovascularization and inhibits tumor growth directly. The approval of sorafenib is 
based on the active results from SHARP and ORIENTAL trials. SHARP trial is a phase 
3 trial conducted mainly in European and American subjects to compare the efficacy 
and safety of sorafenib versus placebo in treatment of advanced HCC. The results 
showed a significantly improved survival in sorafenib group compared with placebo 
group. The ORIENTAL trial in parallel to SHARP trial enrolled subjects with advanced 
HCC in Asian-Pacific region using the same design. The results showed a similar 
significant improvement in survival with sorafenib in Asian subjects. A total of 3,371 
subjects with unresectable advanced HCC were enrolled in GIDEON study intended to 
acquire the clinical safety data of sorafenib. The results showed an OS of 13.6, 5.2 and 
2.6 months, and median TTP of 4.7, 4.4 and 3.6 months in subjects with CHILD Grade 
A, B and C, indicating better benefit for earlier treatment with sorafenib. 
Table 6 
Phase 3 Clinical Trial on Sorafenib in Advanced Hepatocellular 
Carcinoma 
Study Endpoints 
SHARP 
(North America and Europe) 
ORIENTAL 
(Asia-Pacific region) 
 
Sorafenib vs Placebo 
Sorafenib vs Placebo 
Median TTP (months) 
5.5 vs 2.8 
2.8 vs 1.4 
Median OS (months) 
10.7 vs 7.9 
6.5 vs 4.2 
DCR (%) 
74.3 vs 67.7 
35.3 vs 15.8 
ORR (%) 
2.3 vs 0.7 
4.3 vs 1.3 
 
To summary, sorafenib is recognized throughout the world as a first-line standard of 
care therapy for advanced HCC and thus has been selected for comparison of first-line 
treatment of participants assigned to the control arm.  
1.3. 
Potential Risks and Benefits 
As described above, current therapies have limited efficacy in advanced hepatocellular 
carcinoma, only less than 10% of subjects can achieve response from the 1st-line 
therapy with sorafenib. Lenvatinib was approved by the FDA in August 2018 as the 
first-line therapy for subjects with unresectable hepatocellular carcinoma and has not 
been widely used yet. The PD-1 antibodies nivolumab and pembrolizumab that were 
approved in recent years have achieved significant response in the exploratory 
application in HCC. For example, for subjects with advanced hepatocellular carcinoma 
who have received sorafenib for treatment, the ORR is 14.3% in those who have 
received PD-1 antibody (nivolumab) and is superior to current therapeutic approaches. 
In particular, when PD-1/PD-L1 antibody is combined with anti-angiogenesis targeted 
drug, efficacy is enhanced; moreover, the combined therapy is safe, well tolerated and 
can achieve a synergistic effect. SHR-1210 is one humanized PD-1 antibody that is 
independently researched and developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
The preclinical data in animal experiments showed a similar affinity and antitumor 
effect with nivolumab and pembrolizumab. At the same time, SHR-1210 combined with 
rivoceranib has achieved an encouraging preliminary result in treatment of advanced 


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hepatocellular carcinoma. Participation in the phase 3 study to receive the study drug 
may provide clinical benefit to subjects with advanced HCC and offer a useful 
therapeutic option for them.  
1.3.1. 
Known Potential Risks 
In the previous clinical studies for multiple solid tumors (including HCC) and 
hematological tumors, the most common (≥ 10%) adverse reactions induced by SHR-
1210 included: reactive capillary endothelial proliferation (RCEP), various rashes, 
immune endocrine dysfunction such as hyperthyroidism/hypothyroidism, fatigue, 
elevated transaminase, most of which were Grade 1-2 and could be recovered after 
symptomatic treatment or dose interruption, had relatively small effect on subject’s 
physiological function and quality of life, and did not hinder continuation of the study 
treatment. RCCEP is a unique skin reaction of SHR-1210. Although with a relatively 
high incidence in the SHR-1210 monotherapy, RCEP was relatively mild in severity 
and clinically tolerable, and could be recovered after discontinuation of the drug. 
Moreover, in the treatment of SHR-1210 combined with rivoceranib, the incidence of 
RCEP was significantly reduced, which may be related to the anti-angiogenic effect of 
rivoceranib. The most common serious adverse reactions of SHR-1210 include 
pneumonitis, abnormal liver function, lung infection and thrombocytopenia. Various 
immune-related adverse reactions are potential risks of SHR-1210, which are class 
effects of PD-1 antibody preparations and include pneumonitis, hepatitis, thyroiditis, 
myocarditis, enteritis, severe cutaneous adverse reactions (including Stevens–Johnson 
syndrome (SJS), toxic epidermal necrolysis (TEN)) etc. Symptomatic treatment will be 
given in accordance with EMSO/NCCN guideline on management of immunotoxicity 
and can ensure the safety of subjects during the trial. Please refer to the investigator’s 
brochure for more details on adverse drug reactions associated with SHR-1210. 
Rivoceranib mesylate tablets were approved by the Chinese drug regulatory authorities 
for the treatment of advanced gastric cancer in October 2014. The recommended initial 
dose is 850 mg, orally, once daily. The most common (≥ 10%) adverse reactions of 
rivoceranib (850 mg QD) are hand and foot skin reactions, hypertension, elevated 
transaminases, elevated bilirubin, elevated alkaline phosphatase, elevated γ-glutamyl 
transferase, proteinuria, diarrhea, leukopenia, thrombocytopenia, anemia, fatigue, etc., 
most of which are mild to moderate reactions and can be recovered or improved after 
the drug is temporarily discontinued and treatment is given. In addition, the use of 
rivoceranib requires special attention to events that have a low incidence but may cause 
serious consequences or even deaths, including various types of bleeding and 
thrombotic events, cardiotoxicity (QT interval prolongation, arrhythmia) and liver 
toxicity. Please refer to the investigator’s brochure for more details on adverse drug 
reactions associated with rivoceranib mesylate. Currently, the known safety information 
on rivoceranib mesylate mainly comes from the experience of dose regimen of 850 mg 
QD, and the experience of 250 mg QD is relatively limited. 
Although the mechanism of action for SHR-1210 and rivoceranib is completely 
different, their pharmacological effects may extensively affect multiple organ systems 
of the body. Based on the preliminary safety data, and given that there could be 
overlapped adverse reactions associated with both drugs during the treatment of SHR-
1210 in combination with rivoceranib 250 mg QD, overlapped adverse reactions that 
require the investigator’s special attention include but not limited to: severe cutaneous 


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adverse reaction, hematological toxicity, abnormal liver function, diarrhea, anorexia, 
proteinuria and fatigue. 
1.3.2. 
Known Possible Benefits 
In the two currently ongoing phase II clinical studies in subjects with advanced HCC, 
the efficacy has been preliminarily shown for SHR-1210 alone or SHR-1210 in 
combination with rivoceranib. So the HCC subjects enrolled in this study may achieve 
partial or even complete response, and some subjects may obtain sustained stable 
disease. The above trial data will provide a strong guidance for the clinical practice for 
HCC treatment and allow more subjects to access and benefit from new therapeutic 
methods.  
 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoints 
• 
To compare the overall survival 
(OS) and progression-free 
survival (PFS) of SHR-1210 
combined with rivoceranib 
mesylate (experimental arm) 
with sorafenib (control arm) as 
first-line therapy for subjects 
with advanced HCC who have 
not previously received 
systemic therapy. 
• 
Overall survival (OS); 
• 
PFS evaluated by the blinded 
independent review committee (BIRC) 
based on RECIST v1.1. 
Secondary Objectives 
Secondary Endpoints 
• 
To compare the efficacy of 
SHR-1210 combined with 
rivoceranib mesylate versus 
sorafenib as first-line therapy in 
subjects with advanced HCC, 
who have not previously 
received systemic therapy, 
through evaluations of PFS, 
time to progression (TTP), 
objective response rate (ORR), 
disease control rate (DCR), and 
duration of response (DoR);  
• 
Time to progression (TTP), objective 
response rate (ORR), disease control 
rate (DCR), and duration of response 
(DoR) evaluated by BIRC based on 
RECIST v1.1; 
• 
PFS, TTP, ORR, DCR and DoR 
evaluated by investigator based on 
RECIST v1.1; 
• 
PFS, TTP, ORR, DCR and DoR 
evaluated by BIRC based on modiﬁed 
RECIST (mRECIST). 
• 
To evaluate the safety of SHR-
1210 combined with rivoceranib 
mesylate versus sorafenib as a 
first-line therapy for advanced 
HCC; 
• 
Incidence and severity of adverse event 
(AE) and serious adverse event (SAE) 
judged in accordance with NCI-CTCAE 
v4.03; vital signs, ECG, and abnormal 
laboratory examinations; 
• 
To evaluate the PK of SHR-
1210 and rivoceranib and the 
immunogenicity of SHR-1210, 
and to analyze the 
immunogenicity combined with 
the concentration of SHR-1210. 
• 
Serum concentration of SHR-1210 and 
plasma concentration of rivoceranib; 
proportion of anti-SHR-1210 antibody 
(ADA) and neutralizing antibody (Nab) 
formed during the study from baseline; 
analysis of the immunogenicity of SHR-
1210 combined with the concentration 
of SHR-1210. 
Exploratory Objectives 
Exploratory Endpoints: 
• 
To evaluate the quality of life 
(QoL), including health related 
quality of life (HRQOL) / 
general health status (GHS), 
physical functioning and role 
• 
Time to deterioration (TTD): defined as 
time from randomization to first 
deterioration (a score decrease by ≥ 10 
from baseline) maintained for two 
consecutive time points, or one time-


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functioning, of subjects with 
advanced HCC who receive 
SHR-1210 combined with 
rivoceranib mesylate as a first-
line therapy versus those who 
receive sorafenib as a first-line 
therapy; 
point followed by death (from any 
cause) within 4 weeks, as determined by 
following subscales of European 
Organization for Research and 
Treatment of Cancer (EORTC) Quality 
of Life Questionnaire-Core 30 (QLQ-
C30):  
­ HRQoL/Global health status 
­ Physical Functioning 
­ Role Functioning 
• 
Average score and its change in the 
score from baseline in all the subscales 
of EORTC QLQ-C30 and EORTC 
QLQ-HCC18 (by cycle);  
• 
To evaluate the health status of 
subjects with advanced HCC 
who receive SHR-1210 
combined with rivoceranib 
mesylate as a first-line therapy 
versus those who receive 
sorafenib as a first-line therapy, 
so as to generate the utility 
score for health economic 
assessment; 
• 
Health utility index and VAS score in 
EQ-5D-5L questionnaire; 
• 
To compare the efficacy of 
SHR-1210 combined with 
rivoceranib mesylate versus 
sorafenib as first-line therapy in 
subjects with advanced HCC 
through evaluations of PFS, 
TTP, ORR, DCR and DoR 
based on immune-modiﬁed 
Response Evaluation Criteria in 
Solid Tumors (imRECIST); 
• 
PFS, TTP, ORR, DCR and DoR 
evaluated by investigator based on 
imRECIST; 
• 
To explore the correlation 
between biomarkers and the 
efficacy of combined 
therapeutic regimen; 
• 
The correlation of the expression level 
of PD-L1 and proportion of strong 
expression of PD-L1 in tumor tissue 
with the efficacy of SHR-1210 
combined with rivoceranib mesylate 
(including but not limited to ORR, OS); 
• 
To evaluate the possible effect 
of immunogenicity of SHR-
1210 on the efficacy and safety 
of SHR-1210 combined with 
rivoceranib mesylate as a first-
• 
Efficacy (e.g., best overall response 
(BOR), ORR, etc.), and safety endpoint 
(eg, immune-related adverse events 
[irAEs], ≥ Grade 3 treatment-related 
adverse events, treatment-related SAEs, 


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line therapy for advanced HCC. 
etc.) listed according to the ADA / Nab 
status of SHR-1210 in the experimental 
arm. 
3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a randomized, open-label, international, multi-center, phase 3 trial to evaluate 
the efficacy and safety of PD-1 antibody SHR-1210 plus rivoceranib mesylate versus 
sorafenib as first-line therapy in subjects with incurable advanced HCC.  
The study will be conducted in subjects with incurable, locally advanced or metastatic 
HCC who did not receive systematic treatment previously. Primary efficacy endpoints 
include both OS and PFS evaluated by the BIRC based on RECIST v1.1, and 
approximately 510 subjects will be enrolled. Eligible subjects will be randomized to 
receive either SHR-1210 combined with rivoceranib mesylate (experimental arm) or 
sorafenib (control arm) in a 1:1 ratio. 
The stratification factors for randomization include:  
1. Macrovascular invasion and/or extrahepatic metastasis (presence vs. absence) 
2. Geographical region (Asia vs. countries outside of Asia) 
3. Baseline AFP (AFP < 400 ng/mL vs. AFP ≥ 400 ng/mL) 
Subjects will receive study treatment after being informed of all pertinent aspects of the 
study, signing the informed consent form and passing the screening for eligibility. 
Experimental arm: SHR-1210, 200 mg, via intravenous infusion, once every two weeks 
(Q2W) + rivoceranib 250 mg, p.o., once per day (QD), continuously, 4 weeks (28 days) 
per cycle of therapy. Control arm: sorafenib, 400 mg, p.o., twice per day (BID), 
continuously, 28 days per cycle of therapy. Study treatment will continue until the 
subject develops an intolerable toxicity, withdrawing informed consent, and disease 
progression confirmed by BIRC according to RECIST v1.1 (when the subject has 
disease progression assessed by the investigator according to RECIST v1.1, the 
investigator must submit the radiological data to BIRC immediately. If BIRC evaluates 
it as non-disease progression according to RECIST v1.1, the subject should continue to 
receive the study drug treatment and continue the tumor radiological evaluation; if 
BIRC confirms it as disease progression based on RECIST V1.1, at this time, the 
investigator needs to assess whether the subject still has clinical benefit. If the subject 
is considered to still have clinical benefit and meet the criteria for treatment beyond  
disease progresses (see Section 6.6 for details), the subject may continue to receive 
study medication; if the subject is no longer considered to have clinical benefit, the 
treatment may be discontinued), or other termination criteria specified by the protocol, 
whichever occurs first. 
Subjects will have safety visits on D1 and D15 of each cycle of therapy within the first 
3 cycles for both experimental and control arms. Beginning from the cycle 4, subjects 
will have safety visits on D1 and D15 of each cycle in the experimental arm; subjects 
in the control arm will only have safety visits on D1 of each cycle; refer to the 


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SCHEDULE OF ACTIVITIES for details. Subjects will continue with safety visits and 
survival follow-up after the end- of- treatment. The study design is shown in Figure 6. 
 
Figure 6. 
Study Design Chart 
Tumor radiological evaluation will be performed every 8 weeks (56 days) ± 7 days from 
the randomization through the first 48 weeks, to assess the efficacy, and every 12 weeks 
(84 days) ± 7 days after 48 weeks. During the trial period, radiological examination and 
evaluation can be added at any time if clinically indicated. Tumor radiological 
assessment will continue until the occurrence of disease progression confirmed by 
BIRC according to RECIST v1.1 criteria or study treatment discontinuation, whichever 
occurs later. Subjects who discontinue treatment for reasons other than BIRC-
confirmed disease progression (according to RECIST v1.1) will also continue with 
regular follow-up by tumor radiological assessments after study treatment is 
discontinued. 
If the subject withdraws informed consent before BIRC confirms disease progression 
according to the RECIST v1.1 criteria or the study treatment is discontinued, other anti-
tumor treatment has begun (except for traditional Chinese medicine), or the subject dies, 
there is no need to continue the radiological evaluation. If the subject does not meet the 
above criteria to stop radiological assessment, the efficacy evaluation of the three 
efficacy evaluation criteria (RECIST v1.1, mRECIST, imRECIST) needs to continue 
even if the disease progression under certain efficacy evaluation criteria occurs.  
Upon approval of Protocol v6.0, disease progression will be confirmed by the 
investigator per RECIST v1.1. If the investigator confirms non-disease progression, the 
subject should continue on study treatment and tumor radiological evaluation as 
required; if the investigator confirms as disease progression, the subject may continue 
to receive study treatment after disease progression at the investigator’s discretion (see 
Section 6.6). 
The study extension phase will be initiated when sufficient follow up is completed and 
the study is ended (at least 2 years follow up of the last subject randomized). The 
Experimental arm (N=255) 
Control arm 
1:1 
randomization 
Safety follow-up/survival follow-up 
The final PFS analysis is planned to be performed after 332 PFS events have been observed. 
The interim OS analysis is planned to be performed after 251 OS events have been observed. 
The final OS analysis is planned to be performed after 359 OS events have been observed. 
Pathologically diagnosed 
advanced hepatocellular 
carcinoma (unresectable or 
metastatic);  
Child-Pugh class: Grade A; 
BCLC stage B-C; 
No systematic treatment;  
At least one measurable lesion 
that can be evaluated with CT 
or MRI;  
ECOG-PS score 0-1; 
Control arm (N=255) 
SHR-1210, 200 mg, via intravenous infusion, Q2W;
Combined with rivoceranib tablet, 250 mg, QD, 
orally;28 days as one cycle of therapy; until 
progression of until BIRC confirmed disease
progression (according to RECIST v1.1) and the
investigator consider the treatment no longer has 
clinically benefit or the toxicity is intolerable 
Sorafenib, 400 mg, BID, orally; 
28 days as one cycle of therapy; until progression of 
disease confirmed by BIRC (according to RECIST
v1.1) and no clinical benefit or intolerable toxicity 


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purpose of the extension phase is to continue to provide access to study drugs for 
subjects who are still on study treatment and still derive clinical benefit at the time of 
end of study. Upon initiation of the extension phase, the Sponsor considers the safety 
and efficacy profile of the experimental treatment regimen within this study to have 
been sufficiently established and data analysis required for regulatory purposes to have 
been completed. The Sponsor will notify the sites when will the study enter the 
extension phase. 
In the extension phase, subjects randomized in the experimental arm will continue on 
SHR-1210 in combination with rivoceranib, and subjects randomized in the control 
arm may have the option to crossover to receive experimental treatment and the 
decision made is upon investigator’s clinical judgment. Subjects who are not eligible 
to crossover to experimental treatment per investigator clinical judgment can continue 
on sorafenib treatment. Subjects will continue to receive study treatment until they are 
no longer benefiting from treatment as assessed by investigator’s clinical judgment. 
The study clinical database will be closed at the initiation of the extension phase. 
Important safety information collection in the extension phase will be captured in the 
safety database. Only data collected prior to implementation of extension phase will 
be summarized in the clinical study report.  
3.2. 
Measures to Minimize Bias 
3.2.1. 
Randomization 
See Section 4.3 for randomization criteria.  
3.2.2. 
Evaluation of Success of Blinding 
Not applicable. 
3.2.3. 
Breaking the Study Blind/Participant Code 
Not applicable. 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects will be allowed to participate in this study only when they meet the 
following criteria. All the medical and non-medical conditions of each subject should 
be considered as to whether they meet the study criteria. 
Investigators should review, confirm and record whether the subject is suitable for 
participation in this study prior to enrollment.  
4.1. 
Inclusion Criteria 
Subjects can be enrolled in this study only when they meet all the inclusion criteria:  
1. Provided informed consent and sign the informed consent form;  
2.  Male or female, ≥ 18 years old;  
3. Histopathologically or cytologically confirmed HCC;  


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4. Subjects must be able to provide fresh or archived tumor tissue (formalin-fixed, 
paraffin-embedded [FFPE] tissue block or at least 5 unstained FFPE slides) as 
well as corresponding pathological report. If less than 5 unstained slides are 
available or tumor tissue is not available (e.g., used up due to previous 
diagnostic tests), subjects may be permitted to enroll on a case-by-case basis 
after discussion with the medical monitor; 
5. Barcelona Clinic Liver Cancer (BCLC) stage B or C (see APPENDIX 1 for 
BCLC classification), and not suitable for surgical or local therapy, or has 
progressed following surgical and/or local therapy;  
6. Local regional therapy (including but not limited to surgery, radiotherapy, 
hepatic artery embolization, TACE, hepatic arterial infusion, radiofrequency 
ablation, cryoablation or percutaneous ethanol injection) must has been 
completed at least 4 weeks (subjects received palliative radiotherapy at least 2 
weeks) prior to baseline radiological scanning, and any toxicity (except 
alopecia) induced by local regional therapy must have resolved to ≤ Grade 1 in 
accordance with National Cancer Institute – Common Terminology Criteria for 
Adverse Event version 4.03 (NCI-CTCAE v4.03);  
7. No previous systematic treatment for advanced HCC; 
8. Have at least one measurable lesion (in accordance with RECIST v1.1, major 
diameter ≥ 10 mm of the measurable lesion in spiral CT scan or short diameter 
of swollen lymph node ≥ 15 mm; the lesion with previous local therapy can be 
used as target lesion after the progression is confirmed in accordance with 
RECIST v1.1);  
9. Child-Pugh class (see APPENDIX 3 for Child-Pugh classification criteria): 
Grade A;  
10. ECOG-PS score (see APPENDIX 4 for ECOG-PS scoring criteria): 0-1; 
11. With a life expectancy of ≥ 12 weeks;  
12. Have the required screening laboratory values including the following 
parameters (within 7 days prior to the start of study treatment):  
(1) Hematology: (except for hemoglobin, no blood transfusion or use of 
granulocyte colony-stimulating factor [G-CSF] or use of drugs for 
correction within 14 days prior to screening);  
 Absolute neutrophil count ≥1.5×109/L; 
 Platelet count ≥ 75×109/L; 
 Hemoglobin ≥ 90 g/L; 
(2) Blood biochemistry: (no infusion of albumin within 14 days):  
 Albumin ≥ 29 g/L; 
 Total bilirubin ≤ 1.5×upper limit of normal (ULN);  
 Alanine aminotransferase (ALT), aspartate aminotransferase (AST) 
and alkaline phosphatase (ALP) ≤5×ULN;  
 Creatinine (Cr) ≤ 1.5×ULN or Cr clearance >50 mL/min 
(Cockcroft-Gault formula as below) 
 Male: Cr clearance =((140-age) ×weight)/ (72×blood Cr) 


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 Female: Cr clearance =((140-age) ×weight)/ (72×blood Cr) × 0.85 
 Weight unit: kg; Blood Cr unit: mg/mL;  
(3) International normalized ratio (INR) ≤2.3 or prothrombin time (PT) 
≤6s beyond normal range;  
(4) urine protein <2+ (subjects with urine protein ≥ 2+ may undergo 24-
hour (h) urine protein quantification and those with 24-h urine protein 
quantity of <1.0 g can be enrolled);  
13. If subjects have active hepatitis B (HBV) infection: HBV- deoxyribonucleic 
acid (DNA) must be < 500 IU/mL (or must be < 2500 copy/mL if copy/mL is 
the only unit available in the study site) and are willing to receive antiviral 
therapy throughout the study (treatment in accordance with local standard of 
care, e.g., entecavir); subjects with positive hepatitis C (HCV) ribonucleic acid 
(RNA) must receive antiviral therapy in accordance with the local standard 
treatment guideline and have ≤CTCAE Grade 1 elevated hepatic function;  
14. Women of childbearing potential (WOCBP): must agree to use a reliable and 
valid contraceptive method (refer to Section 4.4.1) following the date of 
signature of informed consent form until at least 120 days after the last dose of 
study drug. The blood HCG test must be negative within 7 days prior to 
enrollment in the study; and the subjects must not be in lactating period.  
If the female subject has menses, has not reached postmenopausal state 
(absence of menses for ≥ consecutive 12 months, with no other reason found 
except menopause) and has not received sterilization operation (e.g., 
hysterectomy, bilateral tubal ligation or bilateral ovariectomy), she would be 
considered to have childbearing potential.  
15. Male subjects whose partner are women of childbearing potential must agree 
to use  reliable and valid contraceptive method (Section 4.4.1) following the 
date of signature of informed consent form till at least 120 days after the last 
dose of study drug. Male subjects must also agree to abstain from donation of 
sperm in the same period. Male subjects whose partners are pregnant must use 
a condom and no other contraceptive method is not required.  
4.2. 
Exclusion Criteria 
Subjects who meet any one of the following criteria must not be enrolled in this study:  
1. Known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma 
and lamellar cell carcinoma; other active malignant tumor except HCC within 
5 years or simultaneously. Cured localized tumor, for example, basal cell 
carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, 
carcinoma in situ of prostate, carcinoma in situs of cervix, breast cancer in situ 
may be enrolled;  
2. Planning to or previously received organ or allogenic bone marrow 
transplantation;  
3. Moderate-to-severe ascites with clinical symptoms, i.e., requiring therapeutic 
puncture or drainage, or Child-Pugh score >2, except the subjects with small 
amount of ascites in radiological examination but free from clinical symptoms; 


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uncontrolled or moderate to severe pleural effusion, pericardial effusion.  
4. History of gastrointestinal bleeding within 6 months prior to the start of study 
treatment or clear tendency of gastrointestinal bleeding, for example, at risk of 
bleeding or severe esophagogastric varices, locally active peptic ulcer, 
persistent fecal occult blood (+) (the fecal occult blood test should be repeated 
if it is positive at baseline, and gastroduodenoscopy [EGD] would be needed if 
it is still positive in repeated test; the subject can not be enrolled if the EGD 
shows 
esophageal and fundal varices with 
hemorrhagic 
risk 
or 
other 
gastrointestinal disorder with risk of bleeding);  
5. Abdominal fistula, gastrointestinal perforation or intraperitoneal abscess within 
6 months prior to the start of study treatment;  
6. Known genetic or acquired hemorrhage (e.g., coagulation dysfunction) or 
thrombotic tendency, for example, subject with hemophilia; current or recent 
(within 10 days prior to the start of study treatment) use of full-dose of oral or 
intravenous anticoagulant or thrombolytic drug for the purpose of treatment 
(preventive use of low-dose aspirin or low molecular weight heparin is 
allowed); 
7. Current or recent (within 10 days prior to the start of study treatment) use of 
aspirin (> 325 mg/day, maximum dose for antiplatelet) or dipyridamole, 
ticlopidine, clopidogrel and cilostazol;  
8. Thrombosis or thromboembolic event within 6 months prior to the start of study 
treatment, for example, cerebrovascular accident (including transient ischemic 
attack, cerebral hemorrhage, cerebral infarction), pulmonary embolism;  
9. Cardiac clinical symptom or disease that is not well controlled, for example, 
(1) > Grade II cardiac insufficiency in accordance with New York Heart 
Association (NYHA) criteria (see APPENDIX 5) or color Doppler 
echocardiography: LVEF (left ventricular ejection fraction) <50%; (2) unstable 
angina pectoris; (3) myocardial infarction within one year prior to the start of 
study treatment; (4) clinically significant supraventricular or ventricular 
arrhythmia requiring treatment or intervention; (5) QTc > 450ms (man) or QTc > 
470ms (woman) (QTc interval is calculated by Fridericia formula; In case QTc 
is abnormal, it can be evaluated for three times at an interval of 2 minutes and 
the average value will be used);  
10. Hypertension that can not be well controlled through antihypertensive drugs 
(systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) 
(based on the average of BP readings acquired from ≥ 2 measurements), 
allowing to reach the above parameters by the use of antihypertensive therapy; 
previous hypertensive crisis or hypertensive encephalopathy;  
11. Major vascular disease within 6 months prior to the start of study treatment (for 
example, aortic aneurysm requiring surgical repair or peripheral arterial 
thrombosis in recent days);  
12. Serious, uncured or splitting wound and active ulcer or untreated bone fracture;  
13. Major surgical therapy within 4 weeks prior to the start of study treatment 
(except diagnosis), or expected major surgery during the study;  


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14. Inability to swallow tablets, malabsorption syndrome or any condition affecting 
gastrointestinal absorption;  
15. Intestinal obstruction and/or clinical signs or symptoms of gastrointestinal 
obstruction within 6 months prior to the start of study treatment, including 
incomplete obstruction that is related with the original disease or needs routine 
parenteral hydration, parenteral nutrition or tube feeding;  
 
If the subject has signs/symptoms of incomplete obstruction/ obstructive 
syndrome/intestinal obstruction at the initial diagnosis receives clear 
(surgical) therapy to resolve symptoms, the subject may be enrolled;  
16. Evidence on intraperitoneal pneumatosis that can not be explained by puncture 
or recent surgery;  
17. Previous or current presence of metastasis to central nervous system;  
18. Metastatic disease involving main airway or blood vessels (e.g. vena cava  
tumor invasion or complete occlusion of the major portal vein due to HCC, the 
major portal vein is defined as the part of portal vein between the union of the 
splenic and superior mesenteric veins and the first bifurcation into the left and 
right vein) or high-volume mediastinal tumor mass located in the center 
(distance from carina ˂30 mm);  
19. History of hepatic encephalopathy;  
20. Current interstitial pneumonia or interstitial lung disease, or history of 
interstitial pneumonia or interstitial pneumonia requiring hormonal therapy, or 
other pulmonary fibrosis that may interfere with the judgement and treatment 
of immune-related pulmonary toxicity; organizing pneumonia (e.g., 
obliterative bronchiolitis), pneumoconiosis, drug related pneumonitis, 
idiopathic pneumonia, subjects with evidence on active pneumonia or serious 
pulmonary function impairment on thoracic computed tomography (CT) in 
screening period (previous radiation pneumonitis in the radiation area will be 
allowed);active tuberculosis;  
21. Active autoimmune disease or history of autoimmune disease and may relapse 
(including but not limited to autoimmune hepatitis, interstitial pneumonia, 
uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, 
hypothyroidism [with the exception that it can be controlled by hormone 
replacement therapy]). Subjects with skin diseases that do not require systemic 
treatment are eligible, for example, leukoderma, psoriasis, alopecia, subjects 
with controlled type 1 diabetes by insulin are eligible; subjects with asthma that 
has been completely resolved in childhood and don’t need any treatment are 
eligible, but subjects with asthma that require a bronchodilator as medical 
intervention are not eligible; 
22. Use of immunosuppressive medication within 14 days prior to the start of study 
treatment, or systemic corticosteroid therapy to achieve the objective of 
immunosuppression (Prednisone at the dose of >10 mg/day or equivalent);  
23. Use of strong CYP3A4/CYP2C19 inducers, including rifampicin (and its 
analogues) and St. John’s Wort, or strong CYP3A4/CYP2C19 inhibitors within 
14 days prior to the start of study treatment;  


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24. Known history of hypersensitivity to the active substance or to any other 
components of each investigational medicinal product as SHR-1210, 
rivoceranib, sorafenib or other monoclonal antibody or targeted anti-
angiogenic drug;  
25. Severe infection within 4 weeks prior to the start of study treatment, including 
but not limited to hospitalization for infection, bacteremia or complications of 
severe pneumonia; oral or intravenous therapeutic antibiotics within 2 weeks 
prior to the start of study treatment (subjects who are treated with preventive 
antibiotics for prevention, e.g., preventive urinary tract infection or 
exacerbation of chronic obstructive pulmonary disease are eligible for 
participation in the study);  
26. Congenital or acquired immunodeficiency (e.g., HIV infection); 
27. Hepatitis B and hepatitis C co-infection;  
28. Previous treatment with other PD-1 antibody or other immunotherapy against 
PD-1/PD-L1, or previous use of rivoceranib or sorafenib;  
29. Attenuated live vaccine therapy administered within 28 days prior to the start 
of study treatment, or are expected to receive vaccines during SHR-1210 
treatment or within 60 days after the last dose of SHR-1210;  
30. Treatment of other investigational product(s) within 28 days or 5 half-lives 
(whichever is longer) prior to the start of study treatment;  
31. Other factors that may affect the study results or lead to forced termination of 
the study early as judged by investigators, such as alcoholism, drug abuse, other 
serious diseases (including mental disorders) requiring concomitant therapy, 
with serious laboratory examination abnormality, with family or social factors, 
that may affect subject’s safety.  
4.3. 
Randomization Criteria 
Subjects who enter screening and meet the inclusion/exclusion criteria after signing the 
informed consent form, will be randomized in a 1:1 ratio to SHR-1210 combined with 
rivoceranib mesylate group (experimental arm) or sorafenib group (control arm). 
Randomization stratification factors are as follows: 
1. Macrovascular invasion and/or extrahepatic metastasis (presence vs. absence) 
2. Geographical region (Asia vs. countries outside of Asia) 
3. Baseline AFP (AFP < 400 ng/mL vs. AFP ≥ 400 ng/mL) 
4.4. 
Lifestyle Requirements 
4.4.1. 
Contraception 
Male subjects with azoospermia (due to vasectomy or other underlying disease) and 
partners do not need to take contraception. 
Female subjects are considered as not of childbearing potential if: 
(1) Postmenopausal (defined as absence of menses for at least 12 months without other 
medical reasons; female subjects younger than 45 years of age without hormonal 


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contraception or hormone replacement therapy whose follicle-stimulating hormone 
(FSH) levels reached postmenopausal levels). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient; 
Or  
(2) having hysterectomy and/or bilateral ovariectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion surgery at least 6 weeks prior to screening; 
Or  
(3) the presence of congenital or acquired conditions leading to infertility. 
Female subjects of childbearing potential and male subjects with partners who are 
women of childbearing potential are required to use to contraception and follow one of 
the following contraception requirements, from the time the subject signs the informed 
consent until at least 120 days after the last dose of study drug: 
(1) Abstinence (avoid heterosexual intercourse) †. 
Or 
(2) use a reliable and effective method of contraception during heterosexual intercourse. 
Reliable, effective methods of contraception include: 
Single method of contraception (any one of the following methods): 
• Intrauterine device (IUD) 
• Subcutaneous implant contraception  
Two methods combined contraception (two of the following methods must be used 
simultaneously): 
• Vaginal 
diaphragm/spermicide 
(cannot 
be 
combined 
with 
cervical 
cap/spermicide) * 
• Cervical cap/spermicide (only for women who have not given birth) *  
• Contraceptive sponge (only for women who have not given birth) * 
• Male condom or female condom (not used concurrently) 
• Hormonal contraception: Oral contraceptives (estrogen/progesterone or 
progesterone), contraceptive patch, vaginal contraceptive ring, or subcutaneous 
injection contraceptives 
† For those who choose to completely not have a sexual life, abstinence (avoiding 
heterosexual intercourse) can be used alone for contraception. Periodic abstinence (e.g., 
based on ovulation, symptomatology etc.) and external ejaculation are not reliable and 
effective contraception. 
In addition, the subject needs to be aware that once he/she stops using the selected 
contraceptive method, or he/she or his/her partner is suspected or confirmed to be 
pregnant, the investigators need to be notified immediately. 


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4.5. 
Subjects’ Withdrawal from the Study or Discontinuation of Study 
Treatment 
4.5.1. 
Criteria for Discontinuation of Study Treatment 
Discontinuation of study treatment do not represent withdrawal from the study. Subjects 
who discontinued study treatment should continue to complete the remaining study 
visits as required in the protocol. Subjects should discontinue study treatment when any 
of the following conditions occurs:  
 Subject requests discontinuation of study treatment;  
 Efficacy evaluation meets criteria for progression of disease confirmed by 
BIRC (according to RECIST v1.1), unless investigator considers the subject 
still has clinical benefit and meets the criteria for treatment beyond progression 
(Disease progression will be confirmed by the investigator per RECIST v1.1 
upon approval of Protocol v6.0; other procedures and criteria remain 
unchanged, see Section 6.6 of the protocol); 
 Pregnancy in female subject occurs during the study; 
 Unacceptable toxicity despite dose modification, or occurrence of adverse 
event, abnormal laboratory examination, or concomitant diseases, then it is no 
longer in the best interests of the subjects to continue study treatment according 
to the judgment of the investigator;   
 Overall deterioration of health status, inability to continue participation in the 
trial;  
 Significant protocol deviation or violations confirmed by sponsor, e.g., 
ineligibility of subjects after enrollment;  
 Termination of study by the sponsor;  
 
Other reasons for inability to continue study treatment, as considered by 
investigators.  
4.5.2. 
Criteria for Withdrawal from the Study 
Subjects can withdraw from the study voluntarily at any time, or at the request of the 
investigator or the sponsor for safety or behavioral reasons, or inability to comply with 
the visit schedule or procedure required in the protocol at his/her study site. 
The reasons for withdrawal from the study may include:  
 Withdrawal of the informed consent on participation in the study, and refusal 
of further follow-up;  
 Any conditions which require subject’s withdrawal, per Investigator’s 
discretion e.g., subject’s loss of the ability to express his/her wishes freely due 
to imprisonment or segregation;  
 Lost to follow-up;  
 Termination of study by the sponsor. 


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4.5.3. 
The Procedures of Withdrawal from the Study or Discontinuation of 
Study Treatment 
Subjects should comply with the follow-up schedule specified in the protocol after 
discontinuation of study treatment. The efficacy and safety examination specified in the 
protocol at the end of treatment, and safety follow-up should be completed, and the full 
records of AEs and outcomes, concomitant medications/therapy should be provided. 
Investigators can advise or provide new or alternative therapeutic method to subjects 
according to their actual condition. The subjects with no progression of disease need to 
continue the radiological evaluation according to the scheduled frequency and time, 
until start of a new antitumor therapy or progression of disease. The radiological 
evidence on progression of disease should be obtained as much as possible for such 
subjects.  
If subject refuses to return to the site for further visit, his/her survival status should still 
be followed up, unless the subject withdraws the consent on disclosure of further 
information or continuous contact. If the subject requests withdrawal from the study 
clearly, the investigator should record the extent of subject’s request on withdrawal 
from the study procedure in a written form, i.e., only withdrawal from study treatment 
and/or withdrawal from post-treatment follow-up. When it is necessary to know the 
survival state, only the publicly available information should be used appropriately to 
determine whether the subject survives.  
4.5.4. 
Lost to Follow-Up 
Every possible effort must be made to know and report the subject’s status, including 
contact with the subject. Lost to follow-up is defined as no response to at least three 
contacts. The contact method includes but is not limited to any of the following: 
telephone, fax, message, social media tools and email. All the attempts to make contact 
should be recorded in the medical document. If the subject is confirmed to be dead, the 
study center will use a permitted method to acquire the information on death and cause 
of death. The study center can also utilize public resources, for example, community 
health registry and database, to obtain the contact information. If the subject’s status 
can still not be acquired after all the attempts have been made, investigators should 
report the last date when the subject is known to be survived and record it in the medical 
record.  
4.6. 
Early Termination or Suspension of Study 
The study can be terminated or interrupted prematurely if the reason is sufficient. This 
may be due to the decision of regulatory agency, IRB/EC’s opinion, Data Monitoring 
Committee (DMC)’s opinion, or efficacy or safety issues of the investigational product, 
or base on the sponsor’s judgment. In addition, Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. reserves the right to stop research and development of SHR-1210 at any time. The 
party who makes the decision on termination/interruption of the study will send a 
written notice which records the reason for study termination or interruption to 
investigators, sponsor and regulatory authorities. Investigators should notify the ethics 
committee and the sponsor immediately and provide relevant reasons. 
The reasons for premature termination or interruption of the study may include: 


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 
Discovery of unexpected, significant or unacceptable risk;  
 
The efficacy data support early termination of the study; 
 
Low compliance with study requirements. 
Once the aforementioned drug safety, protocol compliance and data quality issues 
causing study interruption are solved and after obtaining the consent of the sponsor, the 
ethics committee or the local regulatory authority, the study can proceed. 
4.7. 
Definition of End of Study 
Definition of end of study is as follows: 
The date when the last subject randomized has been followed for at least 2 years.  
5. 
STUDY TREATMENT 
5.1. 
Description of the Investigational Product 
5.1.1. 
Acquisition and Accountability 
Management, dispensing and recovery of the investigational product for this clinical 
study will be performed by designated person. Investigators must make sure all the 
investigational products are only used for the subjects who participate in this clinical 
trial, the dosage and administration method should be in accordance with the protocol, 
the remaining drugs should be given back to the sponsor and must not be used for any 
treatment besides this study. 
The study drug should be stored under the conditions specified in the study protocol. 
The drug receipt form must be signed by both parties in duplicate when the drugs are 
dispensed to sites, one for the clinical research center and the other for the sponsor. At 
the end of the study, the remaining drugs and empty boxes will be returned, and the two 
parties need to sign the drug return form. The dispensation and return of study drug 
should be recorded on a specialized form in time. 
Monitors are responsible for monitoring the supply, use, storage of the investigational 
drug and disposing the remaining drug. 
5.1.2. 
Formulation, Appearance, Packaging and Storage of Drug 
Information on SHR-1210 for injection, rivoceranib mesylate tablets and sorafenib 
tosylate tablets are as below（pls. refer to the pharmacy manual in details）:  
Experimental arm: SHR-1210 for Injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: injection (lyophilised powder) 
Strength: 200 mg /vial 
Package: vial 
Administration: intravenous infusion 


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Validity: 24 months  
Storage: Store in a refrigerator (2°C - 8°C). Do not freeze, protect from light 
Experimental arm: rivoceranib mesylate tablets 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: film-coated tablet 
Strength: 0.25 g 
Package: 10 tablets/blister/box 
Administration: oral 
Validity: 24 months 
Storage: Protected from light, stored in closed container/closure at no more than (NMT) 
25ºC 
For the United States of America: Store at 20ºC to 25ºC (68°F to 77°F), excursions 
permitted to 15ºC to 30ºC (59°F to 86°F), [see USP Controlled Room Temperature]. 
Keep away from light  
Control arm: sorafenib tosylate tablets 
Manufacturer: Bayer AG 
Dosage form: film-coated tablet/tablet 
Strength: 0.2 g 
Package: 10 tablets/blister*8 blisters/box (mainland of China), 28 tables/blister*3 
blisters/box (other countries and regions beyond mainland of China) 
Administration: oral 
Validity: 36 months 
Storage: Do not store above 25°C 
5.1.3. 
Storage and Stability 
Investigators or their authorized representatives (e.g., pharmacist) will ensure all the 
investigational products are stored in a controlled secure area that meets the storage 
conditions (see storage conditions in Section 5.1.2), and the storage is in accordance 
with the requirements of applicable laws. 
The study center must be able to record the highest and lowest temperatures per working 
day for all study drugs storage locations (e.g., freezing, cold storage or room 
temperature). The cycle of recording should start with receiving drugs until all the 
remaining study drugs are recovered. Even though there is a continuous monitoring 
system, the study center should also keep record logs to ensure the correct storage 
temperature. The temperature monitoring devices and storage devices (e.g., freezer) 
should be checked on a regular basis, as to ensure it functions normally.  
Any deviations from the recommended storage conditions on the product label should 
be reported promptly to the sponsor. The study center should take active measures as 


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early as possible to place the product under the storage conditions described on the label, 
meanwhile, the temperature deviation and measures taken will be reported to the 
sponsor.  
The study drug affected by the temperature deviation should be isolated temporarily in 
the environment meeting the storage conditions, only can be used until receiving the 
permission by the sponsor. The sponsor will provide the study center with detailed steps 
to report the temperature deviation. 
5.1.4. 
Preparation 
Preparation of SHR-1210 is provided in the investigational product manual in detail.  
5.1.5. 
Dose Regimen 
Each treatment cycle is defined as 4 weeks (28 days). Dose regimens during treatment 
period are shown in Table 7. 
Table 7 
Dosing Regimens for Each Treatment Cycle 
Experimental 
arm: 
SHR-1210 
combined 
with 
rivoceranib 
Rivoceranib  250 mg, once per day (QD) orally, after meals within 30 minutes, 
for administration, one treatment cycle is 4 weeks (28 days).  
SHR-1210 
SHR-1210 intravenous infusion at a dose of 200 mg over 30 
minutes (no less than 20 minutes and no more than 60 minutes, 
including a wash-out period), once every two weeks (Q2W), one 
treatment cycle is 4 weeks (28 days). Complete administration 
before ECG if possible. The interval between two doses should not 
be less than 12 days.  
On the day of rivoceranib PK blood sampling, rivoceranib 
should be administrated at the study center before SHR-1210, 
see SCHEDULE OF ACTIVITIES and BLOOD SAMPLE 
COLLECTION TABLE for details.  
Control arm: 
Sorafenib 
Sorafenib 
400 mg, twice per day (BID), orally under fasted state (at least 1 
hour prior to a meal or 2 hours after a meal), for continuous 
administration, one treatment cycle is 4 weeks (or 28 days). 
 
If a subject in the experimental arm (SHR-1210 in combination with rivoceranib) 
develops a treatment-related AE that leads to permanent discontinuation of rivoceranib 
and the investigator determines that the subject can benefit from SHR-1210 
monotherapy, the subjects may continue to receive SHR-1210 monotherapy until 
meeting the criteria for study treatment discontinuation as specified in this protocol, 
and vice versa. In addition, during the study treatment period, if a subject in the 
experimental arm develops a treatment-related AE that leads to temporary 
discontinuation of SHR-1210 or rivoceranib, the subject may continue to receive 
monotherapy, and the combination therapy can be resumed only after the toxicity 
resolves. 
Study treatment will continue until the subject develops an intolerable toxicity, 
withdrawal of informed consent, and disease progression confirmed by BIRC according 
to RECIST v1.1 (when the subject appears to have met the criteria for disease 


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progression assessed by the investigator according to RECIST v1.1, the investigator 
must submit the radiological data to BIRC immediately. If BIRC evaluates it as non-
disease progression according to RECIST v1.1, the subject should continue to receive 
the study drug treatment and continue the tumor radiological evaluation; if BIRC 
confirms it as disease progression based on RECIST V1.1, at this time, the investigator 
needs to assess whether the subject still has clinical benefit. If the subject is considered 
to still have clinical benefit and meets the criteria for continuing treatment after the 
disease progresses [see Section 6.6 for details] the subject may continue to receive study 
treatment; if the subject is no longer considered to have clinical benefit , the treatment 
may be discontinued),or other discontinuation criteria specified in the protocol, 
whichever occurs first. Administration 3 days after the date of intended SHR-1210 
administration will be considered as delayed administration. Upon the approval of 
protocol v6.0, disease progression will be only judged by investigator per RECIST v1.1. 
If a subject missed a dose of rivoceranib and it was ≥12 hours away from next planned 
dose, the rivoceranib dose should be made up on current day, if < 12 hours away from 
next planned dose, that dose should be skipped and dosing resumed at subsequent dose 
as planned, without doubling the dose of the next day. If a subject receives an overdose 
of rivoceranib, contact the investigator immediately. 
If a subject missed a dose of sorafenib at a scheduled timepoint, the missed dose will 
not be made up and the next dose should be taken as planned. If the subject has an 
overdose of sorafenib, contact the investigator immediately.  
Any vomiting after administration with sorafenib or rivoceranib should not be made up.  
5.1.6. 
Dose Adjustment and Safety Management 
5.1.6.1. Dose Adjustment 
5.1.6.1.1. Criteria for Dose Adjustment of SHR-1210  
Dose adjustment is not allowed for SHR-1210, only dose interruption is allowed.  
5.1.6.1.2. Criteria for SHR-1210 Dose Delay 
The dose of SHR-1210 should be delayed if the following conditions occur:  
• 
Any ≥ Grade 2 drug-related non-cutaneous AE, except Grade 2 drug-related fatigue 
or laboratory abnormalities (unless otherwise specified);  
• 
Any Grade 3 drug-related cutaneous AE;  
• 
Any Grade 3 drug-related laboratory abnormalities, except Grade 3 abnormal 
amylase or lipase unrelated with the symptoms and clinical manifestations of 
pancreatitis;  
• 
The administration will be delayed if the following AST, ALT or total bilirubin 
abnormalities occur:  
– AST and ALT at baseline are within the normal range, and drug-related 
elevated AST or ALT reaches >3×ULN;  
– AST or ALT at baseline elevates no greater than Grade 1, and drug-related 


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elevated AST or ALT reaches >5×ULN; 
– AST or ALT at baseline elevates no greater than Grade 2, and drug-related 
elevated AST or ALT reaches >2 times the baseline or either AST or ALT 
reaches >8×ULN (whichever is lower); 
– Total bilirubin at baseline is within the normal range, and drug-related elevated 
total bilirubin reaches >2×ULN; 
– Total bilirubin at baseline elevates no greater than Grade 1, and drug-related 
elevated total bilirubin reaches >2 times the baseline. 
• 
The administration needs to be delayed for any AE, laboratory abnormalities or 
complications, as judged by investigators;  
• 
If RCEP occurs during the trial, refer to APPENDIX 7 for detailed suggestions on 
grade and management of RCEP. 
• 
If subjects have fever (>38°C) and need medication, or obvious symptoms of 
asthma, shortness of breath, and asphyxia during the trial, SHR-1210 will not be 
given any more at this or next scheduled time point before the symptom is 
recovered. SHR-1210 will be resumed after the symptom is relieved and stabilized 
for more than 7 days, and pneumonia will be excluded through radiological 
examination prior to administration if necessary.  
Subjects who need delayed dose should be monitored every week, and the frequency of 
monitoring can be increased if clinically indicated. It is recommended to monitor liver 
function every three days, until the highest value of AST or ALT starts to decrease. 
When meeting the criteria for resumption of medication (see Section 5.1.6.1.3), the 
study drug can be resumed.  
Tumor evaluation still needs to proceed for all subjects, as required in the protocol, 
regardless of dose delay. During the period of dose delay, safety visits and laboratory 
examinations should also be performed as planned in the protocol, or more frequently 
when clinically indicated (see SCHEDULE OF ACTIVITIES Footnote [4]).  
5.1.6.1.3. Criteria for Resumption of SHR-1210  
When drug-related AE recover to Grade 1 (or lower grade) or baseline level, SHR-1210 
study treatment can be resumed, except the following:  
• 
The therapy can be resumed for the subjects with Grade 2 fatigue that has not been 
recovered;  
• 
The therapy can be resumed for Grade 2 cutaneous AE;  
• 
Subjects with AST, ALT or TBIL grade 1 elevation at baseline, and delayed SHR-
1210 for reasons other than drug-related hepatic AE, the therapy can be resumed in 
the presence of AST, ALT or TBIL Grade 2 elevations; 
• 
As the subjects who delay the dose for drug related elevated AST, ALT or TBIL, 
when these parameters are recovered to baseline CTCAE grade or normal (see 
Section 5.1.6.1.4) but who have not reached the criteria for permanent 
discontinuation of the treatment, the study drugs can be resumed;  


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• 
The therapy can be resumed for drug related grade 2 laboratory abnormalities in 
GGT and/or ALP increase;  
• 
In case the drug related endocrine disorder can be sufficiently controlled only with 
hormone replacement at physiological dose, the treatment can be resumed.  
The dose of SHR-1210 is allowed to be delayed for up to 12 weeks, as calculated from 
the last dose. In case the subject still does not reach the criteria for dose resumption 
after delay for 12 weeks, the study drug needs to be discontinued permanently, except 
the exception mentioned in the Section 5.1.6.1.4. The guideline on management of 
adverse reactions is seen in APPENDIX 6 in detail. Rules for hepatic AEs management 
can be referred to in Section 5.1.6.2.2. 
5.1.6.1.4. Criteria for Permanent Discontinuation of SHR-1210 
The study drug SHR-1210 must be discontinued permanently when the following 
conditions occur:  
• 
Any Grade Stevens-Johnson syndrome and toxic epidermal necrolysis; 
• 
Any Grade 2 drug-related uveitis, ophthalmodynia and blurred vision that has no 
response to local therapy and is not recovered to Grade 1 after delayed dose; or the 
above AE requiring systemic therapy;  
• 
Any Grade 3 drug-related non-cutaneous AE lasting for >7 days, except the 
following:  
- 
When any Grade 3 drug-related uveitis, myocarditis, encephalitis, pneumonia, 
bronchospasm, hypersensitivity or infusion reaction occurs, the study 
treatment must be terminated;  
- 
In case the drug-related endocrine disorders can be sufficiently controlled only 
with hormone replacement therapy at physiological doses, the treatment does 
not need to be terminated; 
- 
The treatment does not need to be terminated for Grade 3 drug-related 
abnormal laboratory examination, however, the study drug must be terminated 
for Grade 3 thrombocytopenia >7 days or related with bleeding.  
• 
Hepatotoxicity meeting the following:  
- 
AST or ALT >10 times of ULN for over two weeks;  
- 
ALT or AST >15 × ULN; 
- 
TBIL >8 times of ULN for subjects with elevated TBIL at baseline, >5 times 
of ULN for subjects with normal TBIL at baseline.  
• 
Any Grade 4 drug-related AE or abnormal laboratory examination, except the 
following:  
- 
Grade 4 granulocytopenia is less than7 days; 
- 
Grade 4 lymphopenia or leukopenia; 
- 
Isolated Grade 4 elevated amylase or lipase, without symptoms or clinical 
manifestations of pancreatitis;  


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- 
Isolated Grade 4 electrolyte imbalance/abnormality without clinical sequela 
that could be corrected through supplements/appropriate management within 
72h after occurrence; 
- 
If Grade 4 drug-related endocrine disorders that can be sufficiently controlled 
only with hormone replacement therapy at physiological doses, the treatment 
does not need to be discontinued.  
• 
The study treatment must be discontinued if SHR-1210 needs to be delayed 
for >12 weeks, except the following:  
- 
After the use of cortisol for treatment of drug-related AEs, the dose of 
SHR-1210 is allowed to be delayed for >12 weeks due to the need for dose 
tapering. Discussion with the sponsor must be made before resuming the dose. 
During the dose delay, tumor assessment should continue as required by the 
protocol. Safety visits and laboratory tests should also be performed at the 
original frequency or more frequently if clinically indicated (see SCHEDULE 
OF ACTIVITIES Footnote [4]); 
- 
SHR-1210 delay for >12 weeks due to non-drug related reasons must be 
discussed with the sponsor prior to resuming treatment. During the dose delay, 
the tumor evaluation should still proceed as required in the protocol. Safety 
visits and laboratory examinations should also be performed as planned in the 
protocol or more frequently when clinically indicated (see SCHEDULE OF 
ACTIVITIES Footnote [4]); 
• 
For intolerable or persistent Grade 2 drug-related AE, the dose of SHR-1210 can 
be interrupted as appropriate, if the treatment-related toxicity can not be 
recovered to Grade 0-1 12 weeks after the last dose of SHR-1210, the drug should 
be discontinued permanently.  
• 
If any drug-related AE (except endocrine lesions) of ≥ Grade 3 (≥ Grade 2 for 
pneumonia) reoccurs, discontinuation of the study treatment can be considered, 
which may be judged by the investigator according to the condition of each subject; 
• 
Judged by investigators, clinical AE, laboratory abnormalities or complications 
may bring major risk to subjects who continue taking the study drug;  
• 
Progression of disease confirmed by BIRC in accordance with RECIST v1.1 (see 
APPENDIX 2 for details) (unless the subject meets the criteria for treatment 
beyond progression in Section 6.6).  
Even though SHR-1210 is discontinued, subjects must continue to perform tumor 
evaluation as required in the protocol.  
After SHR-1210 is discontinued, subjects are allowed to continue rivoceranib 
monotherapy if they are judged by investigators to be able to benefit from rivoceranib 
monotherapy, until occurrence of the events which meet the criteria for discontinuation 
of treatment specified in the protocol.  
5.1.6.1.5. Criteria for Dose Modification of Rivoceranib 
Dose modification methods resulted from rivoceranib-related toxicities include dose 
interruption, adjustment of administration schedule (first adjustment: take 5 days 


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followed by interruption of the drug for 2 days (5 days on 2 days off [5 on 2 off]); re-
adjustment: once every other day [QOD]) and termination of rivoceranib. After the 
administration schedule of rivoceranib is adjusted during the study, will not allow going 
back to initial administration schedule. 
If rivoceranib-related AEs definitely occur during the trial, for example, hypertension, 
proteinuria, hand-foot syndrome, rivoceranib can be interrupted; when the toxicity is 
recovered, maintenance of dose at the current dose level, adjustment of administration 
schedule or discontinuation of dose can be given as appropriate. The subject can 
continue to receive SHR-1210 monotherapy after rivoceranib is discontinued. 
Referring to the experience in phase II clinical studies, the investigator must interrupt 
the dose of SHR-1210 and rivoceranib at the same time (See Section 5.1.6.1.2 criteria 
for SHR-1210 dose delay reference), for the confirmed immune-related toxicities 
during the trial, in particular immune pneumonia/pneumonitis, hepatitis, increased AST, 
ALT, bilirubin, diarrhea or colitis, increased creatinine. The dose can be resumed when 
the toxicity is recovered to ≤Grade 1 or baseline level (for subjects with abnormal ALT, 
AST and TBIL during baseline). It is recommended to resume SHR-1210 first, and then 
administer rivoceranib after 7-14 days of no significant abnormality observed after 
administration of SHR-1210. The subsequent administration schedule for rivoceranib 
will be adjusted (first adjustment: 5 days on 2 days off [5 on 2 off]; re-adjustment: once 
every other day [QOD]).  
Changes in blood pressure should be monitored routinely during rivoceranib 
administration. It is advisable to interrupt the dose of rivoceranib firstly in case Grade 
3 elevated blood pressure occurs (systolic blood pressure ≥ 160mmHg or diastolic blood 
pressure ≥ 100mmHg or more than one antihypertensive agent is needed) and perform 
antihypertensive therapy under specialist’s instructions. Rivoceranib can be resumed 
when the blood pressure is decreased to normal range (systolic blood pressure < 140 
mmHg and diastolic blood pressure < 90 mmHg). If there is still hypertension, the 
administration schedule of rivoceranib must be adjusted. For subjects with hypertensive 
crisis (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 120mmHg, 
and/or with progressive insufficiency of target organs), the rivoceranib should be 
discontinued immediately and symptomatic treatment should be given actively 
(antihypertension, dehydration, anti-convulsion and so on).  
Dose interruption use and adjustment of administration schedule of rivoceranib is 
needed for ≥ Grade 3 hematological toxicities or ≥ Grade 2 non-hematological 
toxicities; for the non-hematological toxicities, symptomatic treatment can be given 
actively for controllable nausea, vomiting and fever with determined cause (<38oC), 
with no need of immediate dose interruption or adjustment of administration schedule.  
Symptomatic treatment should be given promptly for the symptom/sign or laboratory 
abnormalities during the trial, and it is recommended to refer to the following table for 
corresponding dose modification:  


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Table 8 
Dose Adjustment Plan of Rivoceranib 
Drug-related toxicity 
Grade 
Dose interruption of 
rivoceranib (Yes or 
No) 
Criteria on dose 
resumption of 
rivoceranib 
Dosage modification 
method of 
rivoceranib 
Criteria on discontinuation of rivoceranib 
Hematologic toxicities 
Grade 1, Grade 2 
No 
— 
—  
— 
Grade 3 
Yes (except 
lymphocyte count 
decreased) 
When the toxicity is 
recovered to ≤Grade 
2 
First time: at original 
dose 
Second time: 5 days on 
2 days off; 
Third time: once every 
other day 
If Grade 3 or above hematological toxicities 
recur after adjustment for twice, dose of 
rivoceranib must be discontinued.  
Grade 4 
Yes 
When the toxicity is 
recovered to ≤Grade 
2 
First time: 5 days on 2 
days off; 
Second time: once 
every other day 
Other non-hematologic 
toxicity 
Grade 1 
No 
— 
—  
— 
Grade 2 (lasted for 
≥ 7d) 
Yes 
When the toxicity is 
recovered to ≤Grade 
1 
Original dose 
—; 
Grade 3 
Yes 
When the toxicity is 
recovered to ≤Grade 
1 or baseline 
First time: 5 days on 2 
days off;  
Second time: once 
every other day 
If Grade 3 non-hematological toxicities recur 
after adjustment for twice, rivoceranib must be 
discontinued*.  
Grade 4 
Yes 
— 
Permanently 
discontinue 
rivoceranib 
Terminated administration of rivoceranib 


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Drug-related toxicity 
Grade 
Dose interruption of 
rivoceranib (Yes or 
No) 
Criteria on dose 
resumption of 
rivoceranib 
Dosage modification 
method of 
rivoceranib 
Criteria on discontinuation of rivoceranib 
Hypertension 
Grade 3  
Yes 
When the toxicity is 
recovered to ≤Grade 
1  
First time: resume the 
dose at original dose 
level 
Second time: 5 days on 
2 days off; 
Third time: once every 
other day 
If Grade 3 hypertension recurs after adjustment 
for twice, rivoceranib must be discontinued.  
Hypertensive crisis 
Yes 
— 
Permanently 
discontinue 
rivoceranib 
Terminated administration of rivoceranib 
Proteinuria 
(without significantly 
elevated blood 
creatinine) 
Grade 3 (24h urine 
protein 
(quantitative)) 
Yes 
When the toxicity is 
recovered to ≤Grade 
2 
First time: 5 days on 2 
days off; 
Second time: once 
every other day 
If Grade 3 proteinuria recurs after adjustment 
for twice, rivoceranib must be discontinued.  
Hand-and-foot 
syndrome 
Grade 3 
Yes 
When the toxicity is 
recovered to ≤Grade 
1 
First time: 5 days on 2 
days off;  
Second time: once 
every other day 
If Grade 3 hand-foot syndrome recurs after 
adjustment for twice, rivoceranib must be 
discontinued.  
Headache 
Grade 2 headache 
lasted for ≥ 7d after 
symptomatic 
treatment, or Grade 
3 headache 
Yes 
When the toxicity is 
recovered to ≤Grade 
1 
First time: 5 days on 2 
days off;  
Second time: once 
every other day 
If headache recurs after adjustment for twice, 
rivoceranib must be discontinued.  
*: If cerebral hemorrhage, ≥ Grade 2 pulmonary hemorrhage, ≥ Grade 3 other hemorrhage, arterial thrombosis, leukoencephalopathy syndrome, gastrointestinal 
perforation, or nephrotic syndrome occurs during the trial, rivoceranib will be permanently discontinued and symptomatic treatment will be given actively, and 
subsequently a decision will be made on whether SHR-1210 monotherapy should be continued based on the recovery of toxicity. If Stevens-Johnson syndrome or 
toxic epidermal necrolysis occurs, permanently discontinue rivoceranib and SHR-1210. 


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For the significant toxicity that is still ongoing after symptomatic treatment during the 
trial, including Grade 2 non-hematological toxicities lasting for two weeks or more 
(except asymptomatic Grade 2 hypertension), laboratory abnormalities (except 
proteinuria <2g/24h), investigators can consider dose interruption based on the 
subject’s tolerability, and adjust the administration schedule of rivoceranib 
subsequently after the toxicities are recovered.  
During the study, in combination with the recommendations on the dose adjustment 
above, investigators can give appropriate dose adjustment through comprehensive 
analysis of the occurrence of drug-related toxicities (e.g., multiple Grade 2 toxicities 
related with the study drug, poor intolerability to study drug), and can consider adjust 
the administration schedule of rivoceranib after dose interruption and recovery of the 
toxicity.  
5.1.6.1.6. Criteria for Dose Modification of Sorafenib 
Subjects receiving sorafenib will be given 400 mg (two tablets, 200 mg per tablet) orally, 
twice per day, under fasted state (at least 1 hour prior to meal or at least 2 hours after a 
meal) with a cup of warm drinking water.  
Dose adjustment resulted from drug-related toxicities include dose interruption, dose 
reduction and discontinuation. When dose reduction is required during treatment, 
sorafenib should be reduced to 400 mg once per day, if additional dose reduction is 
required, could refer to the locally approved drug label or local standard of care 
practice/treatment guideline. It is not allowed for dose level less than 400mg every other 
day. The criteria for interruption or discontinuation of sorafenib can be found in the 
label of sorafenib tosylate tablets approved by the local health authority in detail or 
local standard of care practice/treatment guideline. For any dose interruption, sorafenib 
treatment can be interrupted for up to 30 days.  
Cutaneous toxicities are the most common adverse reactions of sorafenib. Cutaneous 
related dose modification refer to Table 9 or based on the sorafenib label of approved 
by the local health authority. Other toxicities related dose modifications refer to 
sorafenib label approved by the local health authority.  
In principle, dose escalation is not allowed; however, in accordance with the package 
insert of sorafenib tosylate tablet approved by the FDA, “Following improvement of 
Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a 
reduced dose of sorafenib, the dose of sorafenib may be increased one dose level from 
the reduced dose.” The investigator may make the decision based on the subject’s 
condition. 
Table 9 Dose Adjustment of Sorafenib When Dermatologic Toxicities Occur 
Dermatologic 
Toxicity 
Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless 
swelling, erythema or 
discomfort of the hands or 
Any occurrence 
Continue treatment with 
sorafenib and consider topic 
therapy for symptomatic relief 


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feet which does not 
disrupt the subject’s 
normal activities 
Grade 2: Painful erythema 
and swelling of the hands 
or feet and/or discomfort 
affecting the subject’s 
normal activities 
1st occurrence 
Continue treatment with 
sorafenib and consider topic 
therapy for symptomatic 
relief. If no improvement 
within 7 days, see below 
No improvement within 7 days or 
2nd or 3rd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to 
Grade 0–1  
When resuming treatment, 
decrease sorafenib dose by 
one dose level (400 mg daily 
or 400 mg every other day a) 
 
4th occurrence 
Discontinue the sorafenib 
Grade 3: Moist 
desquamation, 
ulceration, blistering or 
severe pain of the 
hands or feet, or severe 
discomfort that causes 
the subject to be unable 
to work or perform 
activities of daily 
living  
1st or 2nd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to Grade 
0–1  
When resuming treatment, 
decrease sorafenib dose by one 
dose level (400 mg daily or 400 
mg every other day a) 
3rd occurrence 
Discontinue sorafenib 
treatment 
a. Please refer to label of sorafenib approved by the local health authority if needed.  
5.1.6.2. Safety Management on the Safety of Oncology Drugs 
5.1.6.2.1. Rules for Safety Management of Immuno-Oncology Drugs 
The AEs induced by Immuno-Oncology (I-O) drugs vary from other types of antitumor 
drugs, the severity and duration are special. SHR-1210 belongs to this type of drugs, 
thus it is required to achieve early identification and management of the AEs induced 
by it, in order to reduce the incidence of serious toxicities. To identify I-O drug related 
AEs, the investigator may refer to the following definition and diagnosis of immune-
related colitis, pneumonitis and hepatitis: 
Definition of immune-related colitis: A disorder characterized by inflammation of the 
colon. 
Diagnostic work-up of immune-related colitis suggested as follows: 
1) Symptoms include diarrhea, abdominal pain, hematochezia, weight loss, fever and 
vomiting. 
2) To rule out infection: For Grade 2 AEs, work-up of blood (complete blood cell 
count, comprehensive metabolic panel, thyroid-stimulating hormone, erythrocyte 
sedimentation rate, C-reactive protein) and stool (bacterial culture, Clostridium 
difficile, parasites, viral etiology) are recommended to be performed; radiological 
(e.g., CT scan of the abdomen and pelvis) as well as endoscopy and biopsy should 
be considered. For Grade 3-4 AEs, all the work-up listed above for Grade 2 AEs 
should be completed immediately. 


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3) Consider repeating endoscopy for subjects who do not respond to 
immunosuppressive agents. 
 
Definition of immune-related pneumonitis: Focal or diffuse inflammation of the lung 
parenchyma (typically identified on CT radiological). 
Diagnostic work-up of Immune-related pneumonitis suggested as follows: 
1) Respiratory events like cough and dyspnea; 
2) Thoracic CT scan; 
3) Hematology: including complete blood cell count, urea nitrogen, blood electrolytes, 
creatinine, liver function tests, thyroid function tests, blood calcium, C-reactive 
protein, and erythrocyte sedimentation rate; 
4) Infection should be ruled out by bronchoscopy, especially for ≥ Grade 2 AEs; 
5) Consider sputum sample and screening for viral, opportunistic or specific bacterial 
infections depending on the clinical context. 
 
Definition of immune-related hepatitis: A disorder characterized by a viral pathological 
process involving the liver parenchyma. 
Diagnostic work-up of immune-related hepatitis suggested as follows: 
1) Assessed for signs and symptoms of hepatitis; 
2) Transaminases and bilirubin measured before every cycle of treatment; 
3) If hepatitis develops, disease-related causes, concomitant drug administration 
(including alcohol) and infectious causes, particularly viral hepatitis, should be 
ruled out. Other thromboembolic and outflow obstructive etiology should also be 
excluded through radiological; 
4) Liver biopsy may be considered in assisting in the differential diagnosis of more 
severe hepatic reactions. 
In addition, the investigator may refer to the rules for safety management of similar 
products in overseas markets to facilitate evaluation and management of I-O drug 
related AEs occurring in the following systems:  
• 
Gastrointestinal tract 
• 
Kidney 
• 
Lung 
• 
Liver 
• 
Endocrine 
• 
Skin 
APPENDIX 6 and APPENDIX 7 provide the recommended treatment procedures for 
common immune-related adverse reactions. Note that the rules for management of 
hepatic irAEs have been amended in this protocol (see Section 5.1.6.2.3 below).   


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5.1.6.2.2. Principles of Management for Immune-Related Adverse Events 
In overall principle, according to the severity of adverse reaction, interruption of SHR-
1210 is taken as the main measure, resumption of SHR-1210 can be considered when 
the severity of adverse event has recovered to Grade 1 or below, and SHR-1210 should 
be discontinued permanently when serious Grade 3 or life-threatening Grade 4 adverse 
event occurs (For details, refer to Sections 5.1.6.1.2, 5.1.6.1.3 and 5.1.6.1.4 of this 
protocol which state criteria for dose delay, dose resumption, and permanent 
discontinuation of SHR-1210). 
Management of immune-related adverse events should be based on the medical practice 
of the research center and the guidelines.  Recommended treatment procedures for 
common immune-related adverse events are detailed in APPENDIX 6 (Note that the 
rules for management of hepatic irAEs have been amended in this protocol [see Section 
5.1.6.2.3 below]). The classification and management of reactive capillary endothelial 
proliferation (RCEP) are detailed in APPENDIX 7.  
5.1.6.2.3. Rules for Management on Hepatic Adverse Events of SHR-1210 
Below are suggestions on management of hepatic AEs that may occur in the 
experimental arm during the SHR-1210 treatment period of this study: 
• 
If the dose is delayed for 3-5 days and AST or ALT level is not improved but even 
exacerbated, cortisol, i.e., methylprednisolone 0.5-2 mg/kg/day or equivalent oral 
drugs, will be given;   
• 
In case of AST or ALT >8 times of ULN, cortisol, i.e., methylprednisolone 1-
2 mg/kg/day or equivalent oral drugs, will be given immediately, and meanwhile, 
a consultation from the department of gastroenterology is advised;  
• 
If AST or ALT level is not improved but even exacerbated 3-5 days after the start 
of corticosteroids treatment, other immunosuppressants may need to be added, such 
as mycophenolate 1g BID;  
• 
Once AST or ALT is decreased by one CTCAE Grade, the dose can be decreased 
gradually in no less than one month.  
The study drug can be resumed when AST or ALT is recovered to baseline level, unless 
the criteria for permanent discontinuation is reached.  
5.1.6.2.4. Infusion Reaction of SHR-1210 
As SHR-1210 is one fully humanized monoclonal antibody, the possibility of infusion 
or allergic reaction is low, and preventive medication is not needed prior to infusion. 
Allergic reaction is most likely to occur within 24h after infusion. Once the allergic 
reactions occur, the infusion should be slowed down or interrupted based on the 
condition, and clinical supportive treatment is needed. The preventive medication 
should be given prior to the subsequent doses. The allergic reactions are possibly 
characterized by fever, intolerance of cold, chills, headache, rash, pruritus, arthralgia, 
low or high blood pressure, or bronchospasm. All the Grade 3 or 4 infusion reactions 
should be reported to the sponsor within 24 hours and reported as SAE in case of 
meeting the criteria for SAE. See detailed reporting methods in Section 8.2. 


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Response to allergic reactions should be based on the medical practice and guidelines 
of the study site. See recommendations for the treatment of infusion reactions in Table 
10. 
Table 10 
Recommendations for the Treatment of Infusion Reactions 
CTCAE 
Grade 
Clinical 
symptoms 
Clinical treatments 
SHR-1210 
treatment 
Grade 1 
Mild transient 
reactions 
Bedside monitor, close monitoring till 
recovery. 
Preventive medication is recommended prior to 
the infusion afterwards: Diphenhydramine 50 
mg, or equivalent and/or Acetaminophen 325-
1000 mg, administered at least 30 mins before 
the infusion of SHR-1210. 
Continue. 
Grade 2 
Moderate 
reactions 
requiring 
treatment or 
dose 
interruption that 
can be rapidly 
relieved after 
symptomatic 
treatment (e.g., 
antihistamine 
drugs, non-
steroid anti-
inflammatory 
drugs, 
anaesthetics, 
bronchodilators, 
intravenous 
infusion, etc.) 
Normal saline i.v. infusion, Diphenhydramine 
50 mg i.v. or equivalent and / or 
Acetaminophen 325-1000 mg; 
Bedside monitor, close monitoring till 
recovery. 
Corticosteroids or bronchodilators can be 
considered if clinically required;  
The dose of study drug administered will be 
recorded in the source documents;  
Preventive medications are recommended prior 
to the infusion afterwards: Diphenhydramine 
50 mg, or equivalent and/or Acetaminophen 
325-1000 mg, administered at least 30 mins 
before the infusion of SHR-1210. Cortisol 
(equivalent to 25 mg hydrocortisone) can be 
used if necessary.  
Interrupted 
temporarily. 
Resuming the 
medication after 
symptoms 
disappear at 50% 
of the initial 
infusion rate. If 
there is no 
complication 
within 30 minutes, 
increase to the 
original 100% 
infusion rate. 
Closely monitor. If 
relapse, the current 
dose of SHR-1210 
can not be given 
again.  
Grade 
≥ 3 
Grade 3: serious 
reactions, no 
rapid relief after 
treatment and/or 
dose 
interruption; or 
relapse after 
remission; 
sequela 
occurred 
requiring 
hospitalization.  
Grade 4: life-
threatening  
The infusion of SHR-1210 shall be immediately 
discontinued; 
Start normal saline i.v. infusion. 
 
Bronchodilators, 
0.2-1 
mg 
1:1000 
epinephrine solution (s.c.), or 0.1-0.25 mg 
1:10000 epinephrine solution (i.v.), and/or 
diphenhydramine 50 mg combined with 
methylprednisolone 100 mg or equivalent 
drugs (i.v.); 
 
Comply with guidelines for allergic 
reactions of the study site; 
Bedside monitor, close monitoring till recovery.  
Discontinued 
permanently. 
 
5.1.6.2.5. Rules for Management of Adverse Events of Rivoceranib 
Management of rivoceranib-related adverse events can be performed according to 
clinical practice in this study protocol, and the following recommendations are provided 
for your reference.  


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1. Hand-and-foot syndrome 
Hand-foot syndrome (HFSR): is palmar-thenar hypoesthesia or erythema at extremities, 
one of the cutaneous toxicity, is more obvious at the pressed or forced area when it 
occurs. It may appear in tumor subjects during chemotherapies or molecular targeted 
therapies. HFSR is characterized by numbness, hypoesthesia, paresthesia, stabbing pain, 
analgesia or edema pain, cutaneous swelling or erythema, desquamation, chapping, 
hardened blister or serious pain, etc. 
Grading: 
Grade 1: numbness, dysesthesia/paresthesia of hand and/or foot, painless swelling or 
erythema and/or discomfort that has no effect on normal activities. 
Grade 2: painful erythema and swelling of hand and/or foot and/or discomfort that 
affects subject’s daily life. 
Grade 3: moist desquamation, ulcer, blister or serious pain of hand and/or foot and/or 
serious discomfort that makes subject unable to work or engage in daily activities. 
Intense pain, loss of skin function, comparably rare. 
Symptomatic treatment and measures: 
Recommended some necessary supportive treatments include intensive skin care, 
keeping skin clean to avoid secondary infection; avoiding pressure or scratching; using 
moisturizing cream or lubricant, including local use of lotion or lubricant containing 
urea and corticosteroids; and local use of anti-fungal or antibiotic therapy when 
necessary. 
Note: If ≥ Grade 3 hand-foot syndrome occurs for consecutive three times, with an 
aggravating tendency, the administration of rivoceranib should be terminated. 
2. Hypertension 
Subjects should be enrolled strictly in accordance with the requirement of blood 
pressure in the inclusion/exclusion criteria, subjects with hypertension can achieve 
controlled through adjustment of the dose of antihypertensive agents or adding of new 
antihypertensive agents prior to taking the study drugs, the blood pressure should be 
controlled within 140/90 mmHg.   
Monitoring and management of hypertension: 
Daily blood pressure monitoring (based on the average of BP readings acquired from ≥ 
2 measurements) is recommended after the initiation of rivoceranib mesylate treatment. 
Once hypertension occurs, the following treatment can be given: Angiotensin II 
receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEI), β receptor 
blockers, etc. Or combined use of the aforementioned drugs.  
If subjects have hypertension or exacerbation of hypertension during administration, 
should take following actions:  
1) Adjusting the administration of study drugs as specified in the protocol (see 
Section 5.1.6.1.5);  


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2) Starting to take antihypertensive agents or adjusting the dose.  
Advise subjects to record daily blood pressure measurements in a subjects’ diary. If they 
are taking hypertension drugs at the same time, they are required to keep a detailed 
record of the drug name, dosage, method and frequency of use, and related complaints 
or symptoms of discomfort.  
The hypertension treatment drugs are recommended as below:  
1) Angiotensin-converting enzyme inhibitors (ACEI);  
2) Angiotensin II receptor antagonists (ARB);  
3) dihydropyridine calcium channel antagonists;  
4) β receptor blockers.  
Use of diuretics is not recommended for anti-hypertensive therapy; nicardipine, 
diltiazem and verapamil with CYP3A4 inhibitory effect are prohibited. Rivoceranib 
mesylate should be discontinued in subjects with hypertensive crisis.   
3. Proteinuria  
Proteinuria should be closely monitored for all the subjects throughout the treatment, 
and intensively monitored in subjects who have history of hypertension; the 24-hour 
urine protein quantification must be performed for the subjects with urine protein ≥2+. 
Note: Rivoceranib mesylate shall be discontinued in case nephrotic syndrome occurs.  
4. Hemorrhage of digestive tract  
Active symptomatic treatment should be given when gastrointestinal hemorrhage 
occurs, including persistently positive result of fecal occult blood, haematemesis or 
bloody stool. The subjects who are judged as upper gastrointestinal hemorrhage should 
be fasted and given acid suppression agents, drugs for gastric mucosa protection 
hemostasis (Transamin, Reptilase, etc.) treatment, and octreotide can be used when 
necessary; hemostasis, blood transfusion and supportive treatments will be given for 
those with lower gastrointestinal hemorrhage; surgical assistance may be required 
immediately if the hemorrhage can not be controlled. Adjustment of medication in 
accordance with the principle in Section 5.1.6.1.5 in the protocol.   
5. Thrombosis  
Rivoceranib mesylate should be discontinued immediately for any arterial thrombosis 
(e.g., cerebral ischemia, stroke, angina pectoris, myocardial infarction, etc.). 
Rivoceranib mesylate should be temporarily discontinued in case symptomatic venous 
thrombosis occurs.   
Symptomatic treatment, surgery or anticoagulants should be given immediately for 
thrombotic symptoms.   


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5.1.6.2.6. Rules for Management of Adverse Events of Sorafenib 
1. Skin toxicity: 
Hand-foot cutaneous reactions and rash are the most common adverse reactions of 
sorafenib. Usually, the rash and hand-foot skin reactions are mostly CTCAE Grade 1-2 
and mostly occur within 6 weeks after the start of administration of sorafenib. 
Recommended necessary symptomatic and supportive treatments include intensive skin 
care, keeping skin clean to avoid secondary infection; avoiding pressure or scratching; 
using moisturizing cream or lubricant, including local use of lotion or lubricant 
containing urea and corticosteroids; and local use of anti-fungal or antibiotic therapy 
when necessary. Subjects with serious and persistent cutaneous toxicities may need to 
discontinue sorafenib permanently. Permanently discontinued for the serious cases. 
2. Gastrointestinal side effects: 
It is one of the common adverse reactions of sorafenib and mainly characterized by 
abdominal pain and diarrhea, which are generally mild-to-moderate and may be 
associated with the direct irritation of gastrointestinal mucosa of sorafenib after a long 
absorption in digestive tract and change of pH over time during its metabolism. 
Generally, the symptoms can be relieved through eating less residue, low-fiber diet, and 
digestible food. Subjects with serious diarrhea need to be closely observed. Infusion 
should be given as supportive treatment in case of dehydration, which would supply 
enough water and electrolytes.  
3. Hypertension: 
The incidence of hypertension will be increased in subjects given sorafenib. Drug-
related hypertension is mostly mild-to-moderate, usually occurs in early stage after 
taking medicine, and can be controlled with routine antihypertensive agents. The blood 
pressure should be monitored routinely and controlled within 140/90 mmHg. Advise 
subjects to record daily blood pressure measurements in the dairy card in detail. 
Wherever necessary, high blood pressure will be treated in accordance with standard 
antihypertensive regimen, and chief complaints or symptoms as well as dosing 
information (e.g., drug name, dose, route of administration and frequency) will be 
recorded in detail. Permanent discontinuation of sorafenib needs to be considered for 
subjects who still have serious or persistent hypertension after use of antihypertensive 
agents or have hypertensive crisis.  
4. Hemorrhage: 
The incidence of hemorrhage may be increased after administration of sorafenib. Active 
symptomatic treatments should be given when gastrointestinal hemorrhage occurs, 
including persistently positive result of fecal occult blood, hematemesis or bloody stool. 
The subjects who are judged as upper gastrointestinal hemorrhage should be fasted and 
given acid suppression agents, drugs for gastric mucosa protection, hemostasis 
(Transamin, Reptilase, etc.) treatment, and octreotide can be used when necessary; 
hemostasis, blood transfusion and supportive treatments will be given for those with 
lower gastrointestinal hemorrhage; surgical assistance may be required immediately if 
the hemorrhage can not be controlled. Once treatment is needed, it is advisable to 


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consider permanent discontinuation of sorafenib. Hemorrhage or elevated INR occurs 
occasionally in part of subjects taking sorafenib and warfarin simultaneously. INR and 
PT should be detected routinely and attention should be paid to the sign of clinical 
hemorrhage in subjects given concomitant warfarin.  
5. Myocardial ischemia and/or myocardial infarction: 
Discontinuation of sorafenib should be considered for subjects with drug-related 
myocardial ischaemia and/or myocardial infarction.  
6. Gastrointestinal perforation: 
Gastrointestinal perforation is rare. The incidence of gastrointestinal perforation is less 
than 1% reported in subjects given sorafenib. Once it occurs, sorafenib should be 
discontinued.  
7. Liver impairment: 
Sorafenib is mainly eliminated via liver, and its exposure will be elevated in the subjects 
with hepatic impairment. Symptomatic and supportive treatment must be taken, the 
dose of sorafenib must be reduced or interrupted in case of drug related abnormal 
hepatic function. And discontinuation of the treatment should be considered if the 
symptom is serious and ≥ Grade 3 on an ongoing basis.  
Refer to the label of sorafenib tosylate tablets for details.  
5.2. 
Management, Distribution and Recovery of Drugs 
5.2.1. 
Drug Preparation 
The study drug should be prepared by qualified person in accordance with the 
brochure of study drug.  
5.2.2. 
The Disposal of Remaining Drugs 
Investigators or their authorized representatives should record the date and dose of the 
drug administered for each subject. The residual investigational products will return to 
the sponsor regularly for destruction after being counted. If the remaining drugs should 
be destroyed at study sites, investigators must ensure the destruction is in accordance 
with applicable environmental laws and regulations, unit policies and other applicable 
terms, also need to provide relevant procedures for destruction. All the destructions 
should be well recorded. 
5.3. 
Concomitant Therapy 
All treatments and medications (excluding solvent) used from 28 days prior to the 
signature of informed consent form to the end of safety follow-up should be recorded 
in the eCRF with raw data strictly in accordance with the GCP. If adverse events occur, 
the subject should be closely observed, as well as actively given symptomatic treatment 
if necessary, which is fully documented in medical records, and the drug and non-drug 
treatment used shall be recorded and specified in the eCRF. Only the concomitant 


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medication/therapy that is used to manage the study drugs related AE/SAE should be 
recorded after the above collection periods.  
5.3.1. 
Prohibited or Cautiously Used Medications and Treatments During the 
Study 
5.3.1.1. Drugs and Therapies Prohibited for All the Subjects During the Study 
Subjects are prohibited from using modern traditional Chinese medicines that have been 
approved by the NMPA (or by regulatory authorities in other countries) for the 
indication of HCC (including but not limited to Delisheng Injection, Kanglaite Injection, 
Aidi Injection, Huaier Granule and Ganfule Tablets) and immune-modulators 
(including but not limited to interferon, interleukin-2, thymosin, etc.) during the study.   
During the treatment period of this study, subjects are not allowed to receive any local 
therapies against liver tumor lesion and targeted lesion (except palliative local therapies 
described in Section 5.3.2.4), and other systemic antitumor therapies, such as 
chemotherapies, molecular targeted therapies, hormone therapies, immunotherapies, 
and so on. 
Subjects are not allowed to use other investigational products for antitumor therapy 
during the treatment period of this study. 
Section 4.2 (Exclusion Criteria) of the protocol describes other drugs prohibited in this 
study.  
5.3.1.2. Drugs Prohibited for Subjects Given SHR-1210 During the Study  
Subjects are not allowed to receive immunosuppressive therapies simultaneously 
during the treatment period of this study (except management on the treatment-related 
adverse events). 
Systemic corticosteroid cannot be used at the dose of >10 mg/day (Prednisone or 
equivalent) during SHR-1210 treatment period, except for treatment-related AEs 
treatments or short-term preventive therapies. SHR-1210 will be resumed until systemic 
corticosteroid dose has been reduced at ≤10 mg/day (Prednisone or equivalent). 
Vaccination of live vaccine are prohibited within 4 weeks prior to the first dose of study 
drugs until 60 days after the last dose.  
5.3.1.3. Drugs Used Cautiously or Prohibited for Subjects Given Rivoceranib 
During the Study  
There was a study conducted by Bao et al [24], in which apatinib (also known as 
rivoceranib) was evaluated for its in vitro inhibitory effect on the major CYP enzymes 
including CYP3A2/4, CYP2B1/6, CYP2C9/11, CYP2D1/6, and CYP2E1 using human 
and rat microsomes. The IC50 and IC50-shift results indicated that rivoceranib might 
not be a time-dependent inhibitor. Rivoceranib was a weak inhibitor of human CYP2E1 
(IC50>10 μM) but inhibited CYP2B6/2B1 and CYP2D6/2D1 in a competitive way 
(Ki = 3.84/0.59 and 5.41/0.87 μM), and inhibited CYP3A4/3A2 and rat CYP2E1 in a 


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mixed way (Ki = 11.50/1.83 and 13.06 μM). On CYP2C9, Rivoceranib exhibited the 
noncompetitive inhibition (Ki = 0.71 μM) while it inhibited CYP2C11 uncompetitively 
(Ki = 3.30 μM). These results are consistent with the findings in the JHM and LSK IB, 
in which rivoceranib has the most potent inhibitory effect on CYP2C9, with lesser on 
CYP3A4 and CYP2C19.  
• In vitro studies have shown that rivoceranib is mainly metabolized by the liver 
P450 enzymes CYP3A, CYP2C9, and CYP2C19, strong inhibitors and 
inducers of CYP3A and CYP2C19 will significantly increase or decrease 
clearance of rivoceranib with increased or decreased exposures of rivoceranib. 
Therefore, the strong inhibitors and inducers of CYP3A and CYP2C19 will be 
prohibited (see Appendix 11 for listings of strong inhibitors and inducers of 
CYP3A and 2C19, there are no strong inhibitors or inducers of CYP2C9).  
• Sensitive substrates of CYP3A4 will be used with caution.  
• As the potential DDI for rivoceranib as a perpetrator of CYP2C9 exists, the 
following instructions will be implemented until further information is 
available: Drugs metabolized by CYP2C9 with narrow therapeutic index: 
warfarin, and phenytoin, will be prohibited. Drugs that are sensitive substrate 
of CYP2C9, such as celecoxib will be used with caution. 
• 
Drugs metabolized by CYP2D6 with narrow therapeutic index thioridazine, 
and pimozide, will be prohibited. Drugs that are sensitive substrates of 
CYP2D6 atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, 
perphenazine, tolterodine, and venlafaxine will be used with caution. 
The following transporter substrates with narrow therapeutic index are prohibited: P-
gp substrates dabigatran, and digoxin, MATE1, MATE-2K, OCT2 substrate dofetilide 
(FDA’s Web site on Drug Development and Drug Interactions can be found at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm and drug bank for narrow therapeutic index 
https://www.drugbank.ca/categories/DBCAT003972. See Appendix 11) 
The transporter inhibitors are reported to increase transporter substrates’ AUC ≥1.5 to 
≥2 fold, and thus fall into the category of moderate inhibitors. They are to be advised 
used with caution (FDA’s Web site on Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm. See Appendix 11 for detailed listings)  
• 
It is necessary to avoid the concomitant use of drugs that prolong the QT interval 
prior to (approximately 5 half-lives of the concomitant drug) and during study 
enrollment.   These drugs may include antibiotics, fluoroquinolones, macrolides, 
and anti-arrhythmics, angina relieving drugs, antipsychotic drugs, antifungal drugs, 
antimalarial drugs, antihistamines, gastrointestinal antiemetic and promoting drugs, 
and antidepressants, etc. 


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• 
Subjects should be advised to restrict use of proton pump inhibitors (PPIs). 
Subjects should be encouraged to avoid concomitant administration of rivoceranib 
with acidic modifiers or H2 blockers. If these concurrent medicines are needed, 
they should be taken 5 hours after the studied drug administration. For other 
prohibited concurrent medicines please refer to Appendix 11. 
5.3.1.4. Drugs Used Cautiously for Subjects Given Sorafenib During the Study 
Rifampicin, one strong CYP3A4 inducer, once per day at the dose of 600 mg in healthy 
volunteers, for consecutive 5 days, and single dose of oral sorafenib 400 mg, can lead 
to decrease of average AUC of sorafenib by 37%. Therefore, strong CYP3A4 inducers 
(such as dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, 
rifapentine, Hypericum perforatum L [also known as St John's-wort], etc.) should be 
avoided as concomitant medications; they may accelerate metabolism of sorafenib and 
decrease the concentration of sorafenib. 
The combined use of sorafenib with neomycin may lead to decreased bioavailability of 
sorafenib by above 50%.  
In addition, investigators can refer to the label of sorafenib tosylate tablets and combine 
with clinical practice for more detailed descriptions of the drugs prohibited or used 
cautiously for such subjects during the study.  
5.3.2. 
Permitted Concomitant Medications and Treatments During the Study 
5.3.2.1. Antiviral Treatment 
Subjects infected with HBV and HCV must receive antiviral therapy according to 
local standards. Antiviral therapy is recommended as below:  
Subjects with HBV infection can continue the original antiviral therapy if HBsAg is 
positive and they have started antiviral therapy and achieved satisfactory control of 
virus (HBV-DNA <500 IU/mL) prior to inclusion in the study; subjects with suboptimal 
viral control are recommended to switch to other standard anti-HBV medication (e.g., 
Entecavir) as recommended by local guidelines, and subjects can be enrolled when 
HBV-DNA is <500 IU/mL; subjects with newly discovered HBV infection in screening 
period can start standard anti-HBV treatment as recommended by local guidelines (e.g., 
Entecavir) immediately and can be enrolled when HBV-DNA is <500 IU/mL. 
Subjects with HCV infection, if HCV-RNA is positive, subjects must receive antiviral 
therapy in accordance with the local standard guideline on diagnosis and treatment of 
hepatitis C.  
5.3.2.2. Steroids 
Local use of steroids is allowed, for example, topically external use, eye, nasal cavity, 
intra-joint and inhalation; corticosteroids for epinephrine replacement therapy are 
allowed; corticosteroids for treatment of adverse reactions are allowed; transient use of 
steroids for prevention and treatment of allergic reactions (prevention of allergy to 
contrast agents, or treatment of other allergic reactions) are allowed.  


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5.3.2.3. Other Systemic Therapies 
During the treatment period, subjects should be given the best supportive treatment. 
The original hormone replacement therapy is allowed. Bisphosphonate for treatment of 
bone metastasis is permitted.  
5.3.2.4. Palliative Local Treatment 
Palliative therapy for local non-target lesions causing obvious symptoms is allowed, for 
example, bone pain; local radiotherapies or surgery and management of pleural effusion 
and ascites can be considered, however, the following conditions must be met:  
• 
These lesions are known to be present at enrollment;  
• 
Progression of disease must be judged by investigators, for subjects who need local 
therapy due to deterioration of symptoms during the study;  
• 
Subjects with progression of disease must meet the criteria for treatment beyond 
progression (see Section 6.6 for the details);  
• 
The lesions for local therapy cannot be target lesions;  
• 
Subjects should interrupt the dose of investigational product until the end of 
recovery period of palliative therapy, whilst receiving palliative local therapy.  
It is advisable to discuss with the sponsor prior to the start of palliative local therapy. 
The content of palliative therapy should be recorded carefully in eCRF and medical 
record, including the date, sites of treatment, therapeutic methods and dosage, adverse 
reactions, and do on.  
5.3.3. 
Surgery or Palliative Radiotherapy 
Any surgery or palliative radiotherapy should have theoretical basis and necessity 
during the study. At the interval between the treatment and use of investigational 
products, recovery that has no effect on the wound and search for the reason of unknown 
hemorrhage must be performed as much as possible. In accordance with the label of 
rivoceranib, it is advised to interrupt the dose of rivoceranib prior to the operation to 30 
days and after the operation. It is recommended in the label of sorafenib that the time 
of dose interruption of sorafenib will be based on the type of operation and status of 
wound healing and depend on clinician’s specific judgment. Besides that, it is 
recommended to interrupt the dose of study drugs at least 14 days prior to, during and 
at least 14 days after palliative radiotherapy, in this protocol, the dose resumption in the 
subjects receiving surgery depends on the clinical evaluation of wound healing and 
postoperative recovery.  
6. 
STUDY PROCEDURES 
The utmost efforts will be made to ensure all the tests and procedures required in the 
protocol go as planned. However, unexpected things may happen sometimes and be 
beyond investigator’s control, making it difficult to test. In these cases, the investigator 
will take all steps necessary to ensure the safety and interests of the subject. When one 
test required in the protocol can not be performed, investigators need to record the 


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reason. In addition, the study team need to be informed of the accidental situation in 
time.  
6.1. 
Screening Period 
The screening period begins with the signing of the informed consent form and ends 
with the randomization or screening failure. Termination of this study after signing the 
informed consent form and prior to randomization will be regarded as screening failure. 
Subjects with screening failure can be re-screened. They must sign the informed 
consent form again, re-register and obtain a new subject number at the re-screening. 
Subjects can only be re-screened once.  
Subjects must sign the informed consent form before performing any screening 
procedure specified in this study. In case routine radiological evaluation has been 
performed for tumors prior to the signing of the informed consent form, computed 
tomography (CT), magnetic resonance radiological (MRI) or bone scan does not need 
to be repeated in screening period as long as they are completed within 28 days prior to 
the start of study drug (42 days prior to start of study drug is acceptable for bone scan), 
and meet the requirement for radiological evaluation in this study.  
Unless otherwise noted, collection of the following data should be completed within 
28 days prior to the start of study drug:  
• 
Obtain the informed consent form signed by the subject; 
• 
Assign subject number (subjects will be assigned a unique number in the study: the 
subject number reflects the numbering of study sites and numbering of subjects 
within the same study site; the numbering of subjects shall be in accordance with 
the sequence in which the subjects sign the informed consent form, for example, 
001, 002, 003, etc.); 
• 
Collect demographic characteristics; 
• 
Collect medical history (including history of tumor and past medical history, see 
the SCHEDULE OF ACTIVITIES for details);  
• 
Tumor tissue collection (for detailed instructions regarding tumor tissue sampling, 
refer to the laboratory manual. If tumor sample is not accessible in special case, it 
can be discussed with Sponsor on a case-by-case basis); 
• 
Collect concomitant medications/therapies;  
• 
Collect AE;  
• 
Tumor radiological evaluation: the radiological evaluation prior to the signing of 
informed consent form and within 28 days prior to the first dose is acceptable, and 
will be performed based on RECIST v1.1 (evaluated by investigator and BIRC), 
mRECIST (evaluated by BIRC only) and imRECIST (evaluated by investigator 
only). All the measurable and evaluable tumor lesions should be evaluated and 
recorded, including enhanced CT/MRI scan of thorax, abdomen, pelvis and site of 
lesions, brain enhanced MRI or enhanced CT scan (excluding intracranial 
metastasis). Thoracic plain CT scan and abdominal, pelvic and brain MRI can be 


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performed in case of allergy to the contrast agent for enhanced CT; bone scan can 
be performed only when clinically indicated;  
• 
Check eligibility criteria. 
The following information will be collected within 14 days prior to the first dose of 
study drug:  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Perform a careful, comprehensive physical examination: height, weight, head and 
face, skin, lymph nodes, eye, ear, nose, throat, mouth, respiratory system, 
cardiovascular system, abdomen, genitourinary system, musculoskeletal, 
neurological and mental status;  
• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout), 
blood pressure, pulse rate and respiratory frequency;  
• 
Virology (including HBV, HCV, HIV markers, see study flow chart for the specific 
requirement);  
• 
Fecal occult blood test;  
• 
12-lead ECG (performed after sitting still for at least 5 minutes): heart rate and QTc 
interval (calculated using Fridericia’s formula);  
• 
Echocardiography, including LVEF;  
• 
AFP test;  
• 
Thyroid function (TSH, FT3 or TT3, FT4);  
• 
Collect concomitant medications/therapy;  
• 
Collect AE;  
• 
Check eligibility criteria. 
The following information need to be collected within 7 days prior to the first dose of 
study drug:  
• 
Child-Pugh class (see APPENDIX 3 for details); 
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen (BUN) or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase level 
is abnormal and clinically significant);  


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• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
Coagulation parameters: including INR and/or PT (if INR can not be collected, PT 
will be used as the basis for judgment);  
• 
Blood human chorionic gonadotropin (HCG) test for female subjects of 
childbearing potential;  
• 
Collect concomitant medications/therapy;  
• 
Collect AE;  
• 
Check eligibility criteria;  
• 
Subjects can be randomized if they meet all the inclusion criteria and do not meet 
any of the exclusion criteria.  
6.2. 
Treatment Period 
Physical examination and laboratory examinations will be performed during treatment, 
AE and concomitant medications will be collected, drug dispensation, recovery and 
verification will be recorded, the distribution, verification and return of subject’s diary 
will be completed.  
Prior to administration of study drug at specified visits and any other study evaluation 
conducted at clinical centers, all the subjects need to complete EORTC QLQ-C30, 
QLQ-HCC18 and EQ-5D-5L questionnaires.  
The following information must be collected within 72 hours prior to administration of 
study drug at the visits specified in each cycle of therapy:  
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen [BUN] or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase is 
abnormal and clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
The following information must be collected within 24h prior to administration of study 
drug at the visits specified in each cycle of therapy:  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 


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examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout), 
blood pressure, pulse rate and respiratory frequency;  
If dose delay occurs, required examination during study treatment need to be performed 
as planned or more frequently if clinically indicated. Echocardiography and blood HCG 
test can be monitored at any time, if necessary. Also, in accordance with RECIST v1.1 
(investigator and BIRC evaluation), mRECIST (only for BIRC evaluation) and 
imRECIST (only for investigator evaluation), all evaluations during the treatment 
period, with randomization as baseline, will be performed once every 8 weeks (56 days) 
±7 days in the first 48 weeks, once every 12 weeks (84 days) ±7 days afterwards, and 
additionally performed when clinically indicated. When there is no BIRC determined 
progression of disease (according to RECIST v1.1), tumor evaluation should be 
continued, regardless of discontinuation of study treatment, unless death, withdrawal of 
informed consent, start of subsequent antitumor therapy or termination of study by the 
sponsor, whichever comes first; the evaluation includes the enhanced CT/MRI scan of 
thorax, abdomen, pelvis and site of lesions. Thoracic plain CT scan, abdominal and 
pelvic MRI can be performed in case of allergy to the contrast agent for enhanced CT; 
cranial CT/MRI and bone scan can be performed only when clinically indicated. 
Throughout the study, each subject must use the same procedure for radiological 
examination. Investigators must review the results prior to the next cycle of therapy. 
The subjects who have achieved remission (complete remission or partial remission) 
for the first time need to be confirmed by the next scheduled evaluation or repeated 
evaluation ≥ 4 weeks after the first evaluation.  
Subjects with BIRC determined progression (according to RECIST v1.1) can continue 
to use SHR-1210 monotherapy or combination with rivoceranib (experimental arm) or 
sorafenib (control arm) if investigator assess they meet the criteria defined in 
Section 6.6.  
Upon approval of protocol V6.0, disease progression will only need to be confirmed by 
investigator per RECIST v1.1. 
6.2.1. 
Cycle 1 
The following examination/step or collection of the following information needs to be 
completed on Day 1:  
• 
If completed within 24h prior to the first dose in screening period, no examination 
is needed on C1D1:  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Weight and physical examination of important sites: cutaneous system, 
respiratory system, cardiovascular system, abdomen and mental state. In 
addition, physical examination of reactive capillary endothelial proliferation 
needs to be performed on the experimental arm; 


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• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used 
throughout.), blood pressure, pulse rate and respiratory frequency,  
• 
12-Lead ECG (performed after sitting still for 5 minutes): heart rate and QTc 
interval (the latter is calculated by Fridericia formula); for the experimental arm, 
the ECG should be performed 2.5 hours (±1 hour) after the administration of 
rivoceranib; 
• 
Pre-dose sampling: the blood sample will be collected only from experimental arm 
(SHR-1210 combined with rivoceranib): 0.5 hours prior to administration of 
rivoceranib on Day 1 of Cycle 1 (C1D1), 6 mL venous blood will be collected for 
detection of the serum concentration and immunogenicity of SHR-1210; 
• 
ECG blood sampling: Blood sample will be collected at 2.5 hours (±1 hour) after 
rivoceranib on Day 1 of Cycle 1 (C1D1) and ECG should be performed first; PK 
samples will be collected within 15 minutes after ECG. Approximately 2 mL 
venous blood will be collected for detection of concentration of rivoceranib;  
• 
Randomization: subjects will be randomized into either the experimental arm or 
control arm after their data are reviewed and determined to be in accordance with 
the inclusion/exclusion criteria, and the first dose should be given within 24 hours 
following randomization; 
• 
Intravenous infusion of SHR-1210 (experimental arm);  
• 
Oral administration of rivoceranib (experimental arm) or sorafenib (control arm) 
(daily, continuously);  
• 
Distribution of subject’s diary; 
• 
Subject’s self-evaluation results: all the subjects will complete EORTC QLQ-C30, 
QLQ-HCC18 and EQ-5D-5L questionnaires prior to administration of study drug 
and any other study evaluation at clinical centers;  
• 
Collect concomitant medications/therapy;  
• 
Collect AE.  
The following examinations/steps or collection of the following information needs to 
be completed on Day 15 (±3 days):  
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (measured after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout), 
blood pressure, pulse rate and respiratory frequency;  
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  


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• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen [BUN] or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase level 
is abnormal and clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
12-lead ECG (performed after sitting still for at least 5 minutes): heart rate and QTc 
interval (calculated using Fridericia’s formula); it should be performed 2.5 hours 
(±1 hour) after rivoceranib administration in experimental arm;  
• 
Collect concomitant medications/therapies;  
• 
Collect AE;  
• 
Intravenous infusion of SHR-1210 (experimental arm);  
• 
Oral administration of rivoceranib (experimental arm) or sorafenib (control arm) 
(daily, continuously);  
• 
Distribution, verification and return of subject’s diary. 
6.2.2. 
Cycles 2 and 3 
The following examinations/steps or collection of the following information needs to 
be completed on Day 1 (±3 days):  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Child-Pugh class (see APPENDIX 3 for details); 
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout), 
blood pressure, pulse rate and respiratory frequency;  
• 
Virology (only performed on C3D1, including HBV, HCV markers, see study flow 
chart for specific requirement); 
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  


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• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, BUN or urea, creatinine, blood 
glucose, amylase (lipase test needs to be added if amylase level is abnormal and 
clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
Coagulation parameters: including INR and/or PT (if INR can not be collected, PT 
will be used as the basis for judgment);  
• 
Fecal occult blood test;  
• 
AFP;  
• 
Thyroid function (only performed on C3D1, TSH, FT3 or TT3, FT4);  
• 
12-lead ECG (performed after sitting still for at least 5 minutes): heart rate and QTc 
interval (calculated using Fridericia’s formula); it should be performed 2.5 hours 
(±1 hour) after rivoceranib administration in experimental arm; 
• 
Pre-dose sampling: the blood sample will be collected only from experimental arm 
(including SHR-1210 combined with rivoceranib, SHR-1210 monotherapy and 
rivoceranib monotherapy). The time point for sample collection will be with 0.5 
hours prior to administration of rivoceranib on Day 1 of Cycle 2 and 3 (C2D1, 
C3D1). If SHR-1210 and/or rivoceranib is temporarily interrupted, pre-dose 
immunogenicity and PK sample will be collected on schedule. If only rivoceranib 
is temporarily interrupted, time point for collection is within 0.5 hours before SHR-
1210 administration. Approximately 8 mL venous blood will be collected for 
detection of the serum concentration and immunogenicity of SHR-1210 (6 mL) and 
concentration of rivoceranib (2 mL); The exact time of the previous administration 
of rivoceranib will be collected (provided by the subject); 
• 
ECG blood sampling: The blood samples will be collected only for the 
measurement of the concentrations of rivoceranib. Blood samples will be collected 
at 2.5 hours (±1 hour) post rivoceranib administration on Day 1 of Cycle 2 and 3 
(C2D1, C3D1). ECG will be performed first followed by blood collection within 
15 minutes after ECG. If rivoceranib is temporarily interrupted, the post-ECG 
sample will not be collected. Approximately 2 mL venous blood will be collected 
for determine the concentration of rivoceranib; 
• 
Intravenous infusion of SHR-1210 (experimental arm); 
• 
Oral administration of rivoceranib (experimental arm) or sorafenib (control arm) 
(daily, continuously); 
• 
Distribution, verification and return of subject’s diary; 
• 
Subject’s self-evaluation results: all the subjects will complete EORTC QLQ-C30, 
QLQ-HCC18 and EQ-5D-5L questionnaires prior to administration of study drug 
and any other study evaluation at clinical centers;  
• 
Collect concomitant medications/therapy;  


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• 
Collect AE.  
The following examinations/steps or collection of the following information needs to 
be completed on Day 15 (±3 days):  
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (measured after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout.), 
blood pressure, pulse rate and respiratory frequency;  
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood BUN or urea, creatinine, blood 
glucose, amylase (lipase test needs to be added if amylase level is abnormal and 
clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
Collect concomitant medications/therapy;  
• 
Collect AE; 
• 
Intravenous infusion of SHR-1210 (experimental arm); 
• 
Oral administration of rivoceranib (experimental arm) or sorafenib (control arm) 
(daily, continuously); 
• 
Distribution, verification and return of subject’s diary. 
6.2.3. 
Cycle 4 and Onwards 
The following examinations/steps or collection of the following information needs to 
be completed on Day 1 (±3 days):  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Child-Pugh class (see APPENDIX 3 for details); 
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 


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• 
Vital signs (measured after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout.), 
blood pressure, pulse rate and respiratory frequency;  
• 
Virology (once every two cycles, for example, C5D1, C7D1), including HBV, HCV 
markers, see study flow chart for specific requirement); 
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count;  
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen [BUN] or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase level 
is abnormal and clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
Coagulation parameters: including INR and/or PT (if INR cannot be collected, PT 
will be used as the basis for judgment);  
• 
Fecal occult blood test;  
• 
AFP test; 
• 
Thyroid function (once every two cycles, for example, C5D1, C7D1), TSH, FT3 
or TT3, FT4);  
• 
12-lead ECG (performed after sitting still for at least 5 minutes): heart rate and QTc 
interval (calculated using Fridericia’s formula); it should be performed 2.5 hours 
(±1 hour) after rivoceranib administration in experimental arm;  
• 
Pre-dose sampling: the blood sample will be collected only from experimental arm 
(including SHR-1210 combined with rivoceranib, SHR-1210 monotherapy and 
rivoceranib monotherapy). The time point for sample collection will be within 0.5 
hours prior to administration of rivoceranib on Day 1 of Cycle 4 (C4D1), and on 
Day 1 of every three cycles afterwards (0.5 hours prior to administration of 
rivoceranib). If SHR-1210 and/or rivoceranib is temporarily interrupted, predose 
immunogenicity and PK sample will be collected on schedule. If only rivoceranib 
is temporarily interrupted, time point for collection will be within 0.5 hours before 
SHR-1210 administration. C4D1: Approximately 8 mL venous blood will be 
collected for detection of the serum concentration and immunogenicity of SHR-
1210 (6 mL) and concentration of rivoceranib (2 mL); The exact time of the 
previous administration of rivoceranib will be collected (provided by the subject). 
For every three cycles afterwards (e.g. C7D1, C10D1 etc.), approximately 6 mL 
venous blood will be collected for detection of the serum concentration and 
immunogenicity of SHR-1210; 


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• 
ECG blood sampling: the blood samples will be collected only for the measurement 
of the concentrations of rivoceranib. Blood samples will be collected at 2.5 hours 
(±1 hour) after administration of rivoceranib on Day 1 of Cycle 4 (C4D1). ECG 
will be performed first followed by blood collection within 15 minutes after ECG. 
If rivoceranib is interrupted, the post-ECG sample will not be collected within 15 
minutes after the end of ECG. Approximately 2mL venous blood will be collected 
for determining the concentration of rivoceranib;  
• 
Intravenous infusion of SHR-1210 (experimental arm); 
• 
Oral administration of rivoceranib (daily, continuously); 
• 
Distribution, verification and return of subject’s diary; experimental arm: on D1 
and D15 of each cycle; control arm: only on D1 from Cycle 4;  
• 
Subject’s self-evaluation results: All the subjects will complete EORTC QLQ-C30, 
QLQ-HCC18 and EQ-5D-5L questionnaires prior to administration of study drug 
and any other study evaluation at clinical centers on the Day1 of each cycle; 
• 
Collect concomitant medications/therapy;  
• 
Collect AE. 
The following examinations/steps or collection of the following information needs to 
be completed on Day 15 (±3 days) (only in experimental arm):  
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (measured after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout.), 
blood pressure, pulse rate and respiratory frequency;  
• 
Collect concomitant medications/therapy;  
• 
Collect AE;  
• 
Intravenous infusion of SHR-1210; 
• 
Oral administration of rivoceranib (daily, continuously); 
• 
Distribution, verification and return of subject’s diary (only in experimental arm).  
6.3. 
End of Treatment Visit 
When the subject meets any one of the reasons for end of study treatment, relevant 
study procedures for end-of-treatment visit need to be performed. At the end 
of treatment (permanent discontinuation of both of the drugs [SHR-1210 and 
rivoceranib] is required in experimental arm), the end-of-treatment visit will start and 
the following examinations/procedures need to be performed  


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• 
Subject’s self-evaluation results: all the subjects will complete EORTC QLQ-C30, 
QLQ-HCC18 and EQ-5D-5L questionnaires prior to any other study evaluation at 
clinical centers;  
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count; 
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  
• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase level 
is abnormal and clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
12-lead ECG (measured after sitting still for at least 5 minutes): heart rate and QTc 
interval (calculated using Fridericia’s formula);  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Child-Pugh class (see APPENDIX 3 for details); 
• 
Perform a careful, comprehensive physical examination: weight, head and face, 
skin, lymph nodes, eye, ear, nose, throat, mouth, respiratory system, cardiovascular 
system, abdomen, genitourinary system, musculoskeletal, neurological and mental 
status. In addition, physical examination of reactive capillary endothelial 
proliferation needs to be performed on the experimental arm; 
• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout.), 
blood pressure, pulse rate and respiratory frequency;  
• 
Virology (including HBV, HCV markers, see study flow chart for specific 
requirement); 
• 
Fecal occult blood test;  
• 
AFP test;  
• 
Thyroid function (TSH, FT3 or TT3 TF4);  
• 
Coagulation parameters: including INR and/or PT (if INR cannot be collected, PT 
will be used as the basis for judgment); 
• 
Blood human chorionic gonadotropin (HCG) test for WOCBP;  
• 
Collect concomitant medications/therapies;  
• 
Collect adverse events; 


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• 
Tumor radiological evaluation (If previous examination is within 4 weeks of 
end- of- treatment visit, there is no need to repeat these tests); 
• 
Verification and return of subject diary. 
If the ECOG performance, C-P score, vital sign, physical examination, 12-ECG, 
hematology, urinalysis, blood biochemistry, blood electrolyte, coagulation parameters, 
thyroid function, fecal occult blood, virology tests, AFP, HCG or subject’s self-
evaluation are completed within 7 days before withdrawal, these study procedures 
would not be necessary in this visit again. 
6.4. 
Follow-up Period 
Follow-up period is initiated when the end-of-treatment visit is completed. 30 days (±7 
days) after the last dose of study drug, subjects must return to the study center for safety 
follow-up and complete the following parameters for safety evaluation, regardless of 
initiation of new antitumor therapy. The telephone follow-up will be performed 60 days 
(±7 days) and 90 days (±7 days) after the last dose of study drug, only the survival status, 
subsequent antitumor therapy, concomitant medication/therapy and AEs/SAEs within 
the timeframe specified in the protocol need to be collected.  When developing a 
safety follow-up plan, ensure that the visit is scheduled within the safety follow-up 
period (for the experimental arm, 90 days after the last study dose of SHR-1210 or 30 
days after the last study dose of rivoceranib (whichever is longer); for the control arm, 
it is after 30 days after the last study administration.) If the date of the previously 
completed end- of- treatment visit has exceeded the safety follow-up period, there is no 
need to schedule the safety follow-up visit.  
For the subjects in experimental arm, if the date of completed end-of-treatment visit has 
exceeded the first safety follow-up (30 days after the last dose), but the safety follow-
up period has not been exceeded, the subject does not need to go to the site for safety 
follow-up visit, and 1-2 telephone visits can be scheduled during the safety follow-up 
period. In this case, ensure that the interval between visits should not exceed 44 days, 
and a telephone visit should be conducted at the time point of the safety follow-up 
period. 
The following will be performed at safety visit at the study center: 
• 
Subject self-assessed outcomes: The EORTC QLQ-C30, QLQ-HCC18 and EQ-
5D-5L questionnaires should be completed prior to any other clinical evaluation in 
the clinical center during the first safety follow-up period (30 days (±7 days) after 
the last study dose); 
• 
Hematology: including complete blood count and category (white blood cell, red 
blood cell, lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, 
platelet count; 
• 
Urinalysis: including white blood cell, red blood cell, urine protein. In case urine 
protein is ≥ 2＋, 24-hour urine protein quantification must be added;  


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• 
Blood biochemistry: including ALT, AST, total bilirubin, γ-glutamyl transferase 
(GGT), direct bilirubin, ALP, LDH, albumin, blood urea nitrogen [BUN] or urea, 
creatinine, blood glucose, amylase (lipase test needs to be added if amylase level 
is abnormal and clinically significant);  
• 
Blood electrolytes: including potassium, sodium, chlorine, calcium, magnesium, 
phosphorus;  
• 
12-lead ECG (measured after sitting still for at least 5 minutes): heart rate and 
QTc interval (calculated using Fridericia’s formula);  
• 
ECOG-PS score (see APPENDIX 4 for details); 
• 
Child-Pugh class (see APPENDIX 3 for details); 
• 
Weight and physical examination of important sites: cutaneous system, respiratory 
system, cardiovascular system, abdomen and mental state. In addition, physical 
examination of reactive capillary endothelial proliferation needs to be performed 
on the experimental arm; 
• 
Vital signs (performed after sitting still for 5 minutes): including temperature 
(whenever possible, the same method of measurement should be used throughout.), 
blood pressure, pulse rate and respiratory frequency;  
• 
AFP test;  
• 
Thyroid function (TSH, FT3 or TT3, FT4);  
• 
Coagulation parameters: including INR and/or PT (if INR can not be collected, PT 
will be used as the basis for judgment); 
• 
Blood human chorionic gonadotropin (HCG) test for WOCBP;  
• 
Pre-dose sampling: the blood sample will be collected only from experimental arm 
(including SHR-1210 combined with rivoceranib, SHR-1210 monotherapy or 
rivoceranib monotherapy), 30 days (±7 days) after the last dose of SHR-1210. 
When SHR-1210 is interrupted for longer than 30 days and finally is confirmed to 
be unable to resume, for this situation, the subject is required to come for a site visit 
and collect blood sample immediately when investigator confirms the subject is 
permanently terminated SHR-1210 treatment. If the subject has started new anti-
tumor therapy, it’s not necessary to collect the immunogenicity blood sample at 30 
days (±7 days) after the last administration of SHR-1210. Approximately 6 mL 
venous blood will be collected for detection of the serum concentration and 
immunogenicity of SHR-1210;  
• 
Collect concomitant medications/therapies;  
• 
Collect adverse events; 
• 
Tumor radiological evaluation (applicable for the subjects who have not achieved 
radiological progression at the end of study treatment); 
• 
Collect data on survival; 
• 
Collect subsequent antitumor therapy.  


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After the end of safety follow-up, the subjects will enter survival follow-up period. First 
survival follow-up will be performed 30 days (±7 days) after last safety follow-up. 
Investigators must follow up subject’s survival every 30 days (±7 days), until death, 
loss of follow-up, termination of study by the sponsor or reaching other criteria for end 
of study, whichever comes first. Investigators can inquire the subject, his/her family 
members or local physician via phone, collect subject’s survival information (death and 
reason of death) and data on other tumor therapies after the end of study treatment. The 
data on each survival follow-up needs to be recorded in detail in the original medical 
record. 
Subjects who end study treatment for toxicity or other reasons with no radiological 
progression observed still need to receive radiological evaluation according to the 
original frequency, until progression of disease or start of other antitumor therapy 
(except for traditional Chinese medicine), the radiological evidence on PD should be 
obtained from such subjects as much as possible.  
All the treatment-related toxicities must be followed up until they are resolved, 
recovered to baseline or considered as irreversible. AE should be reported and recorded 
according to the requirement during safety follow-up.  
6.5. 
Unscheduled Visits 
For unscheduled visits (e.g., due to AEs) that occur or are needed before the end of 
study, the following items should be recorded: 
• 
Visit date;  
• 
Reason for visit;  
• 
Concomitant medications/therapies (within the collocation period specified in the 
protocol); 
• 
AEs (within the collocation and follow-up period specified in the protocol);  
• 
All the relevant examinations performed (including radiological examination, if 
any);  
• 
Whether the subject can continue or resume study treatment, if yes, record the dose 
administered.  
6.6. 
Treatment Beyond Progression 
If the subject has progression confirmed by BIRC as defined per RECIST v1.1, he/she 
still can continue SHR-1210 alone or combined with rivoceranib (experimental arm) or 
sorafenib (control arm) when he/she can still clinically benefit from and tolerate study 
treatment, as evaluated by investigators. Upon approval of Protocol v6.0, disease 
progression will be confirmed by the investigator per RECIST v1.1. Subjects may 
continue on study treatment beyond the time of investigator-confirmed disease 
progression, at the discretion of the investigator if the subject is perceived to be 
experiencing clinical benefit. 


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6.6.1. 
Criteria on Post-Progression Continuation of SHR-1210 Alone or 
Combined with Rivoceranib in Subjects in Experimental Arm 
A part of subjects receiving immunotherapy can still clinically benefit following 
radiological progression. Although the tumor is enlarged, obvious necrosis or 
degeneration can appear inside the tumor, decreased density inside the tumor foci can 
be shown on CT, it is generally considered that the subject may benefit under this 
circumstance. After progression of disease as defined per RECIST v1.1, and confirmed 
by BIRC subjects meeting all of the following criteria may continue with the study 
treatment until there is no longer benefit from the treatment. Subjects who continue the 
dose following PD will receive periodic visit and efficacy evaluation according to the 
visit schedule specified in the trial. Disease progression will be confirmed by the 
investigator per RECIST v1.1 upon approval of Protocol v6.0; other procedures and 
criteria remain unchanged. 
• 
Investigators judge continuation of study treatment meets the optimal benefit for 
the subject, and the subject does not need to start other antitumor therapy 
immediately;  
• 
The subject can tolerate study treatment;  
• 
Stable ECOG-PS score (≤1);  
• 
No significant clinical symptom/sign of progression of disease, including change 
in laboratory examination parameters;  
• 
Non-rapid progression of disease and progression not involving major organs/sites 
(e.g., spinal cord compression);  
• 
The study treatment can be continued upon the review and approval by the medical 
monitors from the sponsor.  
6.6.2. 
Criteria on Post-Progression Continuation of Sorafenib Treatment in 
Subjects in Control Arm 
The growth of HCC can be possibly inhibited with continuation of the therapy in a part 
of subjects receiving sorafenib after radiological progression, which makes subjects 
clinically benefit. Thus, the subjects meeting all of the following criteria are allowed to 
continue sorafenib treatment after BIRC-confirmed disease progression defined by 
RECIST v1.1 in this study until there is no more benefit from the treatment, disease 
progression will be at the investigator’s confirmation per RECIST v1.1 upon approval 
of Protocol v6.0, other procedures and criteria remain unchanged:  
• 
Investigators judge continuation of sorafenib treatment meets the optimal benefit 
for the subject, and the subject does not need to start other antitumor therapy 
immediately, including but not limited to the second-line Regorafenib;  
• 
The subject can tolerate sorafenib treatment;  
• 
Stable ECOG-PS score (≤1);  
• 
No significant clinical symptom/sign of progression of disease, including change 
in laboratory examination parameters;  


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• 
Non-rapid progression of disease and progression not involving major organs/sites 
(e.g., spinal cord compression);  
• 
The study treatment can be continued upon the review and approval by the medical 
monitors from the sponsor.  
6.6.3. 
Other Precautions for Post-Progression Continuation of Treatment 
The clinical benefit evaluation must take clinical exacerbation, continued benefit from 
the treatment into consideration. Investigator should discuss with the sponsor about the 
decision on post-progression continuation of treatment, as judged by investigators.  
If a decision is made that the subject needs to continue study treatment following 
progression, the subject should be treated, evaluated and followed up as required in the 
protocol.  
The subjects who continue the treatment after PD must be sufficiently informed and 
sign the informed consent form for post-PD continuation of treatment: possible 
alternative therapies, potential risks with continuation of the treatment.  
If the subject terminates the treatment for a global deterioration of health status and has 
no objective evidence on progression of disease, the progression will be reported as 
symptomatic deterioration. Every effort should be made to obtain the objective 
evidence on progression in these subjects after termination of the study treatment (e.g., 
radiological confirmation).  
6.7. 
Study Extension Phase 
The purpose of the extension phase is to continue to provide access to study drugs for 
subjects who are still on study treatment and still derive clinical benefit at the time of 
end of study. It’s a post-trail treatment access phase. Upon initiation of the extension 
phase, the Sponsor considers the safety and efficacy profile of the experimental 
treatment regimen within this study to have been sufficiently established and data 
analysis required for regulatory purposes to have been completed. The Sponsor will 
notify the sites when will the study enter the extension phase. 
In the extension phase, subjects randomized in the experimental arm will continue on 
SHR-1210 in combination with rivoceranib, and subjects randomized in the control arm 
may have the option to crossover to receive experimental treatment and the decision 
made is upon investigator’s clinical judgment. Subjects who are not eligible to 
crossover experimental treatment per investigator clinical judgment can continue on 
sorafenib treatment. Sorafenib can be sourced either locally or centrally which can 
comply with the local regulatory and ethics requirement. 
Subjects will continue to receive study treatment until they are no longer benefiting 
from treatment as assessed by investigator’s clinical judgment. The extension phase 
will continue until the last subject receives the last dose of study drug (expected 
Jan.2025, take the actual occurrence as the standard). Subjects are to undergo periodic 
safety and tumor assessment. The frequency of these assessments during the extension 
phase are to be performed per local standard of care. The investigator should ensure site 
visits occur frequently enough and adequate assessments. Investigator may also refer to 


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the protocol to ensure the periodic visits, tumor assessment and safety management if 
needed.  
In order to collect important safety information for subjects during the extension phase, 
SAEs and pregnancy will continue to be collected. See Section8.3, 8.5 and APPENDIX 
12. 
The study clinical database will be closed at the initiation of the extension phase. 
Important safety information collection in the extension phase will be captured in the 
safety database. 
The schedule of activities for extension phase is presented in APPENDIX 12.  
Subjects who continue on study treatment at the time of extension phase initiation, will 
undergo the end of study treatment visit and perform all the study procedures as the 
protocol required. Subjects who had discontinued study treatment but not yet completed 
the follow up visits (i.e., safety follow up) at the time of extension phase initiation (e.g., 
subject just completed first safety follow up), will undergo the final safety follow up 
visit.  
The time of extension phase initiation may occur at different time points for study sites 
because of different processes at sites. Before extension phase, study sites need to 
ensure that all the data occurring prior to extension phase have been captured into CRFs, 
particularly for safety and survival information. In addition, for the subjects who are 
continuing to receive study treatment, the end of study treatment and end of study page 
in CRFs should be captured as well before entering into extension phase (detailed 
instruction for EOT and EOS page in CRFs for extension subjects. Refer to CRF 
completion guideline). If a scheduled visit occurred within 7 days before the time of 
extension phase initiation or the relevant examinations for end of treatment visit were 
completed within 7 days, these study procedures would not be necessary to be repeated 
on EOT.  
Site monitoring visits will occur at a reduced frequency but must be frequent enough to 
ensure adherence to GCP, study drug accountability, reporting of SAEs and pregnancy.  
During the extension phase, no data are to be entered into CRFs. Study central 
laboratory samples are not to be obtained (e.g., PK, ADA sampling), and radiographic 
images from the site are not to be submitted to BIRC. 
7. 
EVALUATION 
7.1. 
Efficacy Evaluation 
The efficacy endpoints include: 
• 
Overall survival time (OS): defined as the time from randomization to death for 
any cause.  
As well as the following efficacy endpoints evaluated by the BIRC or investigator based 
on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), modified 
RECIST (mRECIST) and immune-modified RECIST (imRECIST):  


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• 
Progression-free survival (PFS): defined as the time from the date of randomization 
to the first occurrence of radiological progression by tumor image evaluation or 
death, whichever comes first, evaluated by the BIRC or investigator based on 
RECIST v1.1, mRECIST or imRECIST. (Radiological progression based on 
imRECIST not considered a PFS event if subsequent assessment evaluated as a 
response or stable after ≥ 4 weeks.)  
• 
Time to progression (TTP): defined as the time from the date of randomization to 
radiological progression of disease, evaluated by the BIRC or investigator based 
on RECIST v1.1, mRECIST or imRECIST. (Radiological progression based on 
imRECIST not considered a TTP event if subsequent assessment evaluated as a 
response or stable after ≥ 4 weeks.) 
• 
Objective response rate (ORR): defined as the percentage of subjects with complete 
response (CR) or partial response (PR) evaluated by the BIRC or investigator based 
on RECIST v1.1, mRECIST or imRECIST. (In respect of ORR based on 
imRECIST, CR and PR can occur after radiological progression). 
• 
Disease control rate (DCR): defined as the percentage of subjects with complete 
response, partial response or stable disease (SD) ≥ 8 weeks evaluated by the BIRC 
or investigator based on RECIST v1.1, mRECIST or imRECIST. (In respect of 
DCR based on imRECIST, CR PR and SD can occur after radiological progression). 
• 
Duration of response (DoR): defined as time from the date of first record of 
objective response (CR or PR) to the first occurrence of radiological progression 
or death, whichever comes first, evaluated by the BIRC or investigator based on 
RECIST v1.1, mRECIST or imRECIST. (Radiological progression based on 
imRECIST not considered a PD event of DoR if subsequent assessment evaluated 
as a response or stable after ≥ 4 weeks.). 
• 
Best overall response (BOR): defined as the best response parameter between the 
date from randomization to objectively recorded progression or subsequent 
antitumor therapy, whichever comes first. For subjects with no progression or 
subsequent antitumor therapy documented, BOR will be determined based on all 
the response evaluation results. (The BOR based on imRECIST is defined as the 
best response between the date of randomization and the initiation of subsequent 
antitumor therapy or during the entire study period). 
7.2. 
Tumor Radiological Evaluation 
7.2.1. 
Tumor Evaluation Based on RECIST v1.1, mRECIST and imRECIST 
RECIST v1.1 (investigator and BIRC evaluated), mRECIST (only BIRC evaluated) and 
imRECIST (only investigator evaluated) will be used for evaluation of tumor response 
in this study, see APPENDIX 2 for the evaluation criteria. 
The tumor evaluation in screening period (at baseline) should include the enhanced 
CT/MRI scan of thorax, abdomen and pelvis. CT scan requires intravenous contrast 
agent and will scan the whole liver area, at least including 1) hepatic arterial phase and 
2) portal venous phase. Enhanced MRI can be used in case of contraindications for CT 
contrast agent. The enhanced MRI of the whole liver should at least include 1) hepatic 
arterial phase and 2) portal venous phase. Cranial enhanced CT or enhanced MRI has 


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to be performed at baseline as well. Systemic bone scan should be performed for 
subjects with known bone metastasis or suspected bone metastasis (exempted in case 
bone scan is performed within 42 days prior to first administration), the bone lesions 
need to be evaluated and followed up after treatment. If clinically indicated, tumors at 
other sites can be evaluated. 
Provision on selection of target lesions: no more than 2 target lesions in each organ, and 
the total number of lesions is not more than 5, more organs involved in tumors should 
be covered as far as possible. At baseline, the number and location of the target lesion, 
the major diameter of each target lesion (except lymph node) and the minor diameter 
of lymph node lesion, as well as the sum of diameters of all lesions should be recorded.  
The baseline evaluation and post-treatment efficacy evaluation should be performed 
using the same method and by the same investigator as far as possible. Following 
randomization, the tumor evaluation will be performed once every 8 weeks (56±7 days) 
in the first 48 weeks, and once every 12 weeks (84±7 days) afterwards. In the absence 
of a BIRC determined progression of the disease (according to RECIST v1.1), tumor 
evaluation should be continued, regardless of whether the subject has terminated the 
study, until the subject dies, withdraws the informed consent, initiates subsequent anti-
tumor therapy or terminated the study by sponsor, whichever comes first. Tumor 
evaluation during treatment includes enhanced CT/MRI scan of thorax, abdomen, 
pelvis and site of lesions; thoracic plain CT scan plus abdominal and pelvic enhanced 
MRI can be performed if the subject is allergic to the contrast agents for enhanced CT; 
cranial enhanced CT/MRI and bone scan can be performed only when clinically 
indicated. Each tumor evaluation must cover all the target lesions, and all the non-target 
lesions if there are no special circumstances.  
Further guidance and recommendations on image acquisition are provided in the Image 
Acquisition Guidelines. 
When clinically indicated, investigators can perform unscheduled tumor evaluation. 
Throughout the study, each subject must use the same procedure of radiological 
examination. Investigators must review the results prior to the next cycle of therapy. 
The subjects who have achieved response (complete response or partial response) for 
the first time need to be confirmed through the next scheduled evaluation or repeated 
evaluation ≥ 4 weeks after the first evaluation.  
When the subject develops disease progression as assessed by the investigator 
according to RECIST v1.1, the investigator is required to submit radiological data 
immediately to BIRC; if BIRC assessed it as non-disease progression according to 
RECIST v1.1, the study drug treatment should be continued for the subject and tumor 
radiological evaluation should continue; if BIRC confirms disease progression 
according to RECIST v1.1, the investigator needs to assess whether the subject still has 
clinical benefit, and if the subject is still considered to have clinical benefit and meets 
the criteria for continued treatment after progression of the disease (see Section 6.6), 
the subject may continue to receive study medication and continue the efficacy 
assessment at the original planned frequency. 
Tumor radiological assessment will continue until the occurrence of disease progression 
confirmed by BIRC according to RECIST v1.1 criteria or study treatment 


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discontinuation, whichever occurs later. Subjects who discontinue treatment for reasons 
other than BIRC-confirmed disease progression (according to RECIST v1.1) will also 
continue with regular follow-up by tumor radiological assessments after treatment is 
completed. Before BIRC confirms the disease progression according to the RECIST 
v1.1 criteria or the treatment is discontinued, if the subject withdraws the informed 
consent, other anti-tumor treatment has begun (except for traditional Chinese medicine), 
or the subject dies, there is no need to continue the radiological evaluation. If the subject 
does not meet the above criteria for stop radiological assessment, the efficacy 
evaluation of the three efficacy evaluation criteria (RECIST v1.1, mRECIST, 
imRECIST) needs to continue even if the disease progression under certain efficacy 
evaluation criteria occurs.  
Once progressive disease occurs, a physical examination of the subject and radiological 
confirmation is required at any times, rather than waiting for the next planned 
radiological examination. If the unplanned radiological findings do not meet the 
RECIST V 1.1 criteria of progressive disease, follow-up examinations should still be 
performed on the original date for the next radiological examination, unless the next 
planned examination is less than 14 days of this one.  
If there has not been any disease progression confirmed by a radiological examination 
when the subject is about to withdraw from the study, it is recommended that a 
radiological examination be performed in time before the withdrawal (if the time from 
the last radiological examination to the withdrawal is ≤ 4 weeks, additional radiological 
examination will not be required at the time of withdrawal). 
Upon approval of protocol v6.0, radiographic images from the sites are not to be 
submitted to BIRC, therefore, disease progression confirmation by BIRC is not needed. 
7.2.2. 
Determination Process for Disease Progression (PD) 
 
Figure 7. 
Disease Progression Confirmation Process 


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7.3. 
Safety Evaluation 
7.3.1. 
Pregnancy Testing 
Blood pregnancy test will be performed within 7 days prior to the start of administration, 
during the treatment period (if needed), end-of-treatment visit and safety follow-up for 
female subjects of childbearing potential. After obtaining the negative result of 
pregnancy test in screening period, appropriate contraceptive measures should be taken. 
The subject will be withdrawn from the trial if HCG test is positive and the pregnancy 
is confirmed by investigator.  
7.3.2. 
Adverse Events 
The evaluation of AE includes type, incidence, severity (in accordance with NCI-
CTCAE v4.03), start and end time, correlation with SAE and prognosis.  
7.3.3. 
Laboratory Safety Evaluation 
Blood and urine samples will be collected in accordance with the study flow chart, 
analyzed and detected in local laboratory. The items of laboratory tests are shown in 
Table 11. 
Table 11 
Items of Laboratory Tests 
Item 
Contents 
Hematology 
Complete blood cell count and category (white blood cell, red blood cell, 
lymphocyte, monocyte, neutrophil, basophil, eosinophil), hemoglobin, platelet 
count. 
Blood 
Biochemistry/ 
Electrolytes 
Including hepatic function (ALT, AST, TBIL, ALP, GGT, direct bilirubin), renal 
function (BUN or urea, creatinine), albumin, amylase (lipase test must be added if 
Amylase level is abnormal and clinically significant), blood glucose, LDH; 
potassium, sodium, calcium, phosphorus, magnesium, chlorine.  
Coagulation 
Parameters 
INR and/or PT (if INR can not be collected, PT will be used as the basis for 
judgment) 
Urinalysis 
Including white blood cell, red blood cell, urine protein. It will be detected within 
72 hours prior to administration at each visit. If urine protein is ≥ 2＋, 24-hour urine 
protein quantification must be added.  
Alpha 
Fetoprotein 
Test 
Alpha fetoprotein 
Thyroid 
Function 
TSH, FT3 or TT3, FT4 
Virology 
HIV-Ab (screening period only), HBV and HCV test should be included.  
Screening period: all subjects will have HBV serological test for five hepatitis B 
markers (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb). HBV-DNA will be quantified 
if the HBsAg or HBcAb test is positive. All subject will have HCV-Ab test, and 
HCV-RNA will be quantified if the HCV-Ab test is positive.  
Treatment period and end-of-treatment visit: Five hepatitis B markers (HBsAg, 
HBsAb, HBcAb, HBeAg, HBeAb) and HBV-DNA needs to be detected every two 
cycles of therapy (starting C3D1, C5D1, C7D1, etc.) for subjects with positive 
HBsAg or HBcAb at screening; HCV-RNA needs to be detected every two cycles 
of therapy (starting C3D1, C5D1, C7D1, etc.) for subjects with positive HCV-Ab at 
screening. 


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7.3.4. 
Physical Examination and Vital Signs 
Physical examination includes height (first collection only), weight, head and face, skin 
system, lymph nodes, eye, otolaryngology, mouth, respiratory system, cardiovascular 
system, abdomen, genitourinary system, musculoskeletal, neurological and mental 
status. The items of physical examination at different time points are provided in 
Section 6 in detail.  
Vital signs include temperature (whenever possible, the same method of measurement 
should be used throughout), blood pressure (which needs to be measured and recorded 
at least twice to get the mean value as the blood pressure value), pulse rate and 
respiratory frequency (performed after sitting still for 5 minutes).  
In addition, physical examination of reactive capillary endothelial proliferation needs 
to be performed on the experimental arm. 
7.3.5. 
12-lead ECG 
Heart rate and QTc interval (calculated using Fridericia formula: QTcF = QT/ 
(RR^0.33), RR is the normalized heart rate and is calculated as 60 divided by heart rate).  
7.3.6. 
Echocardiography 
Including LVEF evaluation. 
7.3.7. 
ECOG-PS Scores 
Criteria for ECOG-PS score can be found in APPENDIX 4. 
7.4. 
Pharmacokinetics and Immunogenicity Evaluation 
7.4.1. 
Collection Time of Blood Samples 
SHR-1210 combined with rivoceranib experimental arm: 
Pre-dose sampling: on Day 1 from Cycle 1 to Cycle 4 (C1D1, C2D1, C3D1, C4D1); 
and on Day 1 of every 3 cycles afterwards (The time point for sample collection will be 
within 0.5 hours prior to rivoceranib administration). Collect once at 30 days (±7 days) 
after the last dose of SHR-1210. When SHR-1210 is interrupted for longer than 30 days 
and if is confirmed to be unable to resume, the subject is required to come for a site 
visit and collect blood sample immediately. If the subject has started other anti-tumor 
therapy, it’s not necessary to collect the immunogenicity blood sample at 30 days (±7 
days) after the last administration of SHR-1210. If SHR-1210 and/or rivoceranib is 
temporarily interrupted, pre-dose immunogenicity and PK sample will be collected on 
schedule. If only rivoceranib is interrupted at time point mentioned above, blood sample 
will be collected within 0.5 hours prior to SHR-1210 administration. The above samples 
will be used to measure the blood concentration and immunogenicity of SHR-1210, and 
the plasma concentration of rivoceranib in the C2D1-C4D1 samples. The exact time of 
the previous administration of rivoceranib will be collected for C2D1, C3D1 and 


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C4D1(the subject is required to provide it).  
ECG blood sampling: ECG examination is performed 2.5 hours (±1 hour) after the end 
of the rivoceranib administration, and blood is collected within 15 minutes after the 
ECG examination on the first day from Cycle 1 to Cycle 4. If rivoceranib is 
discontinued, blood samples within 15 minutes of ECG will not be collected. Plasma 
concentrations of rivoceranib will be measured in the above samples. 
The actual sampling time and the time for the administration of rivoceranib and SHR-
1210 will be recorded on the day of sampling. (refer to BLOOD SAMPLE 
COLLECTION TABLE). 
7.4.2. 
Processing and Storing of Blood Samples 
Approximately 6 mL venous blood samples for measuring the immunogenicity and 
concentration of SHR-1210 will be collected at each timepoint mentioned above. 
2mL venous blood samples for measuring the plasma concentration of rivoceranib will 
be collected at each time point mentioned above.  
The blood samples mentioned above will be transferred into aliquots and then be placed 
in a low temperature freezer until delivered to the central laboratory for detection. 
Detailed procedures and the shelf life are described in the Laboratory Manual. 
7.4.3. 
Delivery of Blood Samples 
The test tube samples will be delivered firstly using dry ice preservation. The back-up 
tube samples will be sent to the bioanalytical laboratory to confirm the receipt of the 
test tube samples. The frequency and information of delivery are provided in the 
laboratory manual in detail.  
7.5. 
Patient Reported Outcomes (PRO) 
All the subjects will complete EORTC QLQ-C30, EORTC QLQ-HCC18 and EQ-5D-
5L questionnaires prior to the administration of study drug and conduction of any other 
study evaluation at the clinical center from Day 1 of Cycle 1, then repeat the above 
procedure on Day 1 of every cycle. In addition, all subjects will be assessed by above-
mentioned questionnaires in the visit of end-of-treatment and first safety follow-up. 
Questionnaires for PRO evaluation should be validated and in subjects’ local language. 
The questionnaires will be paper-based in this study.  
Questionnaires should be completed prior to initiation of any pertinent study visit which 
involves other study activities (including study treatment) and contact with the 
investigator, to ensure that the results are not influenced by the interaction between the 
subject and the investigator. Provide subjects with a quiet place and advise them to 
complete within 30 minutes. The study site should make every effort to ensure that a 
complete questionnaire is obtained from each subject at each scheduled time point, so 
as to avoid any delay in clinical evaluations. 
If there are privacy requirements for filling out questionnaires in local regulations (e.g., 


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if the questionnaire is not supposed to be seen by the clinical staff), the study site should 
make appropriate arrangements to ensure that the requirements are met as far as 
possible. 
7.5.1. 
EORTC QLQ-C30 and EORTC QLQ-HCC18  
EORTC QLQ-C30 is a core scale in the quality of life measurement questionnaire 
system for all cancer subjects that is systematically developed by European 
Organization for Research and Treatment of Cancer (EORTC), and used for 
measurement of quality of life in all the cancer subjects (for the common part). The 
questionnaire is comprised of 5 functional scales (somatic, role, cognitive, emotional, 
social), 4 symptom scales (fatigue, pain, nausea, vomiting), one global health status 
scale and several separate items (including dyspnea, anorexia and insomnia). This 
questionnaire consists of 30 multiple-choice questions.  
The specific module for different cancers is added on EORTC QLQ-C30, i.e., the 
specific scale for different cancers is formed, HCC module (EORTC QLQ-HCC18) is 
used in this study. The samples of EORTC QLQ-C30 (version 3.0)and EORTC QLQ-
HCC18 scales used in this study are seen in APPENDIX 8 and APPENDIX 9.  
In this study, EORTC QLQ-C30 and EORTC QLQ-HCC18 scales will be used to 
evaluate the quality of life (QoL), including health related quality of life (HRQOL) / 
general health state (GHS), physical functioning and role functioning, of subjects with 
advanced HCC who receive SHR-1210 combined with rivoceranib mesylate as a first-
line therapy versus those who receive sorafenib as a first-line therapy. The following 
endpoints are included:  
• 
TTD, defined as time from randomization to first deterioration, as determine by 
following subscales of EORTC QLQ-C30 (decreased by ≥ 10 points from baseline), 
at least maintained for two consecutive time points, or maintained for one-time 
point but death in the following 4 weeks (for any reason):  
• 
HRQOL/GHS 
• 
Physical functioning 
• 
Role functioning 
• 
Average scores and average change from baseline in all the subscales of EORTC 
QLQ-C30 and EORTC QLQ-HCC18 (by cycle);  
7.5.2. 
EQ-5D-5L 
In this study, the health utility index in European five-dimensional health scale (EQ-
5D-5L) and VAS score will be used to evaluate the health status of subjects with 
advanced HCC who receive SHR-1210 combined with rivoceranib mesylate as a first-
line therapy versus those who receive sorafenib as a first-line therapy, so as to generate 
the utility score for health economic assessment. 
EQ-5D is a validated and reliable, self-report-based measurement developed by Euro 
QoL Group to evaluate health- related quality of life. It is a universal scale and currently 
includes two versions, EQ-5D-3L and EQ-5D-5L. The EQ-5D-5L version used in this 


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study includes the EQ-5D-5L descriptive system and EQ visual analogue scale (EQ-
VAS) (See APPENDIX 10 for a sample scale).  
The EQ-5D-5L descriptive system measures subject’s health state from 5 dimensions 
(5D): mobility, self-care ability, daily activities, pain/discomfort and anxiety/depression. 
Each dimension is further divided into 5 levels (5L): (1) no difficulty, (2) slight 
difficulty, (3) moderate difficulty, (4) serious difficulty, (5) extremely serious difficulty. 
Subjects will be asked to select the most appropriate level in each dimension according 
to their health status.  
EQ-VAS is a vertical visual scale in a length of 20cm. Its top is 100 points and 
represents “the best health state in mind”, whereas the bottom is 0 point and represents 
“the worst health state in mind”. Subjects will be asked to mark the point that best suits 
to their own health state on that day on the scale, that is, to score the overall health state 
on that day.  
EQ-5D-5L descriptive system combined with EQ-VAS can fully reflect the health state 
in the study population.  
7.6. 
Evaluation of Exploratory Tumor Markers  
Before enrollment, subjects must be able to provide fresh or archived tumor tissue 
(formalin-fixed, paraffin-embedded [FFPE] tissue block or at least 5 unstained FFPE 
slides) for the immunohistochemical examination of PD-L1 expression level, so as to 
explore the relation between biomarkers and the efficacy of combination therapy. 
Biopsied specimen, such as the specimen biopsied with fine needle aspiration, cell 
smear from pleural effusion drainage and centrifugation or drilled biopsy are inadequate 
to review and evaluate biomarkers. The bone lesions without soft tissue component or 
decalcified tumor specimen are not acceptable. For fresh tumor biopsied specimen, the 
detailed description of its collection, handling, processing and shipment is provided in 
the Laboratory Manual. 
8. 
ADVERSE EVENT REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definition 
AE is defined as adverse medical events that occur after the subject who receives a drug 
in clinical trial, but do not necessarily have a causal relationship with the treatment. 
Refer to Section 8.3 for details on the AE collection period. AE can be any undesirable 
and unexpected symptom, sign, laboratory abnormality or disease, including at least the 
following conditions: 
1) Aggravation of existing (prior to enrollment of clinical trial) medical 
conditions/disease (including exacerbation of symptoms, signs, laboratory 
abnormalities); 
2) Any new occurrence of AE: any adverse medical conditions newly occurred 
(including symptoms, signs, newly diagnosed diseases); 


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3) Abnormal laboratory test or result of clinical significance. 
The investigator should carefully record any AE occurs in the subjects, including: the 
description of adverse event and all relevant symptoms, time of onset, severity, the 
correlation-ship with investigational drugs, duration, actions taken against the study 
drug, final outcomes and prognosis. 
The word “disease progression” should not be reported as an AE term as disease 
progression is an expected occurrence in the study population, except as described in 
8.2.3 section. When a disease progression occurs, the occurrence that confirms disease 
progression should be reported as an AE. For example, if the subject has epilepsy that 
is determined to be related with brain metastasis, epilepsy should be recorded as the AE 
term, rather than “disease progression” or “brain metastasis”. Progression of the disease 
being studied assessed by measurement of lesions on radiographs or other methods 
should not be reported as an AE. 
8.1.2. 
The Judgment Standard on Severity of AE 
Refer to NCI-CTC AE v4.03 grading criteria for AEs related drugs. Refer to the 
judgment criteria in Table 12 if any AE is unlisted in NCI-CTCAE v4.03. 
Table 12 
The Judgment Standard on Severity of AE 
Grade 
Clinical Description of Severity 
1 
Mild; without clinical symptoms or mild clinical symptoms; only with clinical or laboratory 
abnormalities; no treatment is required. 
2 
Moderate, requiring minimal, local or non-invasive treatment; age-appropriate limits in 
Activities of Daily Living (ADL); involving tools refer to cooking, shopping, calling, 
counting money, etc. 
3 
Severe conditions or serious medical symptoms but not life-threatening; leading to 
hospitalization or hospitalization prolonged; leading to disability; limited in self-care ADL. 
Daily self-care includes bathing, dressing, undressing, eating, going to the bathroom, 
medication, and so on, non-bedridden. 
4 
Life-threatening; emergency treatment is required 
5 
Leading to death 
 
8.1.3. 
Causality Assessment 
Collection of AE starts from the signing of informed consent, records are collected 
regardless of whether the event is related to the investigational drug, whether the subject 
is assigned to the experimental arm, or even whether the drug is used or not. Any 
discomfort or abnormal change in objective laboratory tests during the treatment should 
be recorded accurately. Meanwhile the severity, duration, management and outcome of 
the AE should be recorded. The investigator should determine the relationship between 
AE and study drugs, such as whether the occurrence of AE has relationship with a 
reasonable medication order, the properties of study drug, toxicological and 
pharmacological effects of study drug, subjects’ use of other concomitant drugs, 
subjects’ underlying diseases, medical history, family history and provocative and re-
provocative reactions, etc. The causality relationship between AE and study drug will 


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be assessed to be “related” or “unrelated” which are described in the following.   
Related: there is a rational relationship between AE and the study drug, the AE can be 
attributed to the study drug medically (pharmacologically or clinically).  
Unrelated: there is lack of rational relationship between AE and the study drug, and the 
AE can not be attributed to the study drug medically (pharmacologically or clinically), 
and/or there is other rational reason to explain it, such as underlying disease, 
complication, and concomitant medications.  
8.2. 
Serious Adverse Events 
8.2.1. 
Definition of SAE 
Serious adverse event (SAE) is defined as the medical events that require 
hospitalization or prolonged hospitalization, disability, limiting working ability, life-
threatening or death, and leading to congenital malformation during the clinical trial. 
Including the following medical events: 
• 
Events leading to death; 
• 
Life-threatening events (defined as the subject has is at risk of death at the time of 
the event); 
• 
Events requiring hospitalization or prolonged hospitalization; 
• 
Events that result in persistent or significant disability / incapacity / limiting 
working ability; 
• 
Congenital abnormalities or birth defects; 
• 
Other important medical events (defined as the event threatens the safety of the 
subject, or requires intervention measures for the prevention of any of the above 
outcomes). 
8.2.2. 
Hospitalization 
Adverse event which causes hospitalization (even less than 24 hours) or prolonged 
hospitalization should be considered as SAE. 
Hospitalization does not include the following: 
• 
Rehabilitation facilities 
• 
Nursing homes 
• 
Routine emergency room admissions (within 24 hours) 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures) 
• 
Social reason (medial insurance reimbursement, etc.) 
Hospitalization or prolongation of hospitalization in the absence of a deteriorating 
adverse events will not be considered as SAEs. For example, 


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• 
Admission for treatment of a preexisting condition without the development of new 
adverse events or worsening of the preexisting condition (e.g., for work-up of 
persistent pre-trial laboratory test abnormality); 
• 
Administrative admission (e.g., for yearly physical exam); 
• 
Hospitalization as per the trial protocol during the study (e.g., as required by the 
protocol); 
• 
Elective admission not associated with the aggravation of adverse events (e.g., 
elective surgery); 
• 
Predefined treatments or surgical procedures should be documented throughout the 
study program and/or in the baseline data of individual subject; 
• 
Admission exclusively for the administration of blood products. 
Diagnostic or therapeutic invasive (e.g., operation) and non-invasive procedures should 
not be reported as AE, but if the disease condition leading to the operation should be 
reported if it conforms to the definition of AE, e.g., acute appendicitis during the AE 
reporting period should be reported as AE; therefore, the appendectomy should be 
recorded as the treatment of the AE. 
8.2.3. 
Disease Progression and Death 
Disease progression is defined as the exacerbation of the subject caused by indications 
of the study drug, including radiological progression and progression of clinical 
symptoms and signs. New metastases relative to the primary tumor and the progression 
of the original metastases are both considered to be progressive disease. Events that are 
life-threatening, requiring initial or prolonged hospitalization due to symptoms and 
signs of disease progression, which can lead to persistent or significant disability / 
incapacity / limiting work ability are not reported as SAE. If there is any uncertainty 
about whether SAE is caused by the progression of disease, it should be reported as 
SAE.  
All cases of death that occur during the study period must be reported as SAEs, whether 
or not the subject has received other anti-tumor therapy (see Section 8.3). The word 
“death” should not be reported as an AE or SAE term, but as the outcome of the event; 
the AE that causes or contributes to the fatal outcome should be recorded as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, the AE or SAE should be recorded as “unexplained death”, if the cause of 
death later becomes available, "unexplained death" should be replaced by the 
established cause of death  
If death due to disease progression cannot be attributed by the investigator to a medical 
event, a Grade 5 “Tumor progression” should be recorded in the eCRF and reported as 
an SAE. Evidence that the death is due to disease progression (e.g., radiological changes 
suggesting tumor growth or progression, clinical deterioration associated with a disease 
process) should be provided by the investigator. 
8.2.4. 
Reporting Procedures of SAE 
In case of SAE, regardless of first report or follow-up report, the investigator must fill 


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in the “Clinical Trial Serious Adverse Event (SAE)/Special Interest Event (SIE) Report 
Form” immediately, sign and date it, report it to the sponsor within 24h after learning 
of it, and report it to relevant organizations in time as required by regulations.  
The detailed record content of SAE should include symptoms, severity, and association 
with investigational drugs, time of onset, time of treatment, measures taken, follow-up 
time and method as well as outcome. If the investigator considers that a SAE is not 
related to study drug while potentially related to the study conditions (e.g., termination 
of the original treatment or complications during the trial), the relationship should be 
described in detail in the narrative section of SAE report form. If there is a change in 
the severity of an ongoing SAEs or its relationship with the study drug, follow-up 
reports should be submitted immediately. If misinformation is considered to be present 
in the previously reported SAE, it can be corrected, withdraw or degraded in the follow-
up report, and reported in accordance with the SAE reporting procedures. 
The sponsor’s email to receive safety reports (SAE, SIE, pregnancy) in this study: 
hengrui_drug_safety@hengrui.com 
8.3. 
Collection and Follow-Up of AE/SAE 
The period for AE/SAE collection begins from the time that the subject provides 
informed consent, through and including 90 days after the last dose of SHR-1210 or 
30 days after the last dose of targeted anti-angiogenic therapy, whichever comes later. 
SAEs that occur after this period, if suspected to be related to study drug, should also 
be collected. See Table 13 for detailed requirements. An AE/SAE will be followed up 
until it is resolved, returns to the baseline level or ≤ Grade 1, or reaches a stable state, 
or until other reasonable time points (e.g., loss of follow-up, death). Every effort should 
be made to ensure the final outcome and definite causality assessment is obtained. 
Investigators should inquire about AE/SAE after the last visit at each visit and provide 
follow-up data in time according to the sponsor’s queries.  
For the AE/SAE that occurs after extension phase initiation, only SAE should be 
reported to Sponsor via email, and non-serious AE will not be collected. See Table 14 
for detailed requirements. See Section 错误! 未找到引用源。 for reporting 
requirement of pregnancy.  
Table 13 
AE/SAE Collection Period 
Classification 
Requirement for Collection/Record 
Experimental Arm 
Control Arm 
AEs 
unrelated 
to 
study drug a 
Collection continues until 30 days after the last dose of 
study drug. 
Collection 
continues until 30 
days after the last 
dose of study drug. 
AEs related to study 
drug a 
Collection continues until 90 days after the last dose of 
SHR-1210 or 30 days after the last dose of rivoceranib, 
whichever comes later. 
SAEs unrelated to 
study drug b 
Fatal SAEs: Collection continues until 90 days after 
the last dose of SHR-1210 or 30 days after the last dose 
of rivoceranib, whichever comes later. 
Non-fatal SAEs: Collection continues until 30 days 


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after the last dose of study drug. 
SAEs related to study 
drug b 
No time limit 
No time limit 
a. Non-serious AEs. 
b. Include fatal and non-fatal SAEs. 
Table 14 
SAE Collection During Extension Phase 
Classification 
Subjects 
Treated 
with 
Experimental Drug(s) 
Subjects Treated with Sorafenib 
SAEs unrelated to 
study drug  
Collection continues until 30 days 
after the last dose of study drug. 
Collection continues until 30 days 
after the last dose of study drug. 
SAEs related to study 
drug  
No time limit.  
No time limit 
8.4. 
AEs of Special Interest 
For the AE of special interest (SIE) specified in the study protocol (as below), 
investigators need to fill in the “Clinical Trial Serious Adverse Event (SAE)/Special 
Interest Event (SIE) Report Form” within 24h after the event is known, and report to 
the sponsor. 
• 
≥ Grade 3 infusion reaction 
• 
≥ Grade 3 immune-related AE 
• 
AEs that meet the criteria defined in Section 8.4.1 (Liver Function Test [LFT] 
Abnormalities) 
8.4.1. 
Liver Function Test (LFT) Abnormalities 
Considering the specialty of abnormal liver function at baseline in HCC subjects, 
abnormal values in ALT and/or AST concurrent with abnormal elevations of TBIL that 
meet the criteria outlined below (i.e., meeting the criteria [1] and [2] for elevated ALT 
or AST and bilirubin as well as the criterion [3]) in the absence of other causes of LFT 
abnormalities should always be reported as SIEs.  
1) 
ALT or AST ≥ 3 × ULN (normal at baseline), ALT or AST ≥ 3 × baseline value 
(abnormally elevated at baseline) 
2) 
TBIL ≥ 2 × ULN (normal at baseline), TBIL ≥ 2 × baseline value (abnormally 
elevated at baseline) 
3) 
Excluding other causes of LFT abnormalities (e.g., disease progression, acute 
viral hepatitis, cholestasis, underlying hepatic disease, and concomitant 
medications with hepatotoxicity). 
Subjects should return to the study center as soon as possible after learning the abnormal 
results (preferably within 48 hours). Evaluation should include laboratory examination, 
detailed medical history and physical evaluation. 
Besides repeated measurement of AST and ALT, the laboratory examination should also 
include albumin, creatine kinase, total bilirubin, direct bilirubin, γ-glutamyl transferase, 


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PT/ INR, and alkaline phosphatase. Collection of detailed medical history should 
include history of alcohol, acetaminophen, soft drugs, various supplements, family 
history, occupational exposure, sexual behavior history, travel history, contact history 
with jaundice subjects, surgery, blood transfusion, hepatopathy or allergic disease 
history. Further examinations also include detection of acute hepatitis A, B, C and E as 
well as radiological examination of liver (e.g., biliary passage). 
8.5. 
Pregnancy 
If a female subject becomes pregnant during the clinical trial, the subject must 
discontinue the study drug immediately; if the partner of male subject becomes pregnant 
during the clinical trial, the subject can continue the clinical trial.  
For pregnancy of female subjects or partners of the male subjects during this study, 
investigators should fill in “Pregnancy Report/Follow-up Form in Hengrui Clinical 
Study”, and report to the sponsor within 24 hours after investigator awareness, and 
report to the ethics committee in time.  
The investigator should follow up the pregnancy outcome, until one month after 
delivery, and will report the outcome to Sponsor and Ethics Committee. 
If the outcome of pregnancy is stillbirth, spontaneous abortion, or fetal malformations, 
it should be considered as an SAE and be reported to Sponsor, regardless of causality. 
9. 
CLINICAL MONITORING 
In order to make sure the subject’s rights are protected, all the data should be reported 
accurately, completely and reliably. The trial should be conducted in accordance with 
currently approved protocol/revised protocol, ICH-GCP and appropriate regulations; 
clinical monitoring is needed for the study center. 
10. 
STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared to provide further details regarding 
the definition of analysis variables and analysis methodology to address all study 
objectives. The SAP will serve as a compliment to the protocol and where there is a 
discrepancy between the SAP and protocol, the SAP will supersede it. Any critical 
revision within the SAP of definition(s) or analysis method(s) for the primary endpoints 
will be included in a protocol amendment.  
10.1. Sample Size Determination 
Assuming a 1:1 randomization between sorafenib and SHR-1210+rivoceranib, and a 
median PFS time of 3.6 months for subjects in the sorafenib group and a median PFS 
time of 6 months for subjects in the combination group, 332 PFS events will be 
sufficient to detect a hazard ratio (HR) of 0.60 with 98% power based on Log-rank test 
at significance level of 0.005 one-sided. Similarly, assuming a median survival time of 
10.5 months for subjects in the sorafenib group and a median survival of 14.6 months 
for subjects in the combination group, 359 OS events will be sufficient to detect a 
hazard ratio (HR) of 0.72 with 85% power based on Log-rank test at significance level 


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of 0.020 one-sided. Assuming an accrual period of 18 months, total duration of 36 
months and 19 months for the OS and PFS, respectively, and probability of subject loss 
be approximately 10% per 12 months and per 6 months for the OS and PFS, respectively, 
a sample size of 510 subjects will be enrolled for the study. Power and sample 
calculations were performed using EAST® 6.4.1. software package. 
10.2. Objectives and Statistical Hypotheses 
10.2.1. Primary Objectives and Statistical Hypotheses 
Objectives: To compare efficacy endpoints of OS and PFS evaluated by the BIRC based 
on RECIST v1.1 in 2 experimental arms (SHR-1210 in combination with rivoceranib 
versus sorafenib).  
Hypothesis: SHR-1210 in combination with rivoceranib prolongs OS compared to 
sorafenib. 
Hypothesis: SHR-1210 in combination with rivoceranib prolongs PFS (assessed by 
BIRC based on RECIST v1.1) compared to sorafenib. 
10.2.2. Key Secondary Objectives and Statistical Hypotheses 
Objective: To compare the ORR (assessed by BIRC according to RECIST) of SHR-
1210 in combination with rivoceranib to sorafenib 
Hypothesis: The ORR (assessed by BIRC according to RECIST v1.1) of SHR-1210 
combined with rivoceranib is superior to sorafenib. 
10.3. Analysis Populations 
• 
Intent-to-treat (ITT): This population will include all randomized subjects. Subjects 
will be included in the experimental arm to which they are randomized.  
• 
Safety Analysis Set (SS): This population will include all treated subjects who 
receive at least 1 dose of study treatment. For most subjects, this will be the 
experimental arm to which they are randomized. For subjects who take incorrect 
study treatment for the entire treatment period, safety data will be analyzed based 
on the treatment they actually receive.  
• 
Anti-drug Antibody (ADA) Analysis Set: This population will include all subjects 
who receive SHR-1210 in combination with rivoceranib and had at least 1 ADA 
measurement. 
• 
PK Analysis Set: This population will include all the subjects who receive PD-1 
antibody SHR-1210 combined with rivoceranib and who have at least one result 
for drug concentration at any time during the study. 
10.4. Statistical Analysis Methods 
10.4.1. General Method 
This is a parallel group, controlled study. All statistical tests, unless otherwise specified, 
will be analyzed by experimental arms and using the appropriate statistics according to 


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the data type. Summary statistics for continuous variables will include the mean, 
standard deviation, median, and range (minimum/maximum). Categorical variables will 
be presented as frequency counts and percentages. Time-to-event variables will be 
summarized by Kaplan-Meier (K–M) medians and 95% CI. 
10.4.2. Subject Disposition 
The number of subjects enrolled, treated, discontinued and those with major protocol 
deviations will be counted. The primary reason for study drug and/or study 
discontinuation will be summarized according to the categories in the eCRF. The end 
of study status (alive, dead, withdrew consent or lost to follow-up) at the data cutoff 
date will be summarized.  
10.4.3. Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive 
statistics. Continuous variables include age, weight, vital signs, time since initial cancer 
diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables 
include, gender, ECOG-PS score, geographical region, country, race, Child-Pugh 
classification, hepatitis virus, BCLC staging, metastatic site, and macrovascular 
invasion and/or extrahepatic spread status etc.  
10.4.4. Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary drug codes. 
Prior and concomitant medications will be summarized and listed by drug and drug 
class. Prior medications will be defined as medications taken within 28 days of the first 
dose of study drug that were stopped prior to study drug administration. Concomitant 
medications will be defined as medications that 1) started before the first dose of study 
drug and were continuing at the time of the first dose of study drug, or 2) started after 
the first dose of study drug. Prior and concomitant medications will be listed. 
10.4.5. Primary Efficacy Endpoints Analyses 
The two primary endpoints for the study are OS and PFS (assessed by BIRC based on 
RECIST v1.1). For the PFS endpoint, there is one planned analysis, which is expected 
to occur when ~332 PFS events are observed ~19 months after first subject enrolled. 
For the OS endpoint, it will be evaluated in the following time points: when PFS is 
analyzed (approximately 19 months after first subject enrolled); when ~251 OS events 
(70% at ~23 months after first subject enrolled) and when 359 OS events are observed 
(at ~36 months after first subject enrolled).  
The hypothesis testing of OS and PFS will be evaluated by comparing SHR-1210 plus 
rivoceranib to sorafenib on their events in ITT using a stratified Log-rank test (based 
on randomization stratification factors). The hazard ratio (HR=SHR-1210 plus 
rivoceranib / sorafenib) and the corresponding 95% confidence interval (CI) will be 
estimated in a stratified Cox proportional hazard model with experimental arm and 
randomization stratification factors included in the model. Survival curves for each 
treatment group will be estimated using the Kaplan-Meier (KM) product-limit method. 
A 95% CI for median survival time will be estimated by Brookmeyer-Crowley method. 
The above analyses will be repeated without the stratification factors included in the 


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analysis. In case the proportional hazard is not valid, Wilcoxon test or RMST 
(Restricted Mean Survival Time) method may be performed for OS and PFS analysis. 
Detail of multiplicity control can be found in Section 10.4.12.  
Further detail, including censoring rules, will be provided in the SAP. 
10.4.6. Secondary Efficacy Endpoints Analyses 
Objective response rate (ORR) assessed by BIRC according to RECIST v1.1 will be 
analyzed as a key secondary endpoint when 70% OS events are observed. If both PFS 
and OS primary endpoints are positive, comparison between treatment groups in ORR 
by BIRC according to RECIST v1.1 will be performed using stratified Cochran-Mantel-
Haenszel (CMH) test. Difference in proportions for ORR and its 95% CI using normal 
approximation will be provided. Overall response rates and their corresponding 95% 
exact CIs will be calculated by Clopper-Pearson method for each treatment group. 
The other time-to-event endpoints will be estimated using the Kaplan-Meier (KM) 
product-limit method, unless specified. A 95% CI for median survival time will be 
estimated by Brookmeyer-Crowley method, if necessary.  
For other binary variables, stratified CMH test will be used and two-sided 95% CI for 
treatment difference will be calculated using normal approximation. 
Further elaborations will be provided in the SAP. 
10.4.7. Pharmacokinetics and Immunogenicity  
The incidence of ADA and the proportion of subjects with neutralizing active antibodies 
(Nab) in subjects treated with SHR-1210 in combination with rivoceranib will be 
summarized using descriptive statistics by experimental arm and by visit. ADA/Nab in 
combination with SHR-1210 concentration, safety, and efficacy will be summarized 
using descriptive statistics (see Section 10.4.8). Any other analysis methods will be 
elaborated in the corresponding analysis plan. 
The population PK, exposure-QTc analysis and exposure-response analysis will be 
performed and reported separately. 
10.4.8. Exploratory Endpoints Analyses 
The time to deterioration (TTD) of EORTC QLQ-C30 endpoints will be analyzed using 
similar method for the primary endpoint OS (stratified Cox model and K-M curve). The 
scores of other scales and the average change from the baseline will be summarized 
using descriptive statistics by treatment cycle. 
The correlation of the expression level of PD-L1 and proportion of strong expression 
of PD-L1 in tumor tissue with the efficacy of SHR-1210 combined with rivoceranib 
mesylate (including but not limited to ORR, OS) will be summarized using descriptive 
statistics. If necessary, an ad hoc analysis will be performed and results will be 
presented in a separate supplementary report. 


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Efficacy endpoints (e.g. BOR, ORR) and safety endpoints (e.g. immune-related adverse 
events (irAE), study drug-related AE with CTCAE grade ≥ 3, drug-related SAE) with 
SHR-1210 ADA/Nab status in experimental arm will be summarized using descriptive 
statistics. If necessary, a comparison of efficacy and safety will be performed according 
to the ADA status. 
PFS, TTP, ORR and DoR assessed by investigator based on imRECIST will be 
evaluated using the same analytical methods for the secondary endpoints. 
Other analytical methods for exploratory endpoints will be elaborated in the SAP. 
10.4.9. Handling of Missing Data 
Except for the special cases, the following rules will be applied to the missing date of 
the events. 
If the start date of the event is all missing, it will not be imputed. If the day is missing, 
but the year and month are consistent with the year and month of the study drug 
treatment, the day of the first study drug treatment will be used. Otherwise, the first day 
of the month will be used. If the day of end date is missing, but the year and month are 
consistent with the year and month of the end of study drug treatment, the day of 
end - of-treatment will be used. Otherwise, the last day of the month will be used. 
If the month and day of the event are missing, but the year of occurrence is consistent 
with the year of study drug treatment, the month and day of the first study drug 
treatment will be used. Otherwise, January 1 will be used. 
All imputation dates should be prior to the date of withdrew consent, lost to follow-up 
or death.  
10.4.10. Safety Analyses 
10.4.10.1. Analyses of Adverse Events 
Adverse events will be coded to MedDRA (v 18.1 or higher) for lower level term (LT), 
preferred term (PT) and primary system organ class (SOC). 
A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) that 
had an onset date after the start of the study treatment or that worsened in severity from 
baseline (pretreatment).  
Only those AEs that were treatment-emergent will be included in summary tables. All 
AEs, treatment-emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with 
TEAEs by SOC and preferred term. A subject will be counted only once by the highest 
severity grade per NCI-CTCAE v4.03 within an SOC and preferred term, even if the 
subject experienced more than 1 TEAE within a specific SOC and preferred term. The 
number (percentage) of subjects with TEAEs will also be summarized by relationship 
to the study drug. Treatment-related AEs include those events considered by the 
investigator to be definitely, possibly related to study treatment or with missing 


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assessment of the causal relationship.  
Subject incidence of AE, SAE, AE with CTCAE Grade ≥ 3, SAE with CTCAE Grade 
≥ 3, drug related AE, drug related SAE, AE with incidence ≥ 5%, SAE with incidence 
≥ 5%, AE leading to dose adjustment, AE leading to discontinued treatment etc. will be 
tabulated by experimental arm. Time-to-adverse events of special interest, and duration 
of events will be analyzed using K-M method.  
10.4.10.2. Laboratory Tests Results 
Clinical laboratory (e.g., hematology, blood biochemistry) values will be evaluated as 
appropriate. Abnormal laboratory values will be flagged and identified as those outside 
(above or below) the normal range. The number and percentage of subjects 
experiencing Clinically significant laboratory values at baseline and worst post-dosing 
will be summarized by shift table. 
Laboratory parameters that are graded in NCI-CTCAE v4.03 will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, 
parameters with NCI-CTCAE grading in both high and low directions will be 
summarized separately.  
10.4.10.3. Others 
The number and percentage of findings of clinically significant abnormal for vital signs 
will be summarized by experimental arm. A listing will also be provided for vital signs. 
The analyses of ECOG-PS will include summary statistics of baseline and highest score 
post baseline by experimental arm. 
The analyses of ECG will include summary statistics of baseline and worst clinically 
abnormal grade post baseline by experimental arm.  
10.4.11. Interim Analyses 
In this study, there is only one planned PFS analysis, which is planned at occur when 
~332 PFS events are observed (at ~19 months). OS analyses will be conducted at the 
following time points: at final PFS analysis, at 251 (70%) deaths if there are less than 
251 deaths at the final PFS analysis, and when ~359 OS events are observed (at ~36 
months.  
PFS 
If SHR-1210 in combination with rivoceranib arm demonstrated superiority over 
sorafenib (i.e., one-sided p-value < 0.005), its corresponding alpha level of 0.005 will 
be re-allocated to test the OS hypothesis at 0.025 one-sided with updated efficacy 
boundaries per Lan-DeMets O'Brien-Fleming spending function (see Table 15 ).  
OS 
A formal interim analysis (IA) for OS will be conducted after 70% (~251) of the target 
OS events are observed at ~23 months. The OBF was used for calculating efficacy 
boundaries (original 0.020/updated 0.025 alpha level). With ~251 OS events, the SHR-


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1210 in combination with rivoceranib mesylate will be considered superior than the 
sorafenib at the interim analysis, if the one-sided p-value for OS is less than 0.005/0.007, 
which corresponds to an observed HR of approximately 0.725/0.735. The trial will be 
considered positive at the final analysis, if the one-sided p-value for OS is less than 
0.018/0.023, which corresponds to an observed HR of approximately 0.802/0.810. If 
the null hypothesis for OS is rejected at either the interim (70%) or the final, its 
corresponding alpha level of 0.020 will be re-allocated to PFS so that the hypothesis 
for PFS maybe tested again at 0.025 one-sided. The boundary properties for the planned 
OS analyses based on the original and updated alpha levels can be found in Table 15
 
.  
In an anticipation that the number of OS events is < 251 OS events at the planned PFS 
analysis, a nominal alpha of 0.001% will be spent at the time of the planned PFS 
analysis. Since the trial will not stop early if there are less than 251 deaths, the 0.001% 
is considered for administrative purposes to avoid trial stop early. The study will 
continue to the next planned OS interim analysis (70%) and could continue to final 
analysis after ~251 OS events and ~359 OS events are observed, respectively, according 
to the efficacy boundaries as described in Table 15 . 
The analysis of PFS and the formal interim analysis (IA) of OS will be conducted by a 
Data Monitoring Committee (DMC) that recommends early discontinuation of the 
study for unequivocal efficacy at formal interim analysis (IA) of OS (~70% events), or 
continuation of the study for final analysis of OS. 
10.4.12. Multiplicity 
The two primary endpoints for the study are OS and PFS (assessed by BIRC based on 
RECIST v1.1). There is only one planned PFS analysis, which is expected to occur 
when approximately 332 PFS events are observed at approximately 19 months. OS 
analyses will be conducted at the following time points: at final PFS analysis, at 251 
(70%) deaths if there are less than 251 deaths at the final PFS analysis, and when ~359 
OS events are observed at ~36 months, respectively.  
The Type I error of 0.025 one-side is strongly controlled using the Weighted-Holm 
procedure with α-reallocation approach between PFS and OS endpoints as described in 
Ye et al 2013 [27] and O’Brien-Fleming alpha-spending function (OBF) within OS. The 
allocated α between two endpoints is α1=0.005 (one-sided) for PFS and α2=0.020 (one-
sided) for OS. If PFS endpoint is significant at α1=0.005, its α1 level will be re-allocated 
to endpoint OS so that the hypothesis for OS may be tested using its updated efficacy 
boundaries based on α level 0.025. Similarly, if endpoint OS is significant at α2=0.020 
according to the efficacy boundaries as determined by OBF, and PFS endpoint is not 
significant at α1=0.005, its α2 level will be re-allocated to PFS so that the hypothesis for 
PFS may be tested again at α level 0.025 (one-sided). The boundary properties for the 
planned OS analyses based on the original and updated alpha levels are summarized in 
Table 15 below: 
Table 15 
Boundary Properties for Planned Analyses of OS 
Analysis 
Value 
α=0.020 
α=0.025 
Interim analysis：~70% 
Z 
-2.549 
-2.440 


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Events：251 
p (one-sided) 
0.005 
0.007 
Months：~23 
HR at bound 
0.725 
0.735 
Final analysis 
Z 
-2.089 
-2.000 
Events：359 
p (one-sided) 
0.018 
0.023 
Months：~36 
HR at bound 
0.802 
0.810 
Note: Results were generated using the EAST® 6.4.1. software; HR=Hazard ratio 
(SHR-1210 + rivoceranib / Sorafenib) less than 1 indicates SHR-1210+rivoceranib 
group is superior than Sorafenib arm. The one-sided nominal significance level and 
stopping boundary will be determined by the actual percentage of events when the 
interim analysis is conducted. 
If both PFS and OS endpoints are not significant, then α-reallocation will not perform. 
If both the PFS and OS endpoints are significant, ORR assessed by BIRC according to 
RECIST v1.1 may be tested at 0.025 one-sided. The graphical approach in Figure 8 
shows the α-reallocation strategy for endpoints PFS and OS [28, 29]: 
 
 
 
Figure 8. 
Type I error reallocation strategy for endpoints PFS and OS. 
Above shows the initial one-sided α-allocation for each hypothesis in the ellipse 
representing the hypothesis. The weights for re-allocation from each hypothesis to 
another are represented in the rectangular boxes on the lines connecting hypotheses. 
When there are less than 251 OS events at the planned PFS analysis at ~19 months, a 
nominal α (0.001%, independent of OBF approach to allocate alpha) will be used, but 
the trial will not stop based on this OS result at the time of the PFS analysis. The study 
will continue to the next planned OS interim analysis (70%) and could continue to the 
final analysis after ~251 OS events and ~359 OS events at ~23 and ~36 months, 
respectively, at the alpha level as determined by the OBF boundaries and the actual 
number of OS events observed. The nominal alpha (0.001%) is considered, as this has 
negligible impact on overall Type I error rate and the study will not stop early for a 
positive OS result at the time of the PFS analysis.  
Any changes to the above strategy will be documented elsewhere, if not in a protocol 
amendment, at the earliest time before any formal analysis is being conducted. 
10.4.13. Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, HR 
and 95% CI for the primary endpoints OS and PFS (assessed by BIRC based on 
RECIST v1.1) will be estimated and plotted within each category of the following 
classification variables:  
• 
Age (<65 years vs. ≥ 65 years) 
• 
Gender (male versus female) 
PFS 
α1=0.005 
OS  
α2=0.020 
1.0 
1.0 


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• 
Geographic Region (Asia vs countries outside of Asia) 
• 
Race (Asian vs non-Asian) 
• 
Country (Greater China area [mainland China, Hong Kong and Taiwan] vs US vs 
Europe) 
• 
BCLC stage (Stage B vs Stage C) 
• 
Macrovascular invasion and/or extrahepatic spread (Presence vs. Absence) 
• 
The underlying disease or medical condition related to etiology (HBV vs HCV vs 
others) 
• 
AFP elevation at the baseline (<400 ng/mL vs ≥400 ng/mL) 
• 
Involved disease sites (1 vs 2 vs ≥ 3) 
• 
Previous local therapy (including radiotherapy) (yes vs no) 
• 
Weight (<60 kg vs. ≥60 kg) 
• 
ECOG-PS Score (0 vs. 1). 
10.5. 
Blinded Independent Review Committee 
A BIRC will be established to perform an independent review of all radiological images 
(imaging for tumor assessment will be provided by study centers to BIRC), and to 
determine all instances of response and disease progression on the basis of RECIST 
v1.1 and mRECIST criteria. If the investigator evaluates it as PD according to the 
RECIST v1.1 criteria, all radiological data must be submitted to BIRC, and PD will 
have to be confirmed by BIRC (Please refer to Figure 7 for PD confirmation process), 
and even if BIRC confirms PD per RECIST v1.1, the investigator needs to evaluate 
whether the subject continues to have benefit and meet the criteria for continued 
treatment beyond disease progression, and if so, the subject will continue the treatment 
and continue to be performed tumor radiological assessments. 
The tumor assessment by BIRC will be used for the reporting of the study results. All 
decisions made during the performance of the study will be on the basis of the local 
investigator’s assessment of radiographic images, clinical status, and relevant 
examination of the subjects. Sites will submit specific radiographic image files to the 
centralized data review facility during the study at an ongoing basis or at the sponsor’s 
request. Detail rules and guidelines for radiographic radiological and tumor assessments 
by BIRC will be outlined separately in the DMC charter, Image Acquisition Guidelines, 
and Central Laboratory Manual. 
10.6. Data Monitoring Committee 
The study will establish an independent Data Monitoring Committee (DMC) to 
regularly assess safety data, and analysis will be conducted for assessment of efficacy 
and safety at the time of PFS analysis and OS interim analysis. The DMC will provide 
advice on the measures that must be taken for protection of subjects and overall safety 
evaluation to the sponsor.  
The DMC is the consultant to the study team of the sponsor. The study team of the 
sponsor are responsible for overall conduction of the study, including management of 


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the exchange and communication of study data, analysis based on the advice from the 
DMC, and making decisions on continuation of, amendment to or termination of the 
study.  
After the study is initiated, the DMC will hold meeting to evaluate safety data on a 
regular basis, as to ensure the subject’s safety is carefully supervised. The sponsor can 
also consult the DMC in a retrospective manner based on the safety signals discovered, 
and hold retrospective safety review meetings as required. The DMC can make 
recommendations for continuing, revising or terminating the study based on observed 
safety or efficacy data. Prior to the meeting, the DMC will look up and review the study 
data acquired, including the characteristics of the study population, dose information, 
safety and efficacy data in PFS analysis.  
The composition, responsibilities, frequency, format, operation and management of the 
DMC will be detailed in a separate DMC charter. 
11. 
DATA MANAGEMENT METHODS 
11.1. Recording of Data 
Electronic data capture system (EDC) will be used for collection and management of 
clinical study data in this study. 
11.1.1. Recording of Source Document 
The source document should be completely maintained as the original document in 
clinical trial. They should be filled in and maintained by investigators. The subject's 
information on the cover of the source document should be checked firstly prior to 
filling in each time, the handwriting should be legible and easy to read, so that the 
monitor can check the data with eCRF. 
11.1.2. Filling of eCRF 
The data in eCRF comes from original documents such as medical record and 
laboratory examination report, and should be consistent with the original documents. 
Any observation and examination result during the trial should be filled in the eCRF 
promptly, correctly, completely, standardized and truthfully. 
The reason for data modification needs to be filled in accordance with the system 
implication, when the data in eCRF are corrected. 
11.1.3. eCRF Review 
Investigators should fill in, save and submit the eCRF promptly after the end of each 
visit. The system logic verification program will check the integrity and logic of the 
data entered in EDC system, and query the problem data. The principal investigator or 
data entry personnel are allowed to modify or explain the problem data, and multiple 
queries can be raised until the problem data are resolved, when necessary. Monitors, 
data administrator and medical auditors will review eCRF data when necessary and 
query the doubtful data. Investigators should respond to the queries from the system 
and data auditors in time. After completion of data clearance, investigators will sign the 


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electronic signature of the completed eCRF. 
11.2. Data Management 
11.2.1. Establishment of EDC Database 
Data administrator will establish study data collection system and database in 
accordance with the protocol, and provide on-line use prior to enrollment of the subject. 
All EDC users need to complete relevant training, fill in training records, and account 
application forms to obtain the corresponding account of the login system.  
11.2.2. Data Review and Database Lock 
Prior to database lock, the project team need to summarize all the events of deviation 
from protocol during the trial, and hold data review meeting. Any decision made during 
the data review meeting should be documented. 
After all data have been reviewed, database lock will be confirmed by investigators, 
sponsor and statisticians. The data documents can not be modified after locking. Post-
locking data need to be properly maintained for future reference.  
11.2.3. Data Archiving 
After completion of the study, subject’s eCRF in a format of PDF should be generated 
in EDC system, and saved onto a CD-ROM, and submitted to sponsor and the 
organization to maintain the file for inspection. 
The storage and management of study documents must be performed in accordance 
with the requirement of ICH-GCP, investigators should inform the sponsor in advance 
when destroying any document or data related with the trial. After marketing approval of 
the investigational drug in the last country or region, or if the trial was discontinued, 
the sponsor must keep the study documents for at least 15 years. 
12. 
SOURCE DATA AND SOURCE DOCUMENT 
According to the International Council for Harmonization (ICH) E6, relevant 
regulations and study centers’ requirements for the protection of subjects’ personal 
information, each study center must keep records of treatment and research related to 
this study properly. As one part of the study funded or involved by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd., each study center should allow Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. or its authorized representative and regulatory authorities to 
audit (replicate if allowed by the law) the clinical records, as to perform quality review 
and audit, as well as evaluation of safety, study progress and data verification.  
The source data are all the information necessary to reconstruct and evaluate clinical 
study, and are the original record of clinical findings, observations or other activities. 
Examples of these source documents and data include, but are not limited to: hospital 
records, laboratory records, memoranda, subject’s diaries, pharmacy dispensing records, 
recording of consultation meetings, recording data of automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, and records kept at the 


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pharmacy, at the laboratories and at medico-technical departments involved in the study.  
13. 
QUALITY ASSURANCE AND QUALITY CONTROL 
In order to ensure the quality of the trial, the clinical study plan is discussed and 
established by the sponsor and investigators prior to the official start of the trial. And 
they should confirm whether the personnel involved in the trial has received appropriate 
GCP training. 
Each study site must manage the investigational drugs in accordance with SOP, 
including receiving, storage, dispensation, recovery and destroying (if applicable). 
According to ICH-GCP guidelines, necessary procedures must be taken during the 
design and implementation of the study, to ensure that the collected data are accurate, 
consistent, complete and reliable. All the results and abnormal findings observed in the 
clinical trial should be verified and recorded promptly to ensure the reliability of data. 
The instruments, equipment, reagents and standard materials used in the clinical trial 
should have strict quality standards, and ensure that they are working under normal 
conditions. 
The investigators input the required information into the eCRF, the monitors check the 
complete and accurate filling, and instruct the personnel at the study center for 
necessary modification and supplementation. 
Regulatory Authorities, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), the Sponsor's monitors and/or auditors may conduct a systematic 
review of the clinical trial-related activities and documents to assess whether the trial 
has been conducted in accordance with the trial protocol, SOP and the requirements of 
relevant laws and regulations, and whether the trial data are timely, truthfully, 
accurately and completely recorded. The audit should be performed by the personnel 
who are not directly involved in the clinical trial. 
14. 
REGULATIONS, ETHICS, INFORMED CONSENT AND 
PROTECTION OF SUBJECTS 
14.1. Considerations on Regulations 
This study will be conducted completely in accordance with ICH E6 GCP guideline and 
the principle of Declaration of Helsinki, and national laws and regulations, as to provide 
the maximum protection for individuals. This study will comply with the requirements 
in ICH E2A guideline (clinical safety data management: definition and criteria of 
accelerated reporting).  
Legal basis for design of this protocol: 
1) Drug Registration Regulations; 
2) Good Clinical Practice; 
3) Technical Guidelines for Clinical Pharmacokinetics of Chemical drugs; 


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4) Based on the ethical principle and consensus in the international ethical guidelines, 
including Declaration of Helsinki and the international ethical guidelines by the 
Committee of International Organization in Medical Science (CIOMS); 
5) ICH Guidelines; 
6) Other applicable laws and regulations. 
14.2. Ethics 
Investigators will make sure this study will be performed completely in accordance with 
the requirement on protection of subjects specified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56 and/or ICH E6.  
The sponsor and investigator must not amend this study protocol unilaterally without 
mutual agreement. Only limited to eliminate the direct and immediate injury to subjects, 
investigators can change or deviate from the study protocol prior to approval by the 
ethics committee/IRB. At the same time, all the deviations or changes made and their 
reasons, and the recommended amendment to the protocol should be submitted to the 
ethics committee/IRB for review as soon as possible. Investigators must explain and 
record any deviation from the protocol. 
During the clinical study, any amendment made to the study protocol should be 
submitted to the ethics committee, corresponding amendment should also be made to 
other study documents when necessary and submitted and/or approved as required by 
the ethics committee. Investigators are responsible for periodic submission of the mid-
term report to the ethics committee in accordance with relevant requirement and should 
inform the ethics committee that the trial has ended after the end of trial. 
14.3. Independent Ethics Committee 
The protocol, informed consent form, recruiting materials and all the subjects’ materials 
will be submitted to the ethics committee for review and approval. The subjects can be 
enrolled only after approval of the protocol and informed consent form. Any 
amendment to the protocol can be implemented only after review and approval by the 
ethics committee. All the amendments to the informed consent form also have to be 
approved by the ethics committee, and it will be decided by the ethics committee 
whether the new version of informed consent form needs to be re-signed for the subjects 
who have signed the previous version. 
14.4. Informed Consent 
14.4.1. Written Information Required for Informed Consent Form and Subjects 
The informed consent form will describe the investigational product and course of study 
in detail, and make a sufficient explanation of the risks of the study to subjects. The 
required informed consent form must be signed by the subject prior to conduct of any 
study related procedure. 
The informed consent form must be in compliance with ICH-GCP, local regulatory 
requirements and legal requirements, including applicable privacy laws. 


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14.4.2. Course and Record of Informed Consent 
The informed consent starts before subject’s agreement on participation in the clinical 
study, and sustains throughout the clinical study. The risks and possible benefits of 
participation in the study will be discussed with subjects or their legal representatives 
carefully and adequately. Subjects (or LARs) will be asked to read and review the 
informed consent form that are approved by the ethics committee. Investigators will 
explain the clinical study to subjects (or LARs) and answer any question possibly 
proposed by subjects (or LARs). Only after the subject has signed the informed consent 
form he/she is able to enter the study. Throughout the course of the clinical study, 
subjects (or LARs) can withdraw their informed consent at any time. One copy of 
informed consent form will be kept by subjects. Even if consulted subjects (or LARs) 
refuse to participate in this study, their rights will still be fully protected, and the quality 
of their medical care will also not be affected. 
14.5. Confidentiality of Subject’s Information 
The confidentiality of subject’s information will be strictly maintained by investigators, 
study personnel involved, the sponsor and their representatives. The confidentiality 
covers the biological samples in addition to the clinical data. Thus, the study protocol, 
documents, data and all the other incurred information will be strictly kept in confidence. 
Without the prior written approval by the sponsor, all the relevant study or data 
information can not be revealed to any unauthorized third party. 
Other authorized representatives of the sponsor, ethics committee/IRB, regulatory 
departments and representative of pharmaceutical company which supplies 
investigational product can check all the documents and records which are required to 
be maintained by investigators, including but not limited to medical records and 
subject’s medication records. The study center should have the access to these records. 
The subject’s contact information will be stored at each study center safely and only 
provided for internal use during the study. At the end of study, all the records will 
continue to be stored in a secure place in accordance with the time limit specified by 
local ethics committee/IRB and regulations. 
The study data collected for statistical analysis and scientific report should not include 
subject’s contact information or identification information. Individual subjects and their 
study data will be given a separate study identification number. EDC and study 
administration system used in each clinical study center are confidential and protected 
by password. At the end of study, all the identification data in the database will be 
eliminated and archived at each clinical study center, respectively.  
The sponsor will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with applicable privacy laws. 
15. 
PUBLICATION OF STUDY RESULTS 
Study results are the property of Jiangsu Hengrui Pharmaceuticals Co., Ltd. In order to 
protect confidential and/or patentable information, protect patient privacy, and ensure 
the accuracy of study results, Hengrui Medicine Co., Ltd., as the Sponsor, has the right 


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to review all planned publications, including articles in journals as well as abstracts, 
posters, and slides for oral presentations at academic conferences. 
• The Investigator should provide full-text of all planned publications to Sponsor 
at least 30 days prior to submission. 
• If Sponsor deems it necessary to apply for a patent to protect intellectual 
property, the Investigator should agree to delay the publication plan for no 
more than 60 days. Prior to the submission of planned publications, Sponsor 
shall have the right to request the Investigator to remove any undisclosed 
Confidential Information (except study results). 
 
  
 


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16. 
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359:1350-1355, 2018. 
15 El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in subjects with advanced 
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dose escalation and expansion trial. The Lancet 389:2492-2502, 2017. 
16 Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in subjects with advanced 
hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-
randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952. 
17 Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with 
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18 Lee MS, Ryoo BY, Hsu CH, et al: Randamized efficacy and safety results for 
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20 Qin S, Galle PR, Ren Z, et al: Efficacy and Safety of Atezolizumab + Bevacizumab 
vs Sorafenib in Chinese Patients With Unresectable HCC in the Phase III IMbrave150 
Study, European Association for the Study of the Liver, 2019 
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22 Xu J-M, Zhang Y, Jia R, et al: Anti-programmed death-1 antibody SHR-1210 (S) 
combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric 
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and Expansion Study. Clin Cancer Res. 2019 ;25(2):515-523 
23 Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member 
of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 
1992;11(11):3887-95. 
24 Huang CY, Wang Y, Luo GY, Han F, Li YQ, Zhou ZG, Xu GL: Relationship between 
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randomised, phase 2 trial. The Lancet Oncology. February 26, 2020. 
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27 Ye Y, Li A, Liu L, Yao B. A group sequential Holm procedure with multiple primary 
endpoints. Statistics in Medicine Res 2013 Mar 30;32(7):1112-24. 
28 Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20. 
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Guidance, January 2017]


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APPENDIX 1. Barcelona Clinic Liver Cancer (BCLC) Classification 
BCLC Stage 
ECOG-PS Score 
Tumor Status 
Child-Pugh Class 
0 (very early 
stage) 
0 
Single lesion <2 cm 
carcinoma in situ 
A 
A (early stage) 
0 
Single lesion or 3 nodules 
≤3 cm 
A-B 
B (intermediate 
stage) 
0 
multinodular 
A-B 
C (advanced 
stage) 
1-2 
Portal vein invasion, N1, M1 
A-B 
D (terminal stage) 
3-4 
Any 
C 
Note: All the conditions need to be met for stages 0, A and B; any one of them just needs to be met for 
stage C and D (PS score or tumor status). N1: lymph node metastasis, M1: distant metastasis. 
 
 


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APPENDIX 2. Response Evaluation Criteria in Solid Tumors Version 
1.1 (RECIST v1.1) and Its Comparison with Immune-Modified 
RECIST (imRECIST) and Modified RECIST (mRECIST) 
RECIST v1.1 
1. Measurability of tumor at baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 
20 mm by chest X-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with 10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible radiological techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
 
Bone scan, PET scan or plain films are not considered adequate radiological 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 


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 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional radiological techniques such 
as CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred 
for selection as target lesions. 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
1.2 Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Radiological based 
evaluation should always be done rather than clinical examination unless the lesion 
being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and 10 mm diameter as assessed using calipers (e.g. skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is suggested. As noted above, when lesions can be evaluated by 
both clinical exam and radiological, radiological evaluation should be undertaken since 
it is more objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions on chest X-ray may be considered measurable if they are 


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clearly defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a subject to be considered in complete response. Because tumor markers 
are disease specific, instructions for their measurement should be incorporated into 
protocols on a disease specific basis. Specific guidelines for both CA-125 response (in 
recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have been 
published. In addition, the Gynecologic Cancer Intergroup has developed CA125 
progression criteria which are to be integrated with objective tumor assessment for use 
in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such 
as germ cell tumors, where known residual benign tumors can remain). When effusions 
are known to be a potential adverse effect of treatment (e.g. with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment can be considered if the 
measurable tumor has met criteria for response or stable disease in order to differentiate 
between response (or stable disease) and progressive disease.  
2. Tumor response evaluation 
2.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 


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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
2.2 Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if CR criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm. Case report forms or other data collection methods may therefore be 
designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 
and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible, therefore providing this 
default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm.  
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 


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2.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol.  
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Non-complete Response or non-PD: Persistence of one or more non-target lesion and/or 
maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. Note: 
the appearance of one or more new lesions is also considered progression. 
2.4 Special notes on assessment of progression of non-target disease  
The concept of progression of non-target disease requires additional explanation as 
follows. 
When the subject also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to quality for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare.  
When the subject has only non-measurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can 
be applied when assessing subjects for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e. an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is 
seen, the subject should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
2.5 New lesions 


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The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change 
in radiological modality or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the subject’s baseline lesions show partial 
or complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a ‘new’ cystic lesion, which it is not.  
A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the subject who has visceral disease at baseline and while on study has a CT 
or MRI brain ordered which reveals metastases. The subject’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain radiological at 
baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the 
basis of FDG-PET radiological can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positivel FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
2.6 Missing assessments and not evaluable designation 
When no radiological/measurement is done at all at a particular time point, the subject 
is not evaluable (NE) at that time point. If only a subset of lesion measurements are 
made at an assessment, usually the case is also considered NE at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion would not change the assigned time point response. 


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2.7 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, 
this means that subjects with CR may not have a total sum of ‘zero’ on the case report 
form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point 
assessments may complicate best response determination. The analysis plan for the trial 
must address how missing data/assessments will be addressed in determination of 
response and progression. For example, in most trials it is reasonable to consider a 
subject with time point responses of PR-NE-PR as a confirmed response. 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy. The objective response status of such subjects is to be determined by 
evaluation of target and non-target disease as shown in Tables 1-3 below. 
Conditions that define ‘early progression, early death and inevaluability’ are study 
specific and should be clearly described in each protocol (depending on treatment 
duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it 
is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
before assigning a status of complete response. FDG-PET may be used to upgrade a 
response to a CR in a manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by 
disease specific medical literature for the indication. However, it must be acknowledged 
that both approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
Table 1 
Time point response: subjects with target (+/– non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or No 
PD 


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Any  
Any  
PD 
Any  
Yes or No 
Yes 
PD 
PD 
Note: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, 
NE=not evaluable. 
Table 2 
Time point response: subjects with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: CR=complete response, PD=progressive disease, NE=not evaluable. 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Table 3 
Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
Note: CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, 
NE=not evaluable. 
a.  If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 


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meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the subject had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
2.8 Confirmatory measurement/duration of response 
Confirmation  
In non-randomized trials where response is the primary endpoint, confirmation of PR 
and CR is required to ensure responses identified are not the result of measurement 
error. In randomized trials (phase 2 or 3) or studies where stable disease or progression 
are the primary endpoints, confirmation of response is not required since it will not add 
value to the interpretation of trial results. In the case of SD, measurements must have 
met the SD criteria at least once after study entry at a minimum interval (in general not 
less than 6–8 weeks) that is defined in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
first met for CR/PR (whichever is first recorded) until the first date that recurrent or PD 
is objectively documented (taking as reference for PD the smallest measurements 
recorded on study). The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from 
date of randomization) until the criteria for progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD). The clinical relevance of the duration of stable disease varies in 
different studies and diseases. If the proportion of subjects achieving stable disease for 
a minimum period of time is an endpoint of importance in a particular trial, the protocol 
should specify the minimal time interval required between two measurements for 
determination of stable disease. 
Note: The DoR and stable disease as well as the PFS are influenced by the frequency 
of follow-up after baseline evaluation. It is not in the scope of this guideline to define a 
standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between trials are to be made. 
2.9 Progression-free survival/proportion progression-free 
Phase 3 trials in advanced cancers are increasingly designed to evaluate PFS or TTP as 
the primary outcome of interest. Assessment of progression is relatively straightforward 
if the protocol requires all subjects to have measurable disease. Increasingly, trials allow 
entry of both subjects with measurable disease as well as those with non-measurable 
disease only. In this circumstance, care must be taken to explicitly describe the findings 
which would qualify for PD for those subjects without measurable lesions. Because the 


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date of progression is subject to ascertainment bias, timing of investigations in study 
arms should be the same. 


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Comparison of imRECIST with RECIST v1.1 
Source: Hodi FS, Ballinger M, Lyons B, et al. Immune-Modified Response Evaluation Criteria In Solid 
Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. J 
Clin Oncol. 2018 Mar 20;36(9):850-858.  
Full text link: http://ascopubs.org/doi/abs/10.1200/JCO.2017.75.1644?url_ver=Z39.88-
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed 
Briefly, immune-modified Response Evaluation Criteria in Solid Tumors (imRECIST) 
allows for collection of additional scans and for BOR to occur after radiologic PD 
assessment(s) in subjects continuing treatment (see Table 4 below). New lesions are 
added to the total tumor burden along with the sum of the target lesions when 
measurable; when not measurable, they are not factored into the PD assessment. In 
addition, progression in non-target lesions does not define PD. For analysis of 
imRECIST-defined PFS (imPFS), imRECIST PD or death is considered an event; 
however, an imRECIST PD is not considered an imPFS event if the time point response 
at the subsequent scan (≥ 4 weeks later) is imRECIST SD/PR/CR. An imRECIST PD 
followed by no additional assessments is considered an imPFS event. 
Table 4 
Comparison of RECIST 1.1 with imRECIST 
Criterion 
RECIST v1.1 
irRC 
imRECIST* 
Tumor 
burden 
Unidimensional 
Up to 5 target lesions/2 per organ 
Bidimensional 
per 
WHO 
Up to 10 target 
lesions/ 
5 per organ 
Unidimensional, with other 
target 
lesion 
criteria 
(number, measurability) per 
RECIST v1.1 
New 
lesions 
Always represent PD 
New lesions do not categorically define PD 
Measurable new lesions incorporated into the total 
tumor burden 
Non-measurable new lesions preclude CR 
Non-
target 
lesions 
Can contribute to defining CR or 
PD 
(unequivocal progression) 
Non-target progression does not define PD 
Can only contribute to defining CR (complete 
disappearance required) 
PD 
≥ 20% increase in the SLD 
(RECIST) and ≥ 5 mm increase 
compared with nadir, 
unequivocal progression in 
nontarget lesions, and/or 
appearance of new lesions 
Determined only on the basis of measurable disease 
 
 
Negated by subsequent non-PD assessment ≥ 4 
weeks from the 
date first documented (lack of confirmation) 
 
 
≥ 25% increase in 
the SLD compared 
with baseline/ nadir 
≥ 20% increase in SLD 
(RECIST) compared with 
baseline/ nadir 
 
Confirmation of PD not required 
Best response may 
occur 
before 
confirmed PD 
Best response may occur 
after any number of PD 
assessments 
Note: CR=complete response, imRECIST=immune-modified RECIST, irRC=immune-related response 
criteria, PD=progressive disease, RECIST=Response Evaluation Criteria in Solid Tumors, SLD=sum of 
longest diameters. 
*imRECIST follows RECIST v1.1 convention unless otherwise stated. 


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ImRECIST is derived from RECIST v1.1 conventions and immune-related response 
criteria (irRC)1. When not otherwise specified, RECIST v1.1 conventions will apply. 
Table 5 
imRECIST and RECIST v1.1: Summary of Changes 
 
RECIST v1.1 
imRECIST 
New lesions after 
baseline 
Define progression. 
New measurable lesions are added into 
the total tumor burden and followed. 
Non-target lesions 
May contribute to the designation of 
overall progression. 
Contribute only in the assessment of a 
CR. 
Radiographic 
progression 
First instance of ≥ 20% and ≥ 5mm 
increase in the sum of diameters or 
unequivocal progression in non-
target disease. 
Determined only on the basis of 
measurable disease. 
Note: CR=complete response, imRECIST=immune-modified RECIST, RECIST=Response Evaluation 
Criteria in Solid Tumors. 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. 
Non-Target Lesions 
After baseline, changes in non-target lesions will contribute only in the assessment of 
CR (i.e., a CR is attained only with the complete disappearance of all tumor lesions, 
including non-target lesions) and will not be used to assess PD. 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be assessed 
at all tumor assessment timepoints. New lesions will also be evaluated for measurability 
with use of the same criteria applied to prospective target lesions at baseline per 
RECIST, (e.g., non−lymph node lesions must be ≥ 10 mm; see note for new lymph node 
lesions below). Up to a maximum of 5 new lesions total (and a maximum of 2 lesions 
per organ), all with measurements at all timepoints, can be included in the tumor 
response evaluation. New lesion types that would not qualify as target lesions per 
RECIST cannot be included in the tumor response evaluation but can be used for CR 
exclusion. 
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the sum 
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached. 
                                                 
1 Wolchok et al. Clin Can Res 2009;15:7412−20; Nishino et al. J Immunother Can 2014;2:17; Nishino et al. Clin 
Can Res 2013;19:3936−43. 


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Calculation of Sum of the Diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated as a measure of tumor burden. 
The sum of the diameters is calculated at baseline and at each tumor assessment for the 
purpose of classification of tumor responses. 
Sum of the Diameters at Baseline: The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1. 
Sum of the Diameters at Tumor Assessment: For every on-study tumor assessment 
collected per protocol or as clinically indicated the sum of the diameters at tumor 
assessment will be calculated using tumor radiological scans. All target lesions selected 
at baseline and up to 5 new measurable lesions (with a maximum of 2 new lesions per 
organ) that have emerged after baseline will contribute to the sum of the diameters at 
tumor assessment. Hence, each net percentage change in tumor burden per assessment 
with use of modified RECIST accounts for the size and growth kinetics of both old and 
new lesions as they appear. 
Note: In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed. That is, if at first 
appearance the short axis of a new lymph node lesion ≥ 15 mm, it will be considered a 
measurable new lesion and will be tracked and included in the SLD. Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will 
be included in the SLD, even if the short axis diameter decreases to <15 mm (or even 
<10 mm). However, if it subsequently decreases to < 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of < 10 mm if 
lymph nodes), then a response assessment of CR may be assigned. 
If at first appearance the short axis of a new lymph node is ≥ 10 mm and < 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion. 
It will not be included in the SLD unless it subsequently becomes measurable (short 
axis diameter ≥ 15 mm). 
The appearance of new lymph nodes with diameter < 10 mm should not be considered 
pathological and not considered a new lesion. 
Response Criteria 
Timepoint Response 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. 
Table 6 provides a summary of the overall response status calculation at each timepoint 
for subjects who have measurable disease at baseline. 
Complete Response (CR): Disappearance of all target and non-target lesions. Lymph 
nodes that shrink to <10 mm short axis are considered normal. 


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Partial Response (PR): At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of diameters, 
in the absence of CR. 
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as PD until the sum of the diameters increases 
by ≥ 20% when compared with the sum of the diameters at nadir. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of all target 
and selected new measurable lesions, taking as reference the smallest sum on study 
(nadir SLD; this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. 
Impact of New Lesions on imRECIST 
New lesions alone do not qualify as progressive disease. However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 
Missing Assessments and Not Evaluable Designation 
When no radiological/measurement is done at all at a particular timepoint, the subject 
is considered not evaluable (NE) at that timepoint. If only a subset of lesion 
measurements is made at an assessment, usually the case is also considered NE at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response. This 
would only happen in the case of PD. For example, if a subject had a baseline sum of 
50 mm with 3 measured lesions and at follow-up only 2 lesions were assessed but those 
gave a sum of 80 mm, the subject will be assigned PD status, regardless of the 
contribution of the missing lesion. 
 
 


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Table 6 
imRECIST Timepoint Response Definitions 
% Change in Sum of the 
Diameters a 
Non-Target Lesion Response 
Assessment 
Overall Immune-Modified 
RECIST Timepoint Response 
−100% from baseline b 
CR 
CR 
−100% from baseline b 
Non-CR or not all evaluated 
PR 
≤ −30% from baseline 
Any 
PR 
> −30% to < +20% 
Any 
SD 
Not all evaluated 
Any 
NE 
≥ +20%from nadir SLD 
Any 
PD 
Note: CR=complete response, NE= not evaluable, PD= progressive disease, PR= partial response, 
RECIST=Response Evaluation Criteria in Solid Tumors, SD= stable disease, SLD= sum of the longest 
diameter. 
a. 
Percent change in sum of the diameters (including measurable new lesions when present). 
b. When lymph nodes are included as target lesions, the % change in the sum of the diameters may 
not be 100% even if CR criteria are met, because a normal lymph node is defined as having a short 
axis of < 10 mm. Any pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm in order to meet the definition of CR. 
 
Figure 1 
 
Definition of imPFS event and BOR 
Comparison of mRECIST with Conventional RECIST 
Source：Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. 
Semin Liver Dis. 2010 Feb;30(1):52-60. 
Note the following points regarding modified RECIST (mRECIST): 
• mRECIST are recommended by American Association for the Study of Liver 
Diseases (AASLD) for the assessment of tumor response in HCC. 
• Subjects can be followed with either contrast-enhanced spiral CT or 
contrast-enhanced dynamic MRI. 
• In contrast-enhanced studies, it is mandatory to obtain a dual-phase 
radiological of the liver (high-quality arterial phase radiological obtained on 
the first run, and high-quality portal venous phase radiological obtained on 
the second run). 


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When assessing tumor response, the longest diameter of the target lesion (either viable 
or necrotic) is measured in conventional RECIST, whereas only viable target lesions 
are taken into account in mRECIST (see Table 7 below). 
Table 7 
Comparison of mRECIST with Conventional RECIST  
Conventional RECIST 
mRECIST 
CR=Disappearance of all target lesions. 
CR=Disappearance of any intratumoral arterial 
enhancement in all target lesions. 
PR=At least a 30% decrease in the sum of 
diameters of target lesions, taking as 
reference the baseline sum of the diameters 
of target lesions. 
PR=At least a 30% decrease in the sum of diameters 
of viable (enhancement in the arterial phase) target 
lesions, taking as reference the baseline sum of the 
diameters of target lesions. 
SD=Any cases that do not qualify for either 
PR or PD. 
SD=Any cases that do not qualify for either PR or 
PD. 
PD=An increase of at least 20% in the sum 
of the diameters of target lesions, taking as 
reference the smallest sum of the diameters 
of target lesions recorded since treatment 
started. 
PD=An increase of at least 20% in the sum of the 
diameters of viable (enhancing) target lesions, 
taking as reference the smallest sum of the 
diameters of viable (enhancing) target lesions 
recorded since treatment started. 
Note: mRECIST=modified RECIST, CR=complete response, PR=partial response, RECIST=Response 
Evaluation Criteria in Solid Tumors, SD=stable disease, PD=progressive disease. 
 
 
 


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APPENDIX 3. Child-Pugh Classification Criteria for Liver Function 
Measure 
Score 
1 point 
2 points 
3 points 
Hepatic encephalopathy  
None 
Grade 1 or 2 
Grade 3 or 4 
Ascites 
None 
Mild 
Moderate and above 
Prolongation of prothrombin time (s) OR 
international normalized ratio (INR) 
<4 seconds 
OR 
＜1.7 
4-6 seconds 
OR 
1.7-2.3 
＞6 seconds 
OR 
>2.3 
Total bilirubin (μmol/L) 
＜34 
34-51 
＞51 
Serum albumin (g/L) 
＞35 
28-35 
＜28 
Note: 5～6 points for Grade A; 7～9 points for Grade B and 10～15 points for Grade C.  
 
 


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APPENDIX 4. Criteria for Eastern Cooperative Oncology Group - 
Performance Status (ECOG-PS) Score 
ECOG-
PS Score 
Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
 


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APPENDIX 5. New York Heart Association (NYHA) Cardiac 
Function Classification 
The severity of heart failure is poorly related with ventricular function, but clearly 
related with the survival rate, and subjects with mild symptom may still have a high 
absolute risk for hospitalization and death.  
Grade 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath) 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of breath) 
III 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea 
IV 
Symptom of heart failure at rest. If any physical activity is undertaken, 
discomfort increases. In case of no intravenous administration, those who can 
move indoors or at bedside are classified as Grade IVa and those who can not 
get out of bed and need intravenous support are classified as Grade IVh 
 
 
 


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APPENDIX 6.  Recommended Treatment Procedures for 
Common Immune-Related Adverse Events 
When dealing with immune-related AEs, the investigator may refer to the following 
treatment procedures for common immune-related AEs. These procedures are 
recommended based on Management of Toxicities From Immunotherapy: ESMO 
Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up (Annals of 
Oncology 28 (supplement 4):iv119-iv142, 2017)” in combination with this study 
protocol. 
The general principle is that AEs should go through careful assessment and differential 
diagnosis in accordance with medical standards; non-inflammatory causes should be 
considered and properly managed. 
Corticosteroids are the main therapeutic agents for Immuno-Oncology (I-O) drug 
related AEs. Subjects with low-grade toxicities who can walk around may consider oral 
doses equivalent to recommended intravenous doses. If the equivalent dose of oral 
corticosteroids is changed, the lower bioavailability of oral corticosteroids should be 
considered. 
It is recommended to consult with physicians or surgeons, especially prior to invasive 
diagnosis or treatment. 
1. Rules for management of gastrointestinal adverse event 
 


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Figure 1. ICPi-Related Toxicity: Management of Diarrhoea and Colitis 
BID=twice daily, CHF=congestive heart failure, CRP=C-reactive protein, CT=computed 
tomography, FBC=full blood count, ICPi=immune checkpoint inhibitor, i.v.=intravenous, 
LFTs=liver function tests, MMF=mycophenolate mofetil, NYHA=New York Heart Association, 
QD=once daily, PCR=polymerase chain reaction, PJP=Pneumocystis jiroveci pneumonia, 
TB=tuberculosis, TFTs=thyroid function tests, TPN=total parenteral nutrition, 
UEC=urea/electrolytes/creatinine. 


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2. Rules for management of pulmonary adverse events 
 
Figure 2. ICPi-Related Toxicity: Management of Pneumonitis 
ARDS=acute respiratory distress syndrome, ICPi=immune checkpoint inhibitor, 
MMF=mycophenolate mofetil, FBC=full blood count, UEC=urea/electrolytes/creatinine, 
LFT=liver function tests, TFT=thyroid function tests, ESR=erythrocyte sedimentation rate, 
CRP=C-reactive protein, TCLO=transfer factor for carbon monoxide. 


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3. Rules for management of renal adverse events 
 
Figure 3. ICPi-Related Toxicity: Management of Nephritis 
Renal injury occurs in around 1%-4% of subjects treated with ICPi, usually a pattern of acute 
tubule-interstitial nephritis with a lymphocytic infiltrate. Attention needs to be paid to the subject’s 
baseline creatinine, not just abnormal results per biochemistry upper limit of normal (ULN). 
Confounding diagnoses include dehydration, recent i.v. contrast, urinary tract infection, 
medications, hypotension, or hypertension. Early consideration for renal biopsy is helpful which 
may negate the need for steroids and determine whether renal deterioration is related to ICPi or 
other pathology. Oliguria should prompt insubject admission for careful fluid balance and plan for 
renal replacement therapy. Steroid wean: begin to wean once creatinine Grade 1; Grade 2 severity 
episode-wean steroids over 2-4 weeks; Grade 3/4 episode-wean over ≥ 4 weeks. If on steroid 
for >4 weeks-Pneumocystis jiroveci pneumonia (PJP) prophylaxis, calcium/vitamin D 
supplementation, gastric protection and check afternoon glucose for hyperglycaemia. *GN screen: 


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ANA, complement C3, C4, ANCA, anti-GBM, hepatitis B and C, HIV, immunoglobulins and 
protein electrophoresis. 
ANA=antinuclear antibody, ANCA=anti-neutrophil cytoplasmic antibody, GBM= glomerular 
basement membrane, GN=glomerulonephritis, HIV=human immunodeficiency virus, 
ICPi=immune checkpoint inhibitor, irAE=immune-related adverse event; i.v.=intravenous. 


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4. Rules for management of endocrine adverse event 
 
Figure 4. ICPi-Related Toxicity: Thyroid Function 
CT=computed tomography, CTLA4=cytotoxic T-lymphocyte associated antigen 4, 
DDx=differential diagnosis, FT4=free thyroxine, ICPi=immune checkpoint inhibitor, 
PD-1=programmed death 1, PD-L1=programmed death ligand 1, T3=triiodothyronine, 


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T4=thyroxine, TFTs=thyroid function tests, TPO=thyroid peroxidase, TSH=thyroid-stimulating 
hormone. 
 
Figure 5. ICPi-Related Toxicity: Management of Hypophysitis 
*Pituitary Axis bloods: 9 am cortisol (or random if unwell and treatment cannot be delayed), 
ACTH, TSH/FT4, LH, FSH, oestradiol if premenopausal, testosterone in men, IGF-1, prolactin. 
Mineralocorticoids replacement is rarely necessary in hypopituitarism. 
**Initial replacement advice for cortisol and thyroid hormones: 
•  If 9 am cortisol < 250 or random cortisol < 150 and vague symptoms: 
   - Replace with hydrocortisone 20/10/10 mg 
   - If TFTs normal, 1–2 weekly monitoring initially (always replace cortisol for 1 week prior to 
thyroxine initiation) 
•  If falling TSH +/- low FT4 
   - Consider need for thyroxine replacement (guide is 0.5-1.5 mg/kg) based on symptoms +/- 
check 9 am weekly cortisol 
   - See Thyroid Guidelines for further information regarding interpretation of an abnormal 
TSH/T4 
ACTH=adrenocorticotropic hormone, FSH=follicle-stimulating hormone, FT4=free thyroxine, 
HRT=hormone replacement therapy, ICPi=immune checkpoint inhibitor, IGF-1=insulin-like 
growth factor-1, i.v.=intravenous, LH=luteinizing hormone, MRI=magnetic resonance 
radiological, NSAIDs=nonsteroidal anti-inflammatory drugs, od=once daily, TSH=thyroid-
stimulating hormone, TFTs=thyroid function tests. 


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5. Rules for management of cutaneous adverse events 
 
Figure 6. ICPi-Related Toxicity: Management of Skin Rash/Toxicity 
Recognised skin AEs include: (1) most common: erythema, maculopapular and pustulopapular rash; 
(2) rare: toxic epidermal necrolysis, Steven-Johnson syndrome and DRESS; (3) vasculitis may also 
be present with purpuric rash. 
BSA, body surface area; DRESS, drug rash with eosinophilia and systemic symptoms; ICPi, 
immune checkpoint inhibitor. 


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6. General recommendations for immunization related toxicity treatment 
Management of skin rash/toxicity: 
• 
For Grade 1–2 skin AEs, continue (at least 1 week) with ICPis. Start topical 
emollients, antihistamines in the case of pruritus and/or topical (mild strength) 
corticosteroid creams. Reinitiate ICPi when ≤ Grade 1. 
• 
For Grade 3 skin AEs, interrupt ICPi and start immediate treatment with topical 
emollients, antihistamines and high strength corticosteroid creams. [II, B] 
• 
For Grade 4 skin AEs, discontinue ICPi (permanently), consider admitting subject 
and always consult dermatologist immediately. Start i.v. corticosteroids [1–2 mg/kg 
(methyl) prednisone] and taper based on response of AE. [II, B] 
• 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare 
but life-threathening severe cutaneous adverse reaction. Patients with SJS/TEN 
usually develop mucosal erosions or ulcers with variable extents of skin 
detachment after immunotherapy for a period of 1-3 weeks, it also may occur 
several months after treatment initiation. SJS and TEN are thought be a spectrum 
of the same disease. SJS, overlapping SJS/TEN, and TEN are characterized by 
separation of the dermis involving <10%, 10%-30%, and >30% body surface area 
(BSA). The management of Stevens-Johnson syndrome (SJS)/toxic epidermal 
necrolysis (TEN) is detailed in below Table 16. 
Table 16 
SJS/TEN management and treatment 
Early identification and management 
·Inform patients of the symptoms and signs of SJS/TEN; advise patients to promptly 
notify investigator if signs of SJS/TEN occur 
·Consider withhold study drugs (SHR-1210 and rivoceranib) and monitor patients 
closely every 3 days with Grade 2 immune-related rash for progression to 
involvement of greater BSA and/or mucous membrane involvement. Initiate 
therapy with topical corticosteroids. Consider initiation of prednisone (or 
equivalent) 0.5-1 mg/kg tapered over at least 4 weeks 
·In cases of suspected SJS, withhold study drugs and consider early admission for 
further monitoring and treatment. 
Initial assessment on presentation 
·Review patient history, and a full list of patient medications 
·Total body skin examination with attention to ALL mucous membranes as well as a 
complete review of systems 
·Rule out any other etiology of the skin problem, such as an infection, another drug, 
or a skin condition linked to another systemic disease 
·Perform skin biopsies for full-thickness epidermal necrosis to confirm the diagnosis 


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of SJS/TEN. 
Treatment for SJS/TEN 
·Should permanently discontinue SHR-1210 and rivoceranib once SJS/TEN is 
confirmed 
·Should admit patient immediately with urgent consultation with dermatologist 
·Initiate IV (methyl) prednisolone (or equivalent) 1-2 mg/kg, wean over at least 4 
weeks when toxicity resolves to Grade ≤1. May consider intravenous 
immunoglobulin (IVIG) or cyclosporine as an alternative or in corticosteroid-
refractory cases 
·For mucous membrane involvement of SJS or TEN, seek urgent dermatology, 
ophthalmology, and urology consultation to prevent sequelae from scarring 
·Supportive care should include assessment and management of skin wounds, fluid 
and nutrition status, electrolyte balance, renal and airway function, preventing 
infection, and adequate pain control 
·Seek infectious disease consultation if patient might have secondary cellulitis or if 
patient has other infection risk factors, such as neutropenia, etc. 
 
Immune-related endocrinopathies 
• For subjects with Grade 2 symptomatic hyperthyroism, interrupt ICPi, start beta-
blocker therapy (propranolol or atenolol/metoprolol). Restart ICPi when 
asymptomatic [IV–V, B]. 
• In the case of hypothyroidism, rarely>Grade 2, start HRT depending on the severity 
(50–100 lg/day). Increase the dose until TSH is normal. In the case of inflammation 
of the thyroid gland, start prednisone orally 1 mg/kg. Taper based on recovery of 
clinical symptoms. Consider interruption of ICPi treatment when symptomatic [IV–
V, B]. 
• In the case of hypophysitis (rarely>Grade 2), when headache, diplopia or other 
neurological symptoms are present, start (methyl) prednisone 1 mg/kg orally and 
taper over 2–4 weeks. Start HRT depending on the affected hormonal axis 
(levothyroxine, hydrocortisol, testosterone) [V, B]. 
• In subjects with type I DM Grade 3 to 4 [ketoacidotic (sub)coma], admit to hospital 
immediately and start treatment of newly onset type I DM [I, A]. Role of 
corticosteroids in preventing complete loss of insulin producing cells is unknown 
and not recommended. 
Gastrointestinal hepatotoxicity 
• 
In subjects with non-severe diarrhoea (Grade 1), ICPi can be continued. Treatment 
with antidiarrhoeal medication (e.g. loperamide) should be prescribed [IV–V, B]. 


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• 
In Grade 2 diarrhoea, ICPi should be interrupted and the subject should start with 
corticosteroids depending on the severity and other symptoms (either budesonide 
or oral corticosteroids 1 mg/kg). In the case of no improvement within 3–5 days, 
colonoscopy should be carried out and, in the case of colitis, infliximab 5 mg/kg 
should be administered [IV–V, B]. 
• 
In subjects with severe diarrhoea (Grade 3 to 4), permanently discontinue ICPi. 
Admit subject to the hospital and initiate (methyl) prednisone 2 mg/kg i.v. Add 
MMF if improvement is observed within 2–3 days. Consult a hepatologist if no 
improvement under double immunosuppression. Other immunosuppressive drugs 
to consider are ATG and tacrolimus. Consult or refer subject to an experienced 
center. Taper over 6 weeks under close monitoring of liver tests [IV–V, B]. 
Immune-related pneumonitis 
• 
For subjects with Grade 2 pneumonitis, interrupt ICPi therapy, try to rule out 
infection and start with prednisone 1–2 mg/kg orally. Taper over 4–6 weeks [IV–V, 
B]. 
• 
In Grade 3 and 4 pneumonitis, discontinue ICPi permanently, admit the subject to 
the hospital, even ICU if necessary and immediately start high-dose (methyl) 
prednisone 2–4 mg/kg i.v. Add infliximab, MMF or cyclophosphamide in the case 
of deterioration under steroids. Taper over a period of 4–6 weeks [IV–V, B]. 
Cardiac toxicity 
• 
When a myocarditis is suspected, admit the subject and immediately start high-
dose (methyl) prednisone (1–2 mg/kg). In the case of deterioration, consider adding 
another immunosuppressive drug (MMF or tacrolimus) [V, B]. 
Rheumatological toxicity 
• 
For mild arthralgia, start NSAIDs, and in the case of no improvement, consider 
low -dose steroids (10–20 mg prednisone). In the case of severe polyarthritis, refer 
subject to or consult a rheumatologist and start prednisone 1 mg/kg. Sometimes 
infliximab or another anti-TNFa drug is required for improvement of arthritis [V, 
B]. 
Renal toxicity 
• 
In case of nephritis, rule out other causes of renal failure first. Interrupt or 
permanently discontinue ICPi depending on the severity of the renal insufficiency. 
Stop other nephrotoxic drugs. Start (methyl) prednisone 1–2 mg/kg. Consider renal 
biopsy to confirm diagnosis [V, B]. 
Notes: ALT=alanine transaminase, AST=aspartate transaminase, ATG=anti-thymocyte globulin, 
DM=diabetes mellitus, HRT=hormone replacement therapy, ICPi=immune checkpoint inhibitor, 
ICU=intensive care unit, Ig=immunoglobulin, MMF=mycophenolate mofetil, MRI=magnetic 
resonance radiological, NSAIDs=nonsteroidal anti-inflammatory drugs, TNFa=tumor necrosis 
factor alpha, TSH=thyroid-stimulating hormone. 
For other rules that are not listes in this protocol, you may refer to the full text of 
Management of Toxicities From Immunotherapy: ESMO Clinical Practice Guidelines 


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for Diagnosis, Treatment and Follow-Up (Annals of Oncology 28 (supplement 
4):iv119-iv142, 2017) or discuss with the clinical research associate from the sponsor. 
Source: Management of Toxicities From Immunotherapy: ESMO Clinical Practice Guidelines for 
Diagnosis, Treatment and Follow-Up. Haanen JBAG, Carbonnel F, Robert C, et al. on behalf of the 
ESMO Guidelines Committee. Ann Oncol. 28 (Supplement 4): iv119–iv142, 2017. 


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APPENDIX 7. Grade and Management of Reactive Capillary 
Endothelial Proliferation (RCEP) 
RCEP mostly occurs on the surface of the skin, a small number can be found in the oral 
mucosa, nasal mucosa and orbital conjunctiva. RCEP occurring in the skin, initially 
expressed as a bright red spot on the body surface, diameter ≤ 2 mm, with the increase 
of medication times, the lesion range can be gradually increased, mostly nodular, also 
patchy, the color is bright red or dark red, need to observe the clinical symptoms and 
signs. It can be treated according to the following grading standards and treatment 
recommendations: 
Grade 
Clinical Manifestation 
Treatment Suggestions 
Grade 1 
Single or multiple, nodule with 
longest diameter ≤10 mm, 
with or without rupture 
bleeding 
Continue administration, enhance 
local treatment for those with rupture 
and bleeding to prevent infection 
Grade 2 
Single or multiple, nodule with 
longest diameter >10mm, 
with or without rupture 
bleeding 
Continue the study treatment. 
Conduct local therapy such as laser or 
surgical resection if needed. 
Strengthen local treatment and prevent 
infection for subjects with rupture 
bleeding. 
Grade 3 
Widespread nodules, 
complicated by skin infections, 
maybe need hospitalization  
Interrupt the study treatment until 
resolution of the AE to Grade 1. 
Conduct local therapy such as laser or 
surgical resection if needed. 
Conduct anti-infection treatment for 
subjects with concurrent infection. 
Grade 4‡ 
Multiple and widespread 
nodule, life threatening 
Discontinue the study treatment 
Grade 5‡ 
Death 
Discontinue the study treatment 
† Grading is based on <Management of Immune Checkpoint Inhibitor-Related Toxicity-Guidelines 
of Chinese Society of Clinical Oncology (CSCO) 2019>. 
‡Grade 4 life threatening and Grade 5 death have not occured in the study.  
Avoid scratch or friction when adverse reaction occurs. Protect easily rubbing parts by 
gauze to avoid bleeding and contact the doctor in charge for appropriate treatment 
suggestions. Hemostasis by local compression or local treatment such as laser or 
surgical excision can be used in subjects with ruptured hemorrhage. Anti-infective 
treatment should be given to those complicated with infection. RCEP may occur in 
tissues other than skin (including visceral organs). Related medical examinations such 
as fecal occult blood, endoscopy and radiological should be performed if necessary. 
 
 
 


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APPENDIX 8. EORTC QLQ-C30 (Version 3.0) 
English specimen of EORTC QLQ-C30 (version 3.0) is as below. The local language 
edition will be provided for the subjects in the trial. 
 


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APPENDIX 9. EORTC QLQ-HCC18 
English specimen of EORTC QLQ-HCC18 is as below. The local language edition will 
be provided for the subjects in the trial. 
 
 
 


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APPENDIX 10. 
EQ-5D-5L 
English specimen of EQ-5D-5L is as below. The local language edition will be provided 
for the subjects in the trial. 
 


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APPENDIX 11. 
Information Regarding Concomitant Use of Drugs Effecting CYP Enzymes and Acid Reducing 
Agents  
Cytochrome P450 (CYP) isoforms 
Lists of prohibited strong inhibitors and inducers for CYP isoformsinvolved in rivoceranib metabolism, prohibited substrates with narrow 
therapeutic index of CYP isoforms may potentially be affected by rivoceranib, and sensitive substrates to be used with caution of CYP isoforms 
may potentially be affected by rivoceranib.   
Enzyme 
Way to interfer 
Compound 
Notification 
CYP1A2 
Sensitive substrates 
alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine 
Use with caution 
Strong inhibitors 
ciprofloxacin, enoxacin, fluvoxamine, zafirlukast 
Prohibited 
CYP2B6 
Sensitive substrates 
bupropion 
Use with caution 
Strong inducer 
carbamazepine 
Prohibited 
CYP2C8  
Sensitive substrates 
repaglinide 
Use with caution 
Strong inhibitors 
clopidogrel, gemfibrozil 
Prohibited 
CYP2C9  
Sensitive substrates 
celecoxib 
Use with caution 
 
 


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CYP2C19  
Sensitive substrates 
S-mephenytoin, omeprazole 
Use with caution 
Strong inhibitors 
fluconazole, fluoxetine, fluvoxamine, ticlopidine 
Prohibited 
Strong inducer 
rifampin, ritonavir 
Prohibited 
CYP2D6  
Sensitive substrates 
atomoxetine, desipramine, dextromethorphan , eliglustat, nebivolol, nortriptyline, 
perphenazine, tolterodine, venlafaxine 
Use with caution 
Strong inhibitors 
bupropion, fluoxetine, paroxetine, quinidine, terbinafine 
Prohibited 
CYP3A 
Sensitive substrates 
alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, 
everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, 
saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, 
vardenafil,budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, 
indinavir, lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 
Use with caution 
Strong inhibitors 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and 
ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, 
lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, 
nefazodone, nelfinavir 
Prohibited 
Strong inducer 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
Prohibited 
 
 
 


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Acid Reducing Agents 
The results of DDI study with acidic modifiers are unavailable at present, subjects should be advised to restrict use of proton pump inhibitors (PPIs) 
as listed in the table. Subjects should be encouraged to avoid concomitant administration of the studied drug with acidic neutrolizers or H2 blockers 
as listed in the table. If these medicines are needed, they should be taken 5 hours after the studied drug administration. 
  
Generic name 
Found in brand name(s) 
  
Proton pump 
inhibitor (PPI) 
dexlansoprazole 
Dexilant 
Prohibited 
esomeprazole magnesium 
Nexium 
esomeprazole magnesium and naproxen 
Vimovo 
lansoprazole 
Prevacid 
omeprazole 
Prilosec 
omeprazole and Sodium bicarbonate 
Zegerid 
pantoprazole sodium 
Protonix 
rabeprazole sodium 
AcipHex 
lansoprazole 
Prevacid 24HR 
omeprazole magnesium 
Prilosec OTC 
omeprazole and sodium bicarbonate 
Zegerid OTC 
omeprazole 
Omeprazole 
lansoprazole 
Prevacid 24HR 
omeprazole magnesium 
Prilosec OTC 
omeprazole and sodium bicarbonate 
Zegerid OTC 
omeprazole 
Omeprazole 


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H2 blocker 
cimetidine 
Tagamet 
Avoid concomitant administration with the study drug If these 
medicines are needed, they should be taken 5 hours after the 
study drug administration. 
famotidine 
Pepcid, Duexis 
nizatidine 
Axid, Nizatidine 
ranitidine 
Zantac, Tritec 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
187 
Transporters 
The transporter inhibitors are reported to increase transporter substrates AUC by ≥1.5 to ≥2 fold, and thus fall into the catergory of moderate 
inhibitors. They are to be advised used with caution 
Transporter 
Gene 
Inhibitor 
P-gp(a) 
ABCB1 
amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil 
BCRP 
ABCG2 
curcumin, cyclosporine A, eltrombopag 
OATP1B1, OATP1B3 
SLCO1B1, SLCO1B3 
atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin 
(single dose), simeprevir 
OAT1, OAT3 
SLC22A6, SLC22A8 
p-aminohippuric acid (PAH)(b), probenecid, teriflunomide 
MATE1, MATE2-K 
SLC47A1, SLC47A2 
cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, vandetanib 
(FDA’s Web site on Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
188 
Prohibited substrates with narrow therapeutic index for transporters  
Transporter 
Gene 
Substrate 
P-gp 
ABCB1 
dabigatran, digoxin 
MATE1, 
MATE-2K, OCT2 
SLC47A1, SLC47A2, 
SLC22A2 
dofetilide 
FDA’s Web site on Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm  
Drug bank for narrow therapeutic index   
https://www.drugbank.ca/categories/DBCAT003972 
 
 
 
 


Study Drug Number: SHR-1210 
Protocol Number: SHR-1210-III-310 
Version 6.0, 21 Sep 2022 
 
HENGRUI CONFIDENTIAL 
189 
APPENDIX 12. 
Schedule of Activities: Extension Phase 
 
Assessment  
Study period/Visit 
Subject receive study treatment 
Follow-up period 
Study drug accountability  
Every time study drug is dispensed 
√[1] 
Study treatment [2]  
SHR-1210: 200 mg, once every two weeks (Q2W) 
Rivoceranib: 250 mg, once per day (QD) 
OR Sorafenib[3]: 400 mg, twice per day (BID) 
- 
Safety assessment 
Frequency per standard of care  
√[4] 
Reporting of SAEs and pregnancy 
Reports to Sponsor by email [5].  
Tumor assessments 
Frequency per standard of care  
- 
[1]. Subjects should return all unused study medication. 
[2]. Study treatment may continue until they are no longer benefiting from treatment as assessed by investigator’s clinical judgment. 
[3]. Sorafenib can be sourced either locally or centrally which can comply with the local regulatory and ethics requirement. 
[4]. Safety evaluation should be based on standard of care and investigator’s clinical judgement. 
[5]. The sponsor’s email to receive safety reports (SAEs and pregnancy) in this study: hengrui_drug_safety@hengrui.com. 

SAP_001.pdf: 
 
This statistical analysis plan is the confidential information of Jiangsu Hengrui Medicine (JHM). This statistical analysis plan 
may not be disclosed to parties not associated with the clinical investigation or used for any purpose without the prior written 
consent of JHM. 
 
 
 
A Randomized, Open-Label, International, Multi-
Center, Phase 3 Clinical Study of PD-1 Antibody SHR-
1210 Plus Apatinib (Rivoceranib) Mesylate Versus 
Sorafenib as First-Line Therapy in Subjects with 
Advanced Hepatocellular Carcinoma (HCC) Who 
Have Not Previously Received Systemic Therapy 
 
 
STATISTICAL ANALYSIS PLAN 
（SAP） 
 
 
 
 
 
 
Protocol:   
 
 
 
 
SHR-1210-III-310 
Trial phase:   
 
 
 
Phase 3 
Version No.:   
 
 
 
V 3.0 
Date:   
 
 
 
 
 
19 April, 2022 
 
 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
AUTHORIZED SIGNATURES 
 
Study Title: 
A Randomized, Open-Label, International, Multi-Center, Phase 
3 Clinical Study of PD-1 Antibody SHR-1210 Plus Apatinib 
(Rivoceranib) Mesylate Versus Sorafenib as First-Line Therapy 
in Subjects with Advanced Hepatocellular Carcinoma (HCC) 
Who Have Not Previously Received Systemic Therapy 
 
Protocol:   
SHR-1210-III-310 
Trial phase:  
Phase 3 
SAP Version: 
V 3.0 
Date:   
 
19 April, 2022 
 
Prepared at JHM by: 
 
 
 
 
  
 
 
 
  
 
 
Reviewed and Approved at JHM by: 
 
 
 
  
 
 
 
 
 
      
  
 
 
 
 
 
   
 
  
 
 
   
  
   
 
  
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
TABLE OF CONTENTS 
ABBREVIATIONS 
5 
1. 
INTRODUCTION ............................................................................................. 12 
1.1. Study Design ............................................................................................ 12 
1.2. Objectives and Statistical Hypotheses ..................................................... 14 
1.2.1. 
Primary Objectives ................................................................... 14 
1.2.2. 
Key Secondary Objectives ........................................................ 14 
1.3. Sample Size Determination...................................................................... 14 
2. 
STATISTICAL HYPOTHESES AND DECISION RULES ............................. 14 
3. 
STUDY ENDPOINTS ....................................................................................... 15 
3.1. Primary Endpoints ................................................................................... 15 
3.1.1. 
Overall Survival ........................................................................ 15 
3.1.2. 
Progression-Free Survival by BIRC Assessment per RECIST 
v1.1 ........................................................................................... 16 
3.2. Secondary Endpoints ............................................................................... 18 
3.2.1. 
Progression-Free Survival by Investigator Assessment per 
RECIST v1.1 ............................................................................ 18 
3.2.2. 
Objective Response Rate (ORR) by BIRC or Investigator 
Assessment per RECIST v1.1................................................... 18 
3.2.3. 
Disease Control Rate (DCR) by BIRC or Investigator 
Assessment per RECIST v1.1................................................... 20 
3.2.4. 
Duration of Response (DoR) by BIRC or Investigator 
Assessment per RECIST v1.1................................................... 20 
3.2.5. 
Time to Progression (TTP) by BIRC or Investigator Assessment 
per RECIST v1.1 ...................................................................... 21 
3.2.6. 
Time to Response (TTR) by BIRC or Investigator Assessment 
per RECIST v1.1 ...................................................................... 22 
3.2.7. 
PFS, ORR, DCR, DoR, TTP, TTR Evaluated by BIRC based on 
Modiﬁed RECIST (mRECIST) ................................................ 22 
3.3. Safety Endpoints ...................................................................................... 22 
3.3.1. 
Adverse Events ......................................................................... 23 
3.3.2. 
Laboratory Test ......................................................................... 26 
3.3.3. 
Vital Signs ................................................................................ 26 
3.3.4. 
12-lead ECG ............................................................................. 27 
3.3.5. 
Physical Examination ............................................................... 27 
3.3.6. 
ECOG-PS score ........................................................................ 28 
3.3.7. 
Child-Pugh ................................................................................ 28 
3.3.8. 
Echocardiography ..................................................................... 28 
3.3.9. 
Treatment Exposure .................................................................. 28 
3.4. Pharmacokinetic and Immunogenicity .................................................... 30 
3.5. Exploratory Endpoints ............................................................................. 30 
3.5.1. 
Patient Reported Outcome (PRO) Endpoints ........................... 30 
3.5.2. 
imRECIST Endpoints Evaluated by Investigator ..................... 34 
3.5.3. 
Biomarker Endpoints ................................................................ 36 
4. 
STATISTICAL ANALYSIS METHODS ......................................................... 37 
4.1. General Methods ...................................................................................... 37 
4.2. Definition of Study Window and Baseline .............................................. 38 
4.3. Handling of Missing Data ........................................................................ 38 


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Statistical Analysis Plan (SAP) 
 
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4.3.1. 
Cancer Diagnosis ...................................................................... 38 
4.3.2. 
Adverse Events ......................................................................... 39 
4.3.3. 
Concomitant Medications ......................................................... 39 
4.3.4. 
Study Treatment Date ............................................................... 39 
4.3.5. 
Start Date of New Anti-Cancer Therapy .................................. 40 
4.3.6. 
Death Date ................................................................................ 42 
4.3.7. 
Pharmacokinetics ...................................................................... 42 
4.4. Analysis Populations ................................................................................ 42 
4.4.1. 
Intent-to-Treat Set (ITT): .......................................................... 42 
4.4.2. 
Per-protocol Set (PPS) .............................................................. 42 
4.4.3. 
Safety Analysis Set (SS) ........................................................... 42 
4.4.4. 
Anti-drug Antibody Analysis Set (ADAS) ............................... 43 
4.4.5. 
PK Analysis Set (PKS) ............................................................. 43 
4.4.6. 
PK/QTc Analysis Set (PKQTS)................................................ 43 
4.4.7. 
Patient Reported Outcomes (PRO) Analysis Set ...................... 43 
4.5. Protocol Deviations .................................................................................. 43 
4.6. Subject Disposition .................................................................................. 44 
4.7. Demographics and Baseline Characteristics ............................................ 45 
4.8. Medical History ....................................................................................... 45 
4.9. Prior and Subsequent Anti-Cancer Therapy ............................................ 45 
4.10. Prior and Concomitant Therapy ............................................................... 46 
4.11. Efficacy Analyses .................................................................................... 46 
4.11.1. Primary Efficacy Endpoints Analyses ...................................... 46 
4.11.2. Secondary and Exploratory Efficacy Endpoints Analyses ....... 50 
4.12. BIRC versus Investigator Assessment ..................................................... 52 
4.13. Other Exploratory Endpoints Analyses ................................................... 52 
4.13.1. Patient Reported Outcome (PRO) Endpoints Analyses ........... 52 
4.13.2. Biomarker Endpoints Analysis ................................................. 54 
4.14. Pharmacokinetics and Immunogenicity Endpoint Analyses.................... 54 
4.14.1. Pharmacokinetics ...................................................................... 54 
4.14.2. Immunogenicity Analysis of SHR-1210 .................................. 54 
4.15. Safety Analyses ........................................................................................ 57 
4.15.1. Extent of Exposure ................................................................... 57 
4.15.2. Adverse Events ......................................................................... 58 
4.15.3. Laboratory Tests Results .......................................................... 67 
4.15.4. ECOG-PS .................................................................................. 68 
4.15.5. Child-Pugh ................................................................................ 68 
4.15.6. Vital Signs ................................................................................ 68 
4.15.7. Physical Examination ............................................................... 68 
4.15.8. 12-Lead ECG ............................................................................ 68 
4.15.9. Concentration-QTc Analysis for Rivoceranib .......................... 69 
4.15.10. Echocardiography ..................................................................... 69 
4.16. Interim Analyses ...................................................................................... 69 
4.16.1. Independent Data Monitoring Committee ................................ 70 
4.17. Multiplicity .............................................................................................. 70 
4.18. Subgroup Analyses .................................................................................. 73 
5. 
REFERENCES 75 
6. 
APPENDIX 
76 
 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
 
ABBREVIATIONS 
Abbreviations 
Definition 
AB 
Abdominal Swelling 
AE 
Adverse Event 
ADA 
Anti-drug Antibody 
AFP 
Alpha-fetoprotein 
AP 
Appetite Loss 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
BCLC 
Barcelona Clinic Liver Cancer 
BI 
Body Image 
BID 
Twice Daily 
BIRC 
Blinded Independent Review Committee 
BOR 
Best Overall Response 
CF 
Cognitive Functioning 
CPS 
Combined Positive Score 
CS 
Compound Symmetry  
CSR 
Clinical Study Report 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
Cmax 
Maximum concentration 
CO 
Constipation 
COVID 
Corona Virus Disease 
CPS 
Combined Positive Score 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DCR 
Disease Control Rate 
DI 
Actual Dose Intensity 
DI 
Diarrhoea 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
DY 
Dyspnoea 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
ECOG-PS 
Eastern Cooperative Oncology Group- Performance Status 
EF 
Emotional Functioning 
EMA 
European Medicines Agency 
EORTC 
European Organization for the Research and Treatment of 
Cancer 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
Abbreviations 
Definition 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
Five-level of EuroQol-5D version 
FA 
Fatigue 
FATI 
Fatigue 
FDA 
Food and Drug Administration 
FEV 
Fever 
FI 
Financial Difficulties 
FT 
Free Triiodothyronine 
GGT 
γ-glutamyl Transferase 
GHS 
General Health Status 
h 
Hour 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C Virus 
HR 
Hazard Ratio 
ICH 
International Council for Harmonisation 
ID 
Identity Document 
imBOR 
Immune-modified best of response 
imCR 
Immune-modified complete response 
imNE 
Immune-modified NE 
imPD 
Immune-modified PD 
imRECIST 
Immune-modified RECIST 
imPR 
Immune-modified partial response 
imSD 
Immune-modified stable disease 
irAE 
Immune-related Adverse Events 
IRT 
Interactive Response Technology 
ITT 
Intention- to Treat 
JAUN 
Jaundice 
LLT 
Lower Level Term 
LVEF 
Left Ventricular Ejection Fraction 
KM 
Kaplan Meier 
LSMean 
Least Square Mean 
mRECIST 
modified RECIST 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures Model 
MRI 
Magnetic Resonance Imaging 
Nab 
Neutralizing antibody 
NE 
Not Estimable 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria 
for Adverse Events 
NR 
Not Reached 
NUTR 
Nutrition 
NV 
Nausea and Vomiting 
OBF 
O’Brien-Fleming Alpha-spending Function 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
Abbreviations 
Definition 
OCT 
Optical Coherence Tomography 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PA 
Pain 
PD 
Progressive Disease 
PD-1 
Programmed Death-l 
PFS 
Progression-free Survival 
PF 
Physical Functioning 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
RCEP 
Reactive Capillary Endothelial Proliferation 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RF 
Role Functioning 
RMST 
Restricted Mean Survival Time 
RNA 
Ribonucleic Acid 
RS 
Raw Score 
PT 
Prothrombin Time 
PT 
Preferred Term 
QD 
Every Day 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
QLQ-HCC 
Quality of Life Questionnaire-Supplement Module for 
HCC 
QoL 
Quality of life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SE 
Standard Error 
SF 
Social Functioning 
SFU 
Safety Follow-Up 
SL 
Insomnia 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SS 
Safety Set 
SX 
Sex Life 
TBIL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TPS 
Tumor Proportion Score 
TNF 
Tumor Necrosis Factor 
TSH 
Thyroid Stimulating Hormone 
TL 
Target Lesion 
TTD 
Time To Deterioration 
TTP 
Time To Progression 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
Abbreviations 
Definition 
UI 
Utility Index 
UN 
Unstructured 
VAS 
Visual Analogue Scale 
 
 
 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
AMENDMENT HISTORY 
Version 
Version Date 
Summary of Changes 
1.0 
30-Sep-2020 
Not applicable (N/A) 
2.0 
05-Aug-2021 
Section 3.1.1 Overall Survival and 3.1.2 Progression-free survival by 
BIRC assessment per RECIST v1.1: Updated the section. 
Section 3.3 Safety Endpoints: Clarified the definition of on- treatment 
period. 
Section 3.3.1 Adverse Events: Provided further details for the selected 
adverse events defined by sponsor. Deleted the definitions for time to 
first onset of irAE and time to irAE resolution. Deleted the liver 
function test abnormalities. 
Section 3.3.2 Laboratory Test: Added the definition of potential Hy’s 
law. 
Section 3.3.3 Vital Signs: Updated clinically significant abnormal 
criteria for Systolic Blood Pressure and Diastolic Blood Pressure in 
Table 5. 
Section 3.3.4 12-lead ECG: Clarified the ECG measurements and blood 
sample collected time. 
Section 3.3.6 ECOG-PS score: Added the section. 
Section 3.3.7 Child-Pugh: Added the section. 
Section 3.3.8 Echocardiography: Added the section. 
Section 3.3.9 Treatment Exposure: Added details of treatment exposure. 
Section 3.4 Pharmacokinetic and Immunogenicity and section 4.14 
“Pharmacokinetics and Immunogenicity Endpoint Analyses”: Added the 
efficacy endpoints and safety endpoints, added definitions for Nab and 
ADA and analyses for ADA and Nab. 
Section 3.5.1.1 EORTC QLQ-C30: Added definition of TTD for the 
symptom’s scales/items. Clarified the TTD definition for 
HRQoL/function. 
Section 3.5.3 Biomarker Endpoints and the Other Endpoints: Added the 
categories for expression level. 
Section 4.2 Definition of Study Window and Baseline: Modified the 
visit window and target days in Table 12. 
Section 4.3.7 PK: Updated the rule for PK summary. 
Section 4.3.7 Analysis Populations: Added the PKQTS population. 
Section 4.5 Protocol Deviations: Deleted the non-important protocol 
deviations and Added the summary for all protocol deviations related to 
COVID-19. 
Section 4.7 Demographics and Baseline Characteristics: Updated the 
section. 
Section 4.9 Prior and Subsequent Anti-Cancer Therapy: Added the 
definitions of prior and subsequent anti-cancer therapy. 
Section 4.11 Efficacy Analyses: Updated the section. 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
Section 4.13.1 Patient Reported Outcome (PRO) Endpoints Analyses: 
Added the summary for complete rates of PRO endpoints and updated 
the analysis method. 
Section 4.14.1 Pharmacokinetics: Rephrased the whole section for 
clarification. 
Section 4.14.2 Immunogenicity Analysis of SHR-1210: Modified the 
definition of ADA/Nab positive and negative, time to and duration of 
ADA/Nab response. Added the sections of Demographics and Baseline 
Characteristics, Impact of Immunogenicity on PK of SHR-1210, Impact 
of Immunogenicity on Efficacy of SHR-1210 and Safety of SHR-1210 
for Analyses. 
Section 4.15 Safety Analyses: Added the summary for missing visits due 
to COVID-19 and discontinuation or interruption of study drugs due to 
COVID-19.  
Section 4.15.2 All Adverse Events: Added the overview of summary of 
immune-related TEAEs assessed by investigator and COVID-19 related 
TEAEs. Added some summary tables of AEs. Deleted the summary of 
TEAEs leading to interruption of all study drug. Some analyses were 
combined in one table. 
Section 4.15.2.1.2 irAEs assessed by investigator: Deleted the analyses 
of irAEs including time to first onset of irAE, resolution of irAEs and 
duration of systemically administered corticosteroids. 
Section 4.15.2.1.3 Selected Adverse Events: Added the summaries of 
SHR-1210 selected adverse events and Rivoceranib selected adverse 
events and time to first onset of selected AEs, resolution of selected 
AEs，and duration of systemically administered corticosteroids. 
Section 4.15.2.1.4 COVID-19 related TEAEs: Added the summary of 
COVID-19 related TEAEs leading to any study drug interruption or 
dose reduced by SOC and PT. 
Section 4.15.3 Laboratory Tests Results: Added analyses of urinalysis, 
potential Hy’s law and listing of potential Hy’s law. 
Section 4.15.5 Child-Pugh: Added the analysis of Child-Pugh. 
Section 4.15.7 Physical Examination: Moved to section 4.15.7. 
Section 4.15.9 Concentration-QTc analysis for Rivoceranib: Added the 
analysis. 
Section 4.15.10 Echocardiography: Added the section. 
Section 4.18 Subgroup Analyses: Added the subgroup analyses of ORR 
assessed by BIRC, added PD-L1 categories and modified some 
subgroup categories. Added the analyses of demographic and other 
baseline characteristics by geographical region. 
Minor editorial and consistency changes throughout the document. 
3.0 
19-Apr-2022 
Section 1 Introduction: Updated the protocol version to 5.1 
Section 3.2.6 Time to Response (TTR) by BIRC or Investigator: Added 
the section 
Section 3.2.7 PFS, ORR, DCR, DoR, TTP，TTR Evaluated by BIRC 
based on Modiﬁed RECIST (mRECIST): Added definition for TTR 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
Section 3.3.1 Adverse Events: Added an example for the time to 
resolution of selected AEs. Added the definition for duration of 
systemically administered corticosteroids. 
Section 3.3.2 Laboratory Test: Updated the definition of the concurrent 
measurement. 
Section 3.5.2 imRECIST Endpoints Evaluated by Investigator: Added 
the definition for immune-modified TTR (imTTR) evaluated by 
investigator 
Section 4.3.2 Adverse Events: Updated the imputation rule for missing 
end dates. 
Section 4.3.3 Concomitant Medications: Updated the imputation rule for 
missing end dates. 
Section 4.7 Demographics and Baseline Characteristics: Added non-
viral into the root cause of HCC.  
Section 4.11.2.6 Time to Response: Added the section. 
Section 4.15.2.1.1 All Adverse Events: Added the exposure adjusted 
incidence rate analyses for the overall TEAE, TEAE with CTCAE grade 
≥3, TEAE excluding hypertension, and TEAE excluding hypertension 
with CTCAE grade ≥3.  
Section 4.15.2.1.2 irAEs Assessed by Investigator: Added the analyses 
for number and percentage of subjects with at least one irAE treated 
with any hormone replacement therapy for overall, duration (total days) 
of systemically administered Corticosteroids by medical concept 
category for subjects treated with ≥ 40mg/day systemically 
administered Corticosteroids, duration (total days) of systemically 
administered Corticosteroids ≥ 40mg/day by medical concept 
category, number and percentage of subjects with at least one selected 
AEs thyroid disorder and type 1 diabetes Mellitus for SHR-1210 treated 
with any hormone replacement therapy by medical concept category and 
by maximum CTCAE grade, treatment of Selected AEs hepatotoxicity 
for Rivoceranib. 
Section 4.15.3 Laboratory Test Results: Updated the definition of 
concurrent measurements. 
Section 4.18 Subgroup Analysis: Updated that ORR was based on 
BIRC; Updated that disease organs was based on BIRC, the definition 
for the previous local therapy. Added OS/PFS analysis for Mainland 
China/HongKong/Taiwan. 
Appendix 1. Selected Adverse Events defined by Sponsor: Updated the 
category and SMQs/PTs. 
Appendix 3. SAS code for primary analysis of PFS and OS: Added this 
section. 
Minor editorial and consistency changes throughout the document.  
 
 
 
 


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Statistical Analysis Plan (SAP) 
 
Version 3.0 
1. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the statistical 
methods, data derivations and data presentation to be performed on this study before 
any formal statistical analysis or database locked, and to ensure the credibility of the 
study findings by further elaborating details regarding the definition of analysis 
variables and analysis methodology as pre-specified in study protocol to address all 
study objectives. The SAP will serve as a compliment to the protocol, and where there 
is a discrepancy between the SAP and protocol, the SAP supersedes it. Any critical 
revision within the SAP of definition(s) or analysis method(s) for the primary 
endpoints will be included in a protocol amendment.  
The preparation of this SAP has been developed in conjunction with the International 
Conference on Harmonization (ICH) relevant guidelines, European Medicines 
Agency (EMA/CHMP Note for Guidance on Choice of Control Group in Clinical 
Trials 2001), FDA (Guidance for Industry: Adaptive Designs for Clinical Trials of 
Drugs and Biologics 2018) and study protocol (SHR-1210-III-310 V5.1).  
1.1. 
Study Design 
This is a randomized, open-label, international, multi-center, phase 3 trial to evaluate 
the efficacy and safety of PD-1 antibody SHR-1210 plus rivoceranib mesylate versus 
sorafenib as first-line therapy in subjects with incurable advanced HCC.  
The study will be conducted in subjects with incurable, locally advanced or metastatic 
HCC who did not receive systematic treatment previously. Primary efficacy endpoints 
include both overall survival (OS) and progression free survival (PFS) evaluated by 
BIRC based on RECIST v1.1, and approximately 510 subjects will be enrolled. 
Eligible subjects will be randomized to receive either SHR-1210 combined with 
rivoceranib mesylate (experimental arm) or sorafenib (control arm) in a 1:1 ratio. The 
stratification factors for randomization include: 
1. Macrovascular invasion and/or extrahepatic metastasis (presence vs. absence); 
2. Geographical region (Asia vs. countries outside of Asia); 
3. Baseline AFP (AFP < 400 ng/mL vs. AFP ≥400 ng/mL). 
Subjects will receive study treatment after being informed of all pertinent aspects of 
the study, signing the informed consent form and passing the screening for eligibility. 
Experimental arm: SHR-1210, 200 mg, via intravenous infusion, once every two 
weeks (Q2W) + rivoceranib 250 mg, p.o., once per day (QD), continuously, 4 weeks 
(28 days) per cycle of therapy. Control arm: sorafenib, 400 mg, p.o., twice per day 
(BID), continuously, 28 days per cycle of therapy. Study treatment will continue until 
the subject develops an intolerable toxicity, withdrawing informed consent, and 
disease progression confirmed by BIRC according to RECIST v1.1 (when the subject 
has disease progression assessed by the investigator according to RECIST v1.1, the 
investigator must submit the radiological data to BIRC immediately. If BIRC 
evaluates it as non-disease progression according to RECIST v1.1, the subject should 
continue to receive the study drug treatment and continue the tumor radiological 


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evaluation; if BIRC confirms it as disease progression based on RECIST V1.1, at this 
time, the investigator needs to assess whether the subject still has clinical benefit. If 
the subject is considered to still have clinical benefit and meet the criteria for 
treatment beyond disease progresses, the subject may continue to receive study 
medication; if the subject is no longer considered to have clinical benefit, the 
treatment may be discontinued), or other termination criteria specified by the 
protocol, whichever occurs first. 
Subjects will have safety visits on D1 and D15 of each cycle of therapy within the 
first 3 cycles for both experimental and control arms. Beginning from the cycle 4, 
subjects will have safety visits on D1 and D15 of each cycle in the experimental arm; 
subjects in the control arm will only have safety visits on D1 of each cycle. Subjects 
will continue with safety visits and survival follow-up after the end- of- treatment. 
The study design is shown below: 
Study Design Chart 
 
Tumor radiological evaluation will be performed every 8 weeks (56 days) ± 7 days 
from the randomization through the first 48 weeks, to assess the efficacy, and every 
12 weeks (84 days) ± 7 days after 48 weeks. During the trial period, radiological 
examination and evaluation can be added at any time if clinically indicated. Tumor 
radiological assessment will continue until the occurrence of disease progression 
confirmed by BIRC according to RECIST v1.1 criteria or study treatment 
discontinuation, whichever occurs later. Subjects who discontinue treatment for 
reasons other than BIRC-confirmed disease progression (according to RECIST v1.1) 
will also continue with regular follow-up by tumor radiological assessments after 
study treatment is discontinued. 
If the subject withdraws informed consent before BIRC confirms disease progression 
according to the RECIST v1.1 criteria or the study treatment is discontinued, other 
anti-tumor treatment has begun (except for traditional Chinese medicine), or the 
subject dies, there is no need to continue the radiological evaluation. If the subject 
does not meet the above criteria to stop radiological assessment, the efficacy 
evaluation of the three efficacy evaluation criteria (RECIST v1.1, mRECIST, 
Experimental arm (N=255) 
1:1 
randomization 
The final PFS analysis is planned to be performed after 332 PFS events have been observed. 
The interim OS analysis is planned to be performed after 251 OS events have been observed. 
The final OS analysis is planned to be performed after 359 OS events have been observed. 
Control arm (N=255) 
Sorafenib, 400 mg, BID, orally; 
28 days as one cycle of therapy; until progression of 
disease confirmed by BIRC (according to RECIST 
v1.1) and no clinical benefit or intolerable toxicity 
 
SHR-1210, 200 mg, via intravenous infusion, Q2W;
Combined with rivoceranib tablet, 250 mg, QD,
orally;28 days as one cycle of therapy; until
progression of until BIRC confirmed disease 
progression (according to RECIST v1.1) and the
investigator consider the treatment no longer has 
clinically benefit or the toxicity is intolerable 
Pathologically diagnosed 
advanced hepatocellular 
carcinoma (unresectable or 
metastatic);  
Child-Pugh class: Grade A; 
BCLC stage B-C; 
No systematic treatment;  
At least one measurable 
lesion that can be evaluated 
with CT or MRI;  
ECOG-PS score 0-1; 
 
Safety follow-up/survival follow-up 


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imRECIST) needs to continue even if the disease progression under certain efficacy 
evaluation criteria occurs. 
1.2. 
Objectives and Statistical Hypotheses 
1.2.1. 
Primary Objectives  
To compare efficacy endpoints of OS and PFS evaluated by BIRC based on RECIST 
v1.1 in 2 treatment groups (SHR-1210 in combination with rivoceranib versus 
sorafenib).  
1.2.2. 
Key Secondary Objectives  
To compare the ORR (assessed by BIRC according to RECIST v1.1) of SHR-1210 in 
combination with rivoceranib to sorafenib 
1.3. 
Sample Size Determination 
Assuming a 1:1 randomization between sorafenib and SHR-1210+rivoceranib, and a 
median PFS time of 3.6 months for subjects in the sorafenib group, and 6 months in 
SHR-1210 group, 332 PFS events will be sufficient to detect a hazard ratio (HR) of 
0.60 with 98% power based on Log-rank test at significance level of 0.005 one-sided. 
Similarly, assuming a median survival time of 10.5 months for subjects in the sorafenib 
group, and 14.6 months in SHR-1210 group, 359 OS events will be sufficient to detect 
a hazard ratio (HR) of 0.72 with 85% power based on Log-rank test at significance 
level of 0.020 one-sided. Assuming an accrual period of 18 months, total duration of 
36 months and 19 months for the OS and PFS, respectively, and probability of subject 
loss be approximately 10% per 12 months and per 6 months for the OS and PFS, 
respectively, a sample size of 510 patients will be enrolled for the study. Power and 
sample calculations were performed using EAST® 6.4.1. software package. 
2. STATISTICAL HYPOTHESES AND DECISION RULES 
The following statistical hypotheses will be tested to address the primary objectives: 
H01: HRPFS ≥1 vs H11: HRPFS <1 
H02: HROS ≥1 vs H12: HROS <1 
Where HRPFS and HROS are the hazard ratios of PFS and OS respectively. 
The overall type I error is controlled at 0.025 1-sided by allocating α1=0.005 to the 
PFS comparison and by allocating α2=0.020 to the OS comparison.  
Superiority of SHR-1210 plus rivoceranib over sorafenib in PFS is demonstrated, if 
one-sided p-value obtained from the stratified log-rank test is significant at 0.005 or 
0.025 (if H02 is rejected) in favoring the experimental group.  
Superiority of SHR-1210 plus rivoceranib over sorafenib in OS is demonstrated, if 


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 
one-sided p-value obtained from the stratified log-rank test is significant at 0.005 
at interim analysis (~70% events observed), or at 0.018 at final analysis in 
favoring the experimental group;  
or 
 
one-sided p-value obtained from the stratified log-rank test is significant at 0.007 
at the interim analysis (~70% events observed), or at 0.023 at final analysis (if 
H01 is rejected) in favoring the experimental group. 
The significance levels for interim and final efficacy analyses for OS will be 
determined by using the Lan-DeMets procedure with an O’Brien-Fleming stopping 
boundary based on actual number of deaths observed. 
The following statistical hypothesis will be tested to address the key secondary 
objective: 
H03: Difference of ORR≤0 vs H13: Difference of ORR>0 
If both the PFS and OS endpoints are significant, ORR assessed by BIRC according 
to RECIST v1.1 at the time of 70% OS events observed will be tested at 0.025 one-
sided for SHR-1210 plus rivoceranib compared to sorafenib using stratified Cochran-
Mantel-Haenszel (CMH) test. If both PFS and OS endpoints are not significant, then 
the testing for ORR will not be performed.  
Details of multiplicity control for the comparisons for PFS, OS, and ORR can be 
found in Section 4.17. 
3. STUDY ENDPOINTS 
3.1. 
Primary Endpoints 
3.1.1. 
Overall Survival 
Overall Survival (OS): defined as time from randomization to death due to any cause 
(i.e., date of death or censoring – date of randomization +1). Subjects without 
documented death at the time of analysis will be censored based on the last recorded 
date on which the subjects were known to be alive. 
For any OS analysis, it may be necessary to use all relevant CRF fields to determine 
the last recorded date on which the subject was known to be alive. The last date for each 
individual subject is defined as the latest among the following dates recorded on the 
eCRFs： 
• 
Randomization date 
• 
Start treatment and end of treatment date 
• 
Start and end date of concomitant therapy 
• 
AE start and end dates 


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• 
All subject assessment dates (Laboratory test [laboratory, pharmacokinetic], 
vital signs, 12-lead ECG, echocardiography, physical examination, Child-
Pugh score, ECOG-PS, tumor assessments, subject’s self-evaluation) 
• 
Date of last dose on ‘end of treatment’ eCRF pages 
• 
Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
• 
Date last known alive on the ‘Survival Follow-up’ CRF (do not use date of 
survival follow-up assessment unless status is ‘Alive’)  
• 
End of study date (do not use the date of death in the page) 
During the interim analyses, for subjects who are confirmed to be alive or die after the 
data cut-off date, they will be censored at the cut-off date. 
Reasons for censoring will be derived in Table 1 following the hierarchy shown below: 
Table 1. Censoring Reasons for OS analyses 
No. 
Condition 
Censoring Reason 
1 
No event and [reason of End of study 
(EOS)=Withdrawal by subject] 
Withdrawal of consent 
2 
No event and [EOS=Lost to Follow-up/Physician 
decision in EOS page] 
Lost to follow-up 
3 
No event and none of the conditions in the above 
hierarchy is met 
Alive 
3.1.2. 
Progression-Free Survival by BIRC Assessment per RECIST v1.1  
Progression-free-survival (PFS): defined as the time from the date of randomization to 
the first occurrence of radiological progression by tumor image evaluation or death, 
whichever comes first, evaluated by BIRC based on RECIST v1.1, regardless of 
whether the subject withdraws from randomized therapy. 
PFS data will be censored on the date of the last adequate tumor assessment for subjects 
who do not have an event (PD or death), for subjects who start a new anti-cancer therapy 
(except for traditional Chinese medicine) prior to an event or for subjects with an event 
after 2 or more missing tumor assessments. An adequate post-baseline assessment is 
defined as an assessment where a response of CR, PR, SD, non-CR/non-PD, or PD can 
be determined. Time points where the response is NE or no assessment was performed 
will not be used for determining the censoring date. Subjects who do not have a baseline 
or adequate post-baseline tumor assessment will be censored on the date of 
randomization unless death occurred on or before the time of the planned tumor 
assessment (i.e., ≤16weeks after the date of randomization) in which case the death 
will be considered as an event. 
Given the scheduled visit assessment schedule (i.e., eight-weekly for the first 48 weeks 
then twelve-weekly thereafter) the definition of 2 missed visits is defined as below: 


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 
If the previous tumor assessment is conducted prior to study day 273 (i.e., week 39) 
then two missing visits will equate to 17 weeks after the previous tumor assessment, 
allowing for early and late visits.  
 
If the two missed visits occur over the period when the scheduled frequency of 
tumor assessments changes from eight-weekly to twelve-weekly this will equate to 
21 weeks. The time period for the previous tumor assessment will be from study 
days 273 to 343 (i.e., week 39 to week 49). 
 
From week 49 onwards (when the scheduling changes to twelve-weekly 
assessments), two missing visits will equate to 25 weeks.  
The PFS time will always be derived based on scan dates not visit dates. 
In the instance where there are different dates of scans within the same tumor 
assessment, the response assessment will use the last scan date where lesions are 
defined and an assessment of PD by investigator will be dated on the earliest scan 
date that demonstrates PD assessed by investigator: 
• 
The date of the first scan (from baseline) on which the New Lesion was 
detected (if a New Lesion was detected at that visit) 
• 
The date of the first scan (from baseline) of Target Lesions (if the Target 
Lesion response is progression) 
• 
The date of the first scan (from baseline) on which the Non-Target Lesion(s) 
progressed (if the Non-Target Lesion response is progression). 
The censoring and event date options to be considered for the PFS analyses are 
presented in Table 2. 
PFS (months)= [date of PFS event or censoring – date of randomization + 1]/30.4375 
Table 2.   Censoring Rules for PFS Analyses 
Scenario 
Date of censoring 
No baseline or no adequate post-baseline 
disease assessment 
Censored at date of randomization 
No PD, no death and no new anticancer 
treatment initiated 
Censored at last adequate tumor assessment 
No PD, no death and new anticancer 
treatment initiated 
Censored at last adequate tumor assessment before 
new anti-cancer treatment 
PD or death after 2 or more missing or 
inadequate post-baseline tumor 
assessments 
Censored at last adequate tumor assessment prior to 
the ≥ 2 missed or inadequate post-baseline tumor 
assessment 
Reasons for censoring in hierarchical order are shown in Table 3: 


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Table 3.  Censoring Reasons for PFS Analyses 
No. 
Condition 
Censoring Reason 
1 
No baseline assessment 
No baseline assessment 
2 
Start of new anti-cancer therapy 
Start of new anti-cancer 
therapy 
3 
PD/Death after 2 or more missing or inadequate 
post-baseline tumor assessments 
Event after 2 or more missing 
assessments a 
4 
No PD/Death and Reason of EOS=Withdrawal by 
subject 
Withdrawal of consent 
5 
No PD/Death and Reason of EOS= Lost to follow-
up 
Lost to follow-up 
6 
No PD/Death and [end of study (EOS) page 
present] and no adequate post-baseline tumor 
assessment 
No adequate post-baseline 
tumor assessment 
7 
No PD/Death and none of the conditions in the 
above hierarchy are met 
Ongoing without an event 
a 2 or more missing or inadequate post-baseline tumor assessments. 
3.2. 
Secondary Endpoints 
3.2.1. 
Progression-Free Survival by Investigator Assessment per RECIST v1.1  
Progression-free-survival (PFS): defined as the time from the date of randomization to 
the first occurrence of radiological progression by tumor image evaluation or death, 
whichever comes first, evaluated by the investigator based on RECIST v1.1. regardless 
of whether the subject withdraws from randomized therapy. 
The censoring rule and other rules are the same as PFS by BIRC assessment per 
RECIST v1.1. 
3.2.2. 
Objective Response Rate (ORR) by BIRC or Investigator Assessment per 
RECIST v1.1 
ORR as evaluated by BIRC based on RECIST v1.1: defined as the percentage of 
subjects with complete response (CR) or partial response (PR) evaluated by BIRC 
based on RECIST v1.1. 
ORR as evaluated by investigator based on RECIST v1.1: defined as the percentage 
of subjects with complete response (CR) or partial response (PR) evaluated by 
investigator based on RECIST v1.1. 
The assessment of ORR will include all assessments obtained up until progression, or 
the last assessment in the absence of progression prior to starting new anti-cancer 
therapy.  
Best Objective Response  


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Best objective response (BOR) is calculated based on the overall visit response from 
each RECIST assessment. It is the best response a subject has had following 
randomization but prior to starting any new anti-cancer therapy and prior to RECIST 
progression or the last assessment in the absence of RECIST progression and new 
anti-cancer therapy. 
Categorization of confirmed BOR will be based on RECIST using the following 
response categories: CR, PR, SD, PD and NE. 
• 
CR: at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD. It is reasonable to consider a subject with time point 
responses of CR-NE-CR, CR-NE-NE-CR as a confirmed complete response. 
• 
PR: at least two determinations of PR or better (PR followed by PR or PR 
followed by CR) at least 4 weeks apart and before first documentation of PD (and 
no qualifying for a CR). It is reasonable to consider a subject with one NE or two 
NEs, or one SD occurred between the two response as a confirmed partial 
response.  
• 
SD: at least one SD assessment (or better) ≥ 8 weeks ±1 week after the date of 
randomization and before first documentation of PD (and not qualifying for CR 
or PR). 
• 
PD: first documentation of PD ≤ 17weeks after the date of randomization (and 
not qualifying for CR, PR, SD). 
• 
NE: all other cases. 
BOR will be determined programmatically based on RECIST from the overall visit 
response at each visit using BIRC data including all assessments obtained up until the 
first progression, the start of any new anti-cancer therapy or the last assessment in the 
absence of progression. For subjects whose PFS event is death, BOR will be 
calculated based upon all RECIST assessments prior to death. 
For a best response of SD, the latest of the dates of contributing towards a particular 
overall visit assessment will be used. SD should be recorded at least 8 weeks ±1 
week after randomization. For CR/PR, the initial overall visit assessment which 
showed a response will use the latest the dates contributing towards a particular 
overall visit assessment. 
Change in Tumor Size 
The percentage change from baseline in tumor size will be derived at each scheduled 
tumor assessment visit (i.e., week 8, week 16 etc. hereafter referred to as week X for 
convenience). Best percentage change from baseline in tumor size will be derived as 
the biggest decrease or the smallest increase in tumor size from baseline until 
documented disease progression, excluding assessments after start of new anti-cancer 
therapy. 
This is based on RECIST target lesion (TL) measurements taken at baseline and at the 
time point of interest. Tumor size is defined as the sum of the longest diameters of the 


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TLs based upon RECIST assessments. TLs are measurable tumor lesions. Baseline for 
RECIST is defined to be the last evaluable assessment prior to randomization. The 
change in tumor size at week X will be obtained for each subject by taking the 
difference between the sum of TLs at week X and the sum of the TLs at baseline. To 
obtain the percentage change in TL tumor size at week X the change in tumor size is 
divided by the sum of TLs at baseline and multiplied by 100 (i.e. (week X – baseline) 
/ baseline *100). 
Whenever tumor size data for the week X visit (Note: or visit at which progression 
was documented if before week X) is available then this should be used in the 
analysis. A windowing rule will be applied and will follow the protocol allowed visit 
window; Therefore any RECIST scan performed within ± 1 week of the protocol 
visit will be used for that visit. 
Measurement from the reviewer selected by adjudicator will be used when 
adjudication for overall visit response has occurred, but in the case where no 
adjudication was required, the measurements from the reviewer who was assigned as 
reviewer 1 in Lesion Management Solutionwill be used for this analysis. 
3.2.3. 
Disease Control Rate (DCR) by BIRC or Investigator Assessment per 
RECIST v1.1 
DCR as evaluated by BIRC based on RECIST v1.1: defined as the percentage of 
subjects with complete response, partial response or stable disease (SD) ≥ 8 weeks 
±1 week evaluated by BIRC based on RECIST v1.1. 
DCR as evaluated by investigator based on RECIST v1.1: defined as the percentage 
of subjects with complete response, partial response or stable disease (SD) ≥ 8 
weeks ±1 week evaluated by investigator based on RECIST v1.1. 
3.2.4. 
Duration of Response (DoR) by BIRC or Investigator Assessment per 
RECIST v1.1 
DoR as evaluated by BIRC based on RECIST v1.1: defined as time from the date of 
first record of objective response (CR or PR) to the first occurrence of radiological 
progression or death, whichever comes first, evaluated by BIRC based on RECIST 
v1.1. 
DoR as evaluated by investigator based on RECIST v1.1: defined as time from the 
date of first record of objective response (CR or PR) to the first occurrence of 
radiological progression or death, whichever comes first, evaluated by investigator 
based on RECIST v1.1. 
DoR (months) = [date of event or censoring– first date of CR/PR +1]/30.4375 
The time of the initial response will be defined as the latest of the dates contributing 
towards the first visit response of CR or PR. 
If a subject does not progress following a response, then the corresponding DoR will 
be censored at the PFS censoring time. 


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DoR will not be defined for those subjects who do not have documented response. 
3.2.5. 
Time to Progression (TTP) by BIRC or Investigator Assessment per 
RECIST v1.1 
TTP as evaluated by BIRC based on RECIST v1.1: defined as the time from the date of 
randomization to radiological progression of disease evaluated by BIRC based on 
RECIST v1.1.   
TTP as evaluated by investigator based on RECIST v1.1: defined as the time from the 
date of randomization to radiological progression of disease evaluated by investigator 
based on RECIST v1.1.  
TTP (months)= [date of TTP event or censoring – date of randomization + 1]/30.4375 
Table 4.  Censoring Rules for TTP Analyses 
Scenario 
Date of censoring 
No baseline or no adequate post-baseline 
disease assessment 
Censored at date of randomization 
No PD and no new anti-cancer treatment 
initiated 
Censored at last adequate tumor assessment 
No PD and new anti-cancer treatment 
initiated 
Censored at last adequate tumor assessment before 
new anti-cancer treatment is given 
No PD but death before 2 missing or 
inadequate post-baseline tumor 
assessments and with no new anti-cancer 
treatment 
Censored at last adequate tumor assessment 
PD/death after 2 or more missing or 
inadequate post-baseline tumor 
assessments 
Censored at last adequate tumor assessment prior to 
the ≥ 2 missed or inadequate post-baseline tumor 
assessment 
Reasons for censoring in hierarchical order are shown in Table 5: 
Table 5.  Censoring Reasons for TTP Analyses 
No. 
Condition 
Censoring Reason 
1 
No baseline assessment 
No baseline assessment 
2 
Start of new anti-cancer therapy 
Start of new anti-cancer 
therapy 
3 
PD/Death after 2 or more missing or inadequate 
post-baseline tumor assessments 
PD/Death after 2 or more 
missing assessments a 
4 
No PD and Reason of EOS=Withdrawal by subject 
Withdrawal of consent 
5 
No PD and Reason of EOS= Lost to follow-up 
Lost to follow-up 
6 
Death 
Death 
7 
No PD and [end of study (EOS) page present] and 
no adequate post-baseline tumor assessment 
No adequate post-baseline 
tumor assessment 
8 
No PD and none of the conditions in the above 
hierarchy are met 
Ongoing without PD 


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3.2.6. 
Time to Response (TTR) by BIRC or Investigator Assessment per 
RECIST v1.1 
TTR as evaluated by BIRC based on RECIST v1.1: defined as the time from the date 
of randomization to the date of first record of objective response (CR or PR) evaluated 
by BIRC based on RECIST v1.1.   
TTR as evaluated by investigator based on RECIST v1.1: defined as the time from the 
date of randomization to the date of first record of objective response (CR or PR) 
evaluated by investigator based on RECIST v1.1.  
TTR (months)= [first date of CR/PR– date of randomization + 1]/30.4375 
3.2.7. 
PFS, ORR, DCR, DoR, TTP, TTR Evaluated by BIRC based on Modiﬁed 
RECIST (mRECIST) 
PFS as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
the time from the date of randomization to the first occurrence of radiological 
progression by tumor image evaluation or death, whichever comes first, evaluated by 
BIRC based on mRECIST. 
ORR as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
the percentage of subjects with complete response (CR) or partial response (PR) 
evaluated by BIRC based on mRECIST.  
DCR as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
the percentage of subjects with complete response, partial response or stable disease 
(SD) ≥8 weeks ±1 week evaluated by BIRC based on mRECIST. 
DoR as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
time from the date of first record of objective response (CR or PR) to the first 
occurrence of radiological progression or death, whichever comes first, evaluated by 
BIRC based on mRECIST.  
TTP as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
the time from the date of randomization to radiological progression of disease 
evaluated by BIRC based on mRECIST. 
TTR as Evaluated by BIRC based on Modiﬁed RECIST (mRECIST): defined as 
the time from the date of randomization to the date of first record of objective 
response (CR or PR) evaluated by BIRC based on mRECIST. 
The censoring rules and other rules for PFS, DoR and TTP by BIRC based on 
mRECIST are the same as PFS, DoR and TTP assessed by BIRC per RECISIT. 
3.3. 
Safety Endpoints 
Safety data collected during the on-treatment period will be summarized unless 
specified otherwise. “on-treatment” is defined as the time from the first dose through 
minimum (start day of first new anti-cancer therapy after last dose date-1 day, 90 days 


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+ last dose of study drug). Safety data collected outside the on-treatment period will 
not be summarized unless specified otherwise, but will be listed and flagged. 
3.3.1. 
Adverse Events 
An adverse event (AE) can be any unfavorable and unintended symptom, sign, 
abnormal laboratory finding, or disease, including the worsening of pre-existing 
medical conditions/diseases, any new adverse medical conditions, or abnormal 
clinically significant laboratory values or results that are not caused by concomitant 
disease. For reporting purposes, protocol defined that collection of AE/SAE begins 
from the time of subject informed consent, through and including 90 days after the 
last dose of SHR-1210 or 30 days after the last dose of targeted anti-angiogenic 
therapy, whichever comes later. All serious AEs suspected of study drug related occur 
after this period are also collected. All AEs/SAEs are to be followed up until resolve, 
return to baseline level or ≤ Grade 1 (CTCAE v4.03), reach a stable state, or until 
loss of follow-up or death. All AEs will be coded using a single MedDRA dictionary 
(v 24 or higher) for preferred term (PT) and primary system organ class (SOC). 
Severity of AE will be graded using the NCI CTCAE v4.03 criteria. For the purposes 
of analysis, a treatment-emergent adverse event (TEAE) is an AE with an onset date 
during the on-treatment period. 
• 
Treatment-Related Adverse Events: adverse events with relationship to study 
treatment (as recorded on “Adverse Event” eCRF page, Relationship to study 
treatment= “Related”). Adverse events that have missing causality will be 
considered as related to study drug. 
• 
Adverse Events Leading to Dose Reduction: adverse events leading to dose 
reduction of study treatment (as recorded on “Adverse Event” eCRF page, Action 
to study treatment= “Dose Reduced or Dose interrupted and Reduced”). Note: no 
dose adjustment is allowed for SHR-1210 treatment component; 
• 
Adverse Events Leading to Interruption of Study Drug: adverse events 
leading to interruption of study treatment (as recorded on “Adverse Event” eCRF 
page, Action to study treatment= (“Dose interrupted” or “Dose interrupted and 
Reduced”); 
• 
Adverse Events Leading to Both Dose Reduction and Interruption of Any 
Study Drug: adverse events leading to interruption of study treatment (as 
recorded on “Adverse Event” eCRF page, Action to study treatment= (Dose 
interrupted and Reduced)). Note: no dose adjustment is allowed for SHR-1210 
treatment component; 
• 
Adverse Events Leading to Discontinuation of Study Drug: adverse events 
leading to treatment discontinuation (as recorded on “Adverse Event” eCRF page, 
Action to study treatment= “Drug Withdrawn”). 
Selected Adverse Events Defined by Sponsor： 
• 
Selected Adverse Events for SHR-1210 


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For the purposes of analysis, a set of comprehensive definitions using standardized 
MedDRA queries (SMQs), and Sponsor-defined AEGTs (adverse event grouped 
terms) were adopted to identify selected Adverse Events by medical concept from the 
adverse event clinical database. These medical concepts included SHR-1210 
associated important identified and potential risks, and class effects reported with 
other immune-checkpoint inhibitors, or important identified risks associated with the 
use of rivoceranib. 
A complete list of Selected AEs for SHR-1210 is described in Appendix 1. 
Selected AEs Treated with Systemic Corticosteroids for SHR-1210 
These events are a subset of the SHR-1210 Selected AEs and were determined by 
their temporal relationship with the use of systemic corticosteroids to elucidate the 
possible association of these events and the body’s humoral or cell-mediated 
immunity. Data collected on the concomitant medication page and AE page of the 
eCRF were both used to programmatically identify the selected AEs requiring the use 
of systemic corticosteroids. 
Selected AEs using systemic corticosteroid for SHR-1210 were generated and include 
AEs according to the following criteria: 
 
systemic corticosteroid was given between the AE onset date and the AE 
resolution date. 
Note: The AEs with missing resolution dates were included. The AEs with a 
resolution date same as the systemic corticosteroid initiation date were not 
included. 
Systemic corticosteroid was identified via the ATC codes as show below. Only 
medications with the route of “intramuscular”, “intravenous”, “subcutaneous”, “oral” 
or missing are considered. Medications with the route of “topical” or “other” are 
considered as non-systemic. 
Systemic corticosteroids: 
H02A-corticosteroids for systemic use, plain 
H02B- corticosteroids for systemic use, combination  
 
Selected AEs Requiring Immunosuppressive Treatment Other Than 
Corticosteroids for SHR-1210 
Immunosuppressive agents other than corticosteroids were identified via ATC codes: 
L04AA- selected immunosuppressants 
L04AB-Tumor Necrosis Factor alpha (TNF-α) inhibitors 
L04AC-Interleukin inhibitors 
L04AD-Calcineurin Inhibitors 
L04AX-other immunosuppressants 
 
Selected AEs Requiring Hormone replacement therapy for SHR-1210 


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Hormone replacement for categories of Thyroid disorder and Type 1 Diabetes Mellitus 
will be identified via the ATC codes as shown below: 
H03A-thyroid preparations 
H03B-antithyroid preparations 
A10A-insulins and analogues 
 
• 
Selected Adverse Events for Rivoceranib 
To further characterize the rivoceranib toxicities, selected AEs for rivoceranib were 
also summarized by medical concepts, using MedDRA-standardized SMQs, or 
Sponsor-defined AEGTs. 
A complete list of selected AEs for rivoceranib is described in Appendix 1. 
Selected AEs hepatotoxicity for Rivoceranib Treated with Systemic Corticosteroids 
and Requiring Immunosuppressive Treatment Other Than Corticosteroids will be 
identified as selected AEs for SHR-1210. 
 
Time to First onset of Selected AEs: 
Time (Months) to first onset of selected AEs is defined as: (First date of selected AEs 
occurred–date of first dose + 1)/30.4375. 
Time to Resolution of Selected AEs: 
Time (Months) to resolution for an event is defined as time from occurrence of the AE 
to its complete resolution, which is defined as the record of the event being resolved 
(as recorded on “Adverse Event” eCRF page, Outcome of AE= (Recovered/Resolved, 
Recovered/Resolved with sequelae)). For subjects with multiple episodes of the same 
event (LLT) overlapped adjacent to each other, the onset date of first occurrence of the 
event and the latest end date of the events are used. For example, if a subject 
experiencing the event onset on Day 1 and resolution on Day 7, and another event of 
the same LLT onset on Day 6 and resolution on Day 9, then the event assumed to have 
onset on Day 1 and achieving resolution on Day 9. The time to resolution will be 
calculated to equal 9 days for analysis. In case the AE resulted in death, the time is 
censored at the date of death. If the outcome of the AE is not death, the time is 
censored at the date of death, lost to follow-up or date of last dose of study treatment 
+ 90 days or date of cut-off for analysis, whichever is earliest.  
Immune-Related Adverse Event (irAE) Assessed by Investigator: immune-related 
adverse events (as recorded on “Adverse Event” eCRF page, is this an immune-
related adverse event= “Yes”). The systemic Corticosteroids ,  immunosuppressive 
treatment other than Corti costeroids, and hormone replacement therapy used for 
irAEs will be identified as for selected AEs for SHR-1210. 
Duration of systemically administered Corticosteroids: 


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For subjects treated with high dose (≥ 40mg/day) of systemically administered 
Corticosteroids, duration (total days) of systemically administered Corticosteroids is 
defined as the time from first dose to last dose without overlaps. For example, if a 
subject treated with high dose of systemically administered Corticosteroids, first dose 
of a systemically administered Corticosteroids on Day 1 and last dose on Day 7, and 
first dose of another systemically administered Corticosteroids on Day 6 and last dose 
on Day 9, then the duration of systemically administered Corticosteroids will be 
calculated as 9 days for analysis. The first dose may be less than 40mg/day. 
Duration of high dose with systemically administered Corticosteroids used in subjects 
is defined in days as the total number of days treated with high dose without overlaps. 
No imputation of missing data for the duration will be conducted. 
3.3.2. 
Laboratory Test 
Clinical laboratory assessments are performed within 7 days prior to first dose (Day -
7), Day 15 Cycle 1, Day 1 and 15 on Cycle 2 and 3, Day 1 on Cycle 4 onward, End-
of-Treatment visit and Safety Follow-Up site visit. Clinical laboratory (e.g., 
hematology, blood biochemistry) values are evaluated as appropriate.  
To evaluate if there are any potential risks of drug-induced liver injury (DILI) in HCC 
patients, a summary and a listing for all cases meeting the potential Hy’s law criteria, 
defined as below: 
- 
ALT or AST ≥ 3 × ULN (normal at baseline), or ALT or AST ≥ 3 × baseline value 
(abnormally elevated at baseline) 
AND 
- 
TBIL ≥ 2 × ULN (normal at baseline), or TBIL ≥ 2 × baseline value (abnormally 
elevated at baseline)  
AND 
- 
ALP < 2 × ULN (normal at baseline) or ALP < 2 × baseline (abnormally elevated 
at baseline) 
Concurrent measurements are those occurring within 7 days after ALT/AST abnormal 
elevation. 
3.3.3. 
Vital Signs 
Vital signs are collected on Day -14, Day 1 of each treatment cycle, Day 15 of each 
treatment cycle (for subjects in the Sorafenib group, vital signs are not collected on 
Day 15 of each treatment cycle from Cycle 4 onwards), End-of-Treatment visit and 
Safety Follow-Up site visit for height (cm), temperature (Celsius), systolic blood 
pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (bpm) and respiratory 
rate (resp/min). 


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Table 6. Criteria for Clinically Significant Abnormal Vital Signs 
Vital Sign 
Criteria for Abnormal Low 
Criteria for Abnormal High 
Parameters 
Value 
Change from 
Baseline 
Value 
Change from 
Baseline 
Body Temperature 
≤ 35 ˚C 
≤ -1.1 ˚C 
≥ 38.3 ˚C 
≥ 1.1 ˚C 
Pulse Rate 
< 40 bpm 
-- 
> 120 bpm 
-- 
Respiratory Rate 
< 12 resp/min 
-- 
> 24 resp/min 
-- 
Systolic Blood 
Pressure 
< 90 mmHg, 
  
≤ -30 mmHg 
≥ 160mmHG 
≥ 30 mmHg 
Diastolic Blood 
Pressure 
< 50 mmHg, 
 
≤ -20 mmHg 
≥ 100mmHg 
≥ 20 mmHg 
 
3.3.4. 
12-lead ECG 
ECG measurements are collected on Day -14, at 2.5 hours (±1 hour) after rivoceranib 
administration on Day 1 and Day 15 of Cycle 1 and Day 1 of subsequent treatment 
cycles, End-of-Treatment visit and Safety Follow-Up site visit for heart rate (bpm), 
PR interval (msec), QT interval (msec) and QTcF interval. 
ECG accompanied blood sampling: blood are collected within 15 minutes after the 
ECG examination on the first day from C1 to C4. 
Table 7. Criteria for Markedly Abnormal 12-lead ECG 
Parameters 
Measurement 
Criteria for Markedly Abnormal Value 
PR 
Absolute value 
Max ≥ 300 msec 
Change from 
Baseline 
Baseline >200 msec and change from Baseline ≥ 25%, or  
Baseline ≤ 200 msec and change from Baseline ≥ 50% 
QTcF 
Absolute value 
450 ≤ max.<480 msec 
480 ≤ max.<500 msec 
max. ≥ 500 msec 
Change from 
Baseline 
30 ≤ max. <60 msec 
max. ≥ 60 msec 
3.3.5. 
Physical Examination 
Physical examination are performed within 14 days prior to first dose during the 
treatment period (experimental arm: prior to administration on Day 1 and 15 of each 
cycle of therapy; control arm: prior to administration on Day 1 and 15 of each cycle in 
Cycle 1-3, prior to administration only on Day 1 from Cycle 4), at end-of-treatment 
visit and safety follow-up.  


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Physical examination includes height (first collection only), weight, head and face, 
skin system, lymph nodes, eye, otolaryngology, mouth, respiratory system, 
cardiovascular system, abdomen, genitourinary system, musculoskeletal, neurological 
and mental status. If necessary, OCT (Optical Coherence Tomography) examinations 
are performed. 
3.3.6. 
ECOG-PS score 
ECOG-PS score are performed within 14 days prior to the first dose during the 
screening period, prior to administration on Day 1 of the subsequent cycles of therapy, 
at end-of-treatment visit and safety follow-up. 
3.3.7. 
Child-Pugh 
Child-Pugh class are performed within 7 days prior to the first dose during the 
screening period, on Day 1 of each cycle in Cycles ≥ 2 during the treatment period, 
at end-of-treatment visit and safety follow-up. 
3.3.8. 
Echocardiography 
Echocardiography must include LVEF and can be scheduled at the investigator’s 
discretion during the study. 
3.3.9. 
Treatment Exposure 
Exposure for SHR-1210 will be summarized by cycle and overall. The start date and 
end date of actual cycle for calculating cycle duration are defined as following. 
Start date for cycle X 
- 
the earliest start date of dosing in the Cycle X, if the subject received study 
treatment in that cycle  
- 
the first day of assessments in the Cycle X, if the subject did not receive 
study treatment in that cycle. Use start date in the exposure page if available; 
if start date is not available then use date of collection of vital signs in Cycle 
X day 1 visit. 
End date for cycle X: 
- 
all cycles X except for the last cycle: 
    end date of actual cycle = start date of actual cycle (X+1)–1 day; 
- 
the last cycle: 
end date of actual cycle = start date of actual cycle + 28–1 day 
The exposure data for Rivoceranib/Sorafenib are not collected by cycle. Overall 
exposure for Rivoceranib/Sorafenib will be summarized. 


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Table 8. Derivation of Exposure 
 
SHR-1210 
Rivoceranib 
 
Sorafenib 
Drug administered 
200 mg, via intravenous 
infusion, once every two 
weeks (Q2W), 28 days 
per cycle 
250 mg, p.o., once 
per day (QD), 28 
days per cycle 
400 mg, p.o., 
twice per day 
(BID), 28 days 
per cycle 
 
Duration of exposure (weeks) 
(last dose date of SHR-
1210–first dose date of 
SHR-1210 + 14)/7 
 
(last dose date–first dose date + 1)/7 
 
Duration of exposure (months) 
(last dose date of SHR-
1210–first dose date of 
SHR-1210 + 
14)/30.4375 
 
(last dose date–first dose date + 
1)/30.4375 
 
Intended duration of treatment 
(weeks) 
(end date of SHR-
1210–first date of SHR-
1210 +1)/7 
where end date = start 
date of last cycle with 
non-zero dose of SHR-
1210 + 28–1 
 
(last dose date–first dose date + 1)/7 
 
Intended duration of treatment 
(months) 
(end date of SHR-
1210–first date of SHR-
1210 +1)/30.4375 
where end date = start 
date of last cycle with 
non-zero dose of SHR-
1210 + 28–1 
 
(last dose date–first dose date + 
1)/30.4375 
 
Cycle duration (weeks) 
(end date of actual cycle 
–start date of actual 
cycle + 1)/7 
- 
By cycle actual DI (mg/4-week 
cycle) 
cumulative dose in a 
cycle (mg)/ [cycle 
duration (weeks)/4] 
- 
Overall actual DI (mg/4-week 
cycle) 
[overall cumulative dose (mg)] / [intended duration of treatment 
(weeks)/4] 
Intended DI (mg/4-week cycle) 
200*2=400 
250*28=7000 
400*2*28=22400 
By cycle RDI (%) 
100*[by cycle actual DI] 
/ Intended DI  
- 
Overall RDI (%) 
100*[overall actual DI] / Intended DI  
DI= Actual Dose Intensity; RDI= Relative Dose Intensity 


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3.4. 
Pharmacokinetic and Immunogenicity 
• 
Serum concentration of SHR-1210 and plasma concentration of rivoceranib. 
• 
The number and proportion of subjects with anti-SHR-1210 antibody (ADA) 
positive or neutralizing antibody (Nab) positive. 
Efficacy endpoints (ORR and PFS assessed by BIRC, OS) and safety endpoint (e.g., 
drug exposure, TEAEs, treatment related AEs, TEAEs with CTCAE grade ≥3, 
treatment related AE with CTCAE grade ≥3, SAE, treatment related SAE, TEAEs 
leading to discontinuation form any study drug, TEAEs leading to discontinuation 
form SHR-1210, AE Leading to Dose Reduction/Interruption of any study drug) will 
be summarized according to the ADA status of SHR-1210 in the experimental arm. 
3.5. 
Exploratory Endpoints 
3.5.1. 
Patient Reported Outcome (PRO) Endpoints 
EORTC QLQ-C30 is a core scale in the quality of life measurement questionnaire (QLQ) 
system for all cancer subjects that is systematically developed by European 
Organization for Research and Treatment of Cancer (EORTC), and used for 
measurement of quality of life (QoL) in all the cancer subjects (for the common part). 
And the specific scale for different cancers is formed, HCC module (EORTC QLQ-
HCC18) is used in this study. 
EORTC QLQ-C30 (version 3.0), EORTC QLQ-HCC18 and EQ-5D-5L questionnaires 
will be completed by subjects prior to administration of study drug and any other study 
evaluation at clinical centers on Day 1 of each cycle, End-of-Treatment visit and Safety 
Follow-Up visit whilst on site visit. For subjects who completed self-evaluation within 
7 days of their End-of-Treatment visit shall not be required to complete them again for 
the visit.  
3.5.1.1. 
EORTC QLQ-C30 
The EORTC QLQ-C30 questionnaire comprised of a global health status scale for 
health status/QoL during the past week on a scale of 1=Very poor to 7=Excellent, five 
functional scales (physical, role, cognitive, emotional, social on a 4-point scale of 
1=Not at all, 2=A little, 3=Quite a bit and 4=Very much), three symptom scales 
(fatigue, pain, nausea and vomiting) and a number of single items assessing symptoms 
commonly reported by cancer subjects (e.g., dyspnoea, insomnia, appetite loss, 
constipation, diarrhea) and perceived financial impact of the disease, all of which on a 
4-point scale. All questions, except for the questions of physical functioning, are 
related to experiences during the past week. The 30 items are grouped by global 
health status / QoL scale, functional scales, symptom scales and six single items. A 
linearly transformed score between 0-100 for each of the scales or item will be 
calculated following the EORTC scoring manual [Fayers et al 1999]. A high scale 
score represents a higher response level. Thus, a high score for the functional scale 
represents a high / healthy level of functioning, a high score for the global health 
status / QoL represents a high QoL, but a high score for the symptom scale / item 
represents a high level of symptomatology / problems. 


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Baseline will be defined as the last non-missing assessment prior to randomization for 
symptoms and summaries. 
The HRQoL/global health status will be assessed using the EORTC-QLQ-C30 global 
QoL scale which includes 2 items from the QLQ-C30: “How would you rate your 
overall health during the past week? (Item 29) and “How would you rate your overall 
QoL during the past week? (Item 30). 
Definition of Clinically Meaningful Changes 
Changes in score compared with baseline will be evaluated. A minimum clinically 
meaningful changes is defined as a change in the score from baseline of ≥10 for the 
EORTC QLQ-C30 (Osoba et al 1998). For example, a clinically meaningful 
deterioration is defined as a decrease in the score from baseline of ≥10.  
In practical terms, if items I1, I2, … In are included in a scale, the procedure is as 
follows: 
Raw Score 
RawScore = RS = (I1+I2+…+In)/n 
Linear Transformation 
Apply the linear transformation to 0-100 to obtain the score S, 
Functional scales：           S = (1-(RS- 1) / range) * 100 
Symptom scales / items:       S = ((RS-1) / range) * 100 
Global health status / QoL:     S = ((RS-1) / range) * 100 
Where RS is the mean of the component items. n is the number of items have been 
answered in a scale, I is the value of a corresponding item. Range is the difference 
between the maximum possible value of RS and minimum possible value. Most items 
take values from 1 to 4, giving range = 3. 
Examples: 
Emotional functioning         RS = (Q21 + Q22 + Q23 +Q24) / 4 
                          EF S = (1-(RS- 1) / 3) * 100 
Fatigue                     RS = (Q10 + Q12 + Q18) / 3 
                          FA S = ((RS-1) / 3) * 100 
Table 9：Scoring the EORTC QLQ-C30 version 3.0 
 
Scale 
Number  
of items 
Item 
range 
Version 3.0 
Item numbers 
Function 
scales 


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Global health status/QoL 
 
 
 
 
 
Global health status/QoL (revised) † 
QL2 
2 
6 
29,30 
 
 
 
 
 
 
 
Functional scales 
 
 
 
 
 
  Physical functioning (revised)† 
PF2 
5 
3 
1-5 
F 
  Role functioning (revised)† 
RF2 
2 
3 
6-7 
F 
  Emotional functioning 
EF 
4 
3 
21-24 
F 
  Cognitive functioning 
CF 
2 
3 
20,25 
F 
  Social functioning 
SF 
2 
3 
26,27 
F 
 
 
 
 
 
 
Symptom scales / items 
 
 
 
 
 
  Fatigue 
FA 
3 
3 
10,12,18 
 
  Nausea and vomiting 
NV 
2 
3 
14,15 
 
  Pain 
PA 
2 
3 
9,19 
 
 
 
 
 
 
 
Single item 
 
 
 
 
 
  Dyspnoea 
DY 
1 
3 
8 
 
  Insomnia 
SL 
1 
3 
11 
 
  Appetite loss 
AP 
1 
3 
13 
 
  Constipation 
CO 
1 
3 
16 
 
  Diarrhoea 
DI 
1 
3 
17 
 
  Financial difficulties 
FI 
1 
3 
28 
  
For subjects who failed to answer a few questions, and if at least half of the items from 
the scale have been answered, then use all the items that were completed and apply the 
standard approach for calculating the scale scores (ignore any items with missing values 
when making the calculations). Otherwise, set the scale score to missing. For the single-
item measures, set score to missing. 
Time to Deterioration (TTD)  
For HRQoL/function, TTD will be defined as the time from the date of randomization 
to the date of first deterioration, as determined by following subscales of European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) (i.e., a decreased in the function scales or the global 
health status/HR QoL by ≥  10 from baseline maintained for two consecutive time 
points, or one time-point followed by death [from any cause] within 4 weeks), 
regardless of whether the subject withdraws from study treatment or receives another 
anti-cancer therapy prior to HR QoL/function deterioration, will be calculated for the 
following three scales: 
• 
HRQoL/Global health status; 


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• 
Physical Functioning; 
• 
Role Functioning; 
For the selected symptoms scales/items (more HCC-related), TTD will be defined as 
the time from the date of randomization to the date of first deterioration (i.e., an 
increase in the score by ≥ 10 from baseline maintained for two consecutive time 
points, or one time-point followed by death [from any cause] within 4 weeks), 
regardless of whether the subject withdraws from study treatment or receives another 
anti-cancer therapy prior to deterioration, will be calculated for the following scales. 
• 
Selected symptom scales / items (Fatigue, Nausea and vomiting, Pain, Appetite 
loss, Diarrhoea) 
A change of 10 to 20 points in score represents a “very much” change. 
Subjects whose HRQoL/function/symptom (as measured by EORTC-QLQ-C30) have 
not shown a confirmed deterioration and who are alive at the time of the analysis will 
be censored at the time of the last PRO assessment where the 
HRQoL/function/symptom documenting no deterioration. Also, if 
HRQoL/function/symptom deteriorates after 2 or more missed PRO assessment visits, 
the subject will be censored at the time of the last PRO assessment where the 
HRQoL/function/symptom documenting no deterioration (prior to the two missed 
assessment visits). Given the scheduled visit assessment scheme (on day 1 of each 
cycle, 28 days per cycle),two missing visits will equate to 8 weeks + 3 days. If 
subjects have no evaluable visits or do not have baseline data, they will be censored at 
day 1. 
3.5.1.2. 
EORTC QLQ-HCC18 
The EORTC QLQ-HCC18 questionnaire comprised of 18 items (Q31-Q48) assessing 
symptoms or problems during the past week on a 4-points scale of 1=Not at all, 2=A 
little, 3=Quite a bit and 4=Very much. Q48 is based on experiences during the past 
four weeks. The 18 items are grouped by six domains (fatigue, body image, jaundice, 
nutrition, pain and fever) and single items for abdominal swelling and sex life (Table 
10). A linearly transformed score between 0-100 for each of the scales or item will be 
calculated. A high scale score represents a higher response level. 
The calculation of scores for each scales and definition of Time to deterioration 
(TTD) is the same as EORTC QLQ-C30. 
Table 10 Scoring the QLQ-HCC18 
 
Scale 
Number of 
items 
Item range 
QLQ-HCC 18 
Item numbers 
Symptom scales 
 
 
 
 
Fatigue 
FATI 
3 
3 
45-47 
Body image 
BI 
2 
3 
33, 35 
Jaundice 
JAUN 
2 
3 
36, 37 


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Nutrition 
NUTR 
5 
3 
31, 32, 42-44 
Pain 
PAIN 
2 
3 
38, 39 
Fever 
FEV 
2 
3 
40, 41 
 
 
 
 
 
Single items 
 
 
 
 
Abdominal swelling 
AB 
1 
3 
34 
Sex life 
SX 
1 
3 
48 
3.5.1.3. 
EQ-5D-5L 
The EQ-5D-5L comprises two components: the utility index (UI) and the EQ-VAS. The 
UI is calculated from patient scoring of five dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). For each dimension, subjects are 
asked to mark between 1: ‘no problems’ to 5: “unable to/extreme problems”. The 
responses are combined to produce a five-digit number describing the participant's 
health status (ranging from 11111 for best possible health to 55555 for worst possible 
health). This is converted to a UI score based on an EQ-5D-5L value set elicited from 
general population samples (the base case will be the Chinese valuation set). A subject 
with health state 12345 indicates no problems with mobility, slight problems with self-
care, moderate problems with doing usual activities, severe pain or discomfort and 
extreme anxiety or depression. For the dimensions without assessment, no UI score will 
be calculated. 
For the EQ-VAS, subjects are asked to record their self-rated health on a vertical Visual 
Analogue Scale (VAS) with the end points ‘The worst health you can imagine’ and ‘The 
best health you can imagine’ at the bottom (‘0’) and top of the scale (‘100’), respectively. 
Hence, an improvement in HRQoL is associated with an increase in UI and EQ-VAS. 
3.5.2. 
imRECIST Endpoints Evaluated by Investigator 
The imRECIST criteria will be used in this study for exploratory assessments of 
antitumor activity.  
Immune-modified PD (imPD) needs to be confirmed by a second, consecutive 
assessment at least 4 weeks apart. imPD is also considered to be confirmed if the 
subject 
 
dies after the initial observation of imPD, or 
 
imPD followed by no additional assessments 
Immune-modified Best Overall Response (imBOR) will be derived based on reported 
lesion responses at different evaluation time points from the date of randomization 
until immune-modified disease progression per imRECIST, according to the 
following rules. Best response may occur after any number of PD assessments. Only 
tumor assessment performed on or before the start of any further anti-cancer therapies 
will be considered in the assessment of imBOR. 


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 
imCR: at least two determinations of imCR at least 4 weeks apart and before 
imPD defined as following. It is reasonable to consider a subject with time 
point responses of imCR-imNE-imCR, imCR-imNE-imNE-imCR as a 
confirmed complete response. 
 
imPR: at least two determinations of imPR or better at least 4 weeks apart 
and before imPD defined as following (and not qualifying for a imCR). It is 
reasonable to consider a subject with one imNE or two imNEs, or one imSD 
occurred between the two response as a confirmed partial response.  
 
imSD: at least one imSD assessment or better ≥ 8 weeks ±1 week after the 
date of randomization and before imPD defined as following (and not 
qualifying for imCR or imPR) 
 
imPD: at least two consecutive assessments by investigator. Confirmations of 
imPD at least 4 weeks apart. If the time point response at the subsequent scan 
of any imPD is imRECIST SD/PR/CR, an imRECIST PD is not considered 
an imPD. 
 
imNE: all other cases 
Immune-Modified ORR (imORR) Evaluated by Investigator is defined as the 
percentage of subjects with imCR and imPR evaluated by investigator based on 
imRECIST. 
Immune-Modified DCR (imDCR) Evaluated by Investigator is defined as the 
percentage of subjects with imCR, imPR or imSD ≥ 8 weeks ±1 week evaluated by 
investigator based on imRECIST.  
Immune-Modified PFS (imPFS) Evaluated by Investigator is defined as the time 
from the date of randomization to the first occurrence of imPD or death, whichever 
comes first, evaluated by investigator. Radiological progression based on imRECIST 
not considered a PFS event if new assessment evaluated as a response or stable 
disease after ≥ 4 weeks; imTTP (months) = [date of event or censoring–date of 
randomization+1]/30.4375. 
Immune-Modified TTP (imTTP) Evaluated by Investigator is defined as the time 
from the date of randomization to radiological progression of disease evaluated by 
investigator based on imRECIST. Radiological progression based on imRECIST not 
considered a TTP event if new assessment evaluated as a response or stable after ≥ 4 
weeks; imTTP (months) = [date of event or censoring–date of 
randomization+1]/30.4375. 
Immune-Modified DoR (imDoR) Evaluated by Investigator is defined as time 
from the date of first record of objective response (CR or PR) to the first occurrence 
of radiological progression or death, whichever comes first, evaluated by investigator 
based on imRECIST. Radiological progression based on imRECIST not considered a 
PD event of DoR, if new assessment evaluated as a response or stable after ≥ 4 
weeks; imDoR (months) = [date of event or censoring– first date of 
mCR/imPR+1]/30.4375. 


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Immune-Modified TTR (imTTR) Evaluated by Investigator is defined as time 
from the date of randomization to the date of first record of objective response (imCR 
or imPR) evaluated by investigator based on imRECIST. imTTR (months) = [first 
date of imCR/imPR–date of randomization +1]/30.4375. 
Table 11.  Censoring Rules for imPFS Analyses 
Scenario 
Date of censoring 
No baseline or no adequate post-baseline 
assessment 
Censored at date of randomization 
(imPD not confirmed or no imPD), no 
death and no new anti-cancer treatment 
initiated 
Censored at last adequate tumor assessment 
documenting no imPD 
(imPD not confirmed or no imPD), no 
death and new anti-cancer treatment 
initiated 
Censored at last adequate tumor assessment 
documenting no imPD before new anti-cancer 
treatment is given 
imPD (subsequently confirmed) or death 
after 2 or more missing or inadequate post-
baseline tumor assessments 
Censored at last adequate tumor assessment 
documenting no imPD prior to the ≥ 2 missed or 
inadequate post-baseline tumor assessment 
Table 12.  Censoring Rules for imTTP Analyses 
Scenario 
Date of censoring 
No baseline or no adequate post-baseline 
assessment 
Censored at date of randomization 
(imPD not confirmed or no imPD), and no 
new anti-cancer treatment initiated 
Censored at last adequate tumor assessment 
documenting no imPD 
(imPD not confirmed or no imPD), and 
new anti-cancer treatment initiated 
Censored at last adequate tumor assessment 
documenting no imPD before new anti-cancer 
treatment is given 
(imPD not confirmed or no imPD) but 
death before 2 missing or inadequate post-
baseline tumor assessments and with no 
new anti-cancer treatment 
Censored at last adequate tumor assessment 
documenting no imPD 
imPD not confirmed or no imPD /death 
after 2 or more missing or inadequate post-
baseline tumor assessments 
Censored at last adequate tumor assessment prior to 
the ≥ 2 missed or inadequate post-baseline tumor 
assessment 
3.5.3. 
Biomarker Endpoints  
• 
The correlation of the expression level by combined positive score (CPS, ≥1 
versus ＜1; CPS≥5 versus ＜5) and tumor proportion score (TPS, ≥1% 
versus ＜1%; TPS ≥5% versus ＜5%) in tumor tissue with the efficacy of 
SHR-1210 combined with rivoceranib mesylate (ORR, PFS, OS). 


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4. STATISTICAL ANALYSIS METHODS 
4.1. 
General Methods 
All statistical analyses will be conducted using SAS Version 9.4 or later on the 
Microsoft® Windows Operating System. 
All tabulations of analysis results will include summaries for the following two 
treatment groups: SHR-1210 IV 200 mg Q2W + Rivoceranib vs. Sorafenib, which 
corresponds to the randomized treatment group as following: 
• 
Experimental group= SHR-1210 plus Rivoceranib;  
• 
Control group=Sorafenib.  
The below mentioned general principles will be followed throughout the study: 
• 
Summary statistics for continuous variables will include the N, mean, standard 
deviation (SD), median, range (minimum-maximum), and 25th and 75th quartiles 
(Q1 and Q3).  
• 
Categorical variables will be presented as frequency counts (N) and percentages 
(%) to one decimal place.  
• 
Time-to-event variables will be summarized by Kaplan-Meier (K–M) median and 
95% CI base on the Brookmeyer-Crowley method with log-log transformation; 
standard error will be calculated using the Greenwood formula.  
• 
Means and medians will be presented to 1 more decimal place than the recorded 
data. Standard deviations and standard errors will be presented to 2 more decimal 
places than the recorded data.  
• 
Minimum and maximum values will be presented using the same number of 
decimal places as the recorded data. 
• 
Point estimate that may not be reached will be presented as NR=Not Reached. 
Data summaries will be accompanied by individual subject data listings sorted by 
country/territory, study center and subject identifier. Data available from the electronic 
case report forms (eCRFs) will be listed. The actual day relative to start of treatment 
will be determined and included in listings, where appropriate. In general, study days 
prior to and relative to a defined time origin will be calculated as date of the time origin 
– date of onset and date of onset – date of the time origin + 1, respectively, or indicated 
otherwise. Time in months and weeks will be calculated as study days/30.4375 and 
study days/7, respectively. Change from Baseline is defined as post-baseline minus 
Baseline and Percent Change from Baseline is defined as 100*Change from 
Baseline/Baseline. Data in International System of Units (SI) will be provided for 
reporting analysis data.  


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4.2. 
Definition of Study Window and Baseline 
Baseline is defined as the last non-missing value prior dosing on Day 1, Cycle 1. This 
includes multiple pre-dose assessments for ECOG-PS score, physical examination, 
vital signs, 12-lead ECG and laboratory. For repeated measurements of the same day, 
mean value will be used as baseline for continuous variables and “least” severity grade 
will be used as baseline for categorical variables. 
Quality of life (QoL) questionnaires data collected on Day 1 for every treatment cycle, 
end-of-treatment visit and Safety Follow-Up site visit (SFU) will be mapped to analysis 
visit according to visit window for Baseline, Week 5 and every 4 weeks thereafter (e.g., 
Week 9, 13, etc.) as follows: 
Table 13 Visit Window for Quality of Life Data  
Visit Window 
Target Day (Visit window from date of first dose) 
Baseline 
Study Day<=1 (Last non-missing value prior dosing on Day 1, Cycle 1) 
Week 5 
Study Day=29 (15 to 42) 
Week 9 
Study Day=57 (43 to 70) 
Week 13 
Study Day=85(71 to 98) 
Week 17 
Study Day=113 (99 to 126) 
Week 21 
Study Day=141 (127 to 154) 
Week 25 
Study Day=169 (155 to 182) 
Week 29 
Study Day=197 (183 to 210) 
Week 33 
Study Day=225 (211 to 238) 
Week 37 
Study Day=253 (239 to 266) 
Week 41 
Study Day=281 (267 to 294) 
Week 45 
Study Day=309 (295 to 322) 
Week 49 
Study Day=337 (323 to 350) 
Week 53 
Study Day=365 (351 to 378) 
Etc. 
Etc. 
For windows containing multiple assessments, assessment closest to Target Day will 
be used. For multiple assessments occurred on the same date, the last assessment will 
be identified and used. The time origin for the study day is the date of first dose taken. 
4.3. 
Handling of Missing Data 
Except for the special cases, the following imputation rules will be applied for 
missing/partial date of events: 
4.3.1. 
Cancer Diagnosis 
Initial diagnosis date will be imputed as follows: 
• 
If year is missing or date is completely missing, no imputation will be performed. 


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• 
If only day is missing, it will be imputed to the 1st day of the month. 
• 
If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as January 1st. 
• 
If both day and month are missing and the year is the same as the year of informed 
consent, the month and day will be imputed as January 1st. 
4.3.2. 
Adverse Events 
• 
If start date of an event is completely missing, it will be imputed by the start date 
of study treatment. 
• 
If only the day of the AE start date is missing, but the year and month are the same 
as the year and month of the study drug treatment, then the AE start date will be 
replaced by the start of the study drug treatment.  
• 
If both day and month of the AE start date are missing but the start year is equal to 
the start of study treatment, then the start date will be replaced by the start date of 
study treatment.  
• 
Otherwise, the missing onset day or missing onset month will be replaced by 1. 
• 
If the day of end date is missing, then the AE end date will be replaced by the last 
day of the month. If both day and month of the AE end date are missing then it will 
be replaced by December 31 of the year. However, any resultant date after subject’ 
death, the date of death will be used to impute the end date. Otherwise, the end date 
will not be imputed.  
4.3.3. 
Concomitant Medications 
• 
If the start date is missing completely, then the start date will be replaced by the 
start of study treatment. 
• 
If the day of start date is missing, but the month and year are equal to the start of 
study treatment, then the date will be replaced by the start of study treatment. 
• 
If the day and month of the start date are missing but the start year is equal to the 
start of study treatment, then the medication date will be replaced by the start of 
study treatment. Otherwise, the missing day or month will be replaced by 1. 
• 
If the day of end date is missing, then the end date will be replaced by the last day 
of the month. If both day and month of the AE end date are missing then it will be 
replaced by December 31 of the year. if resulting in a date later than the date of 
subject’ death, the date of death will be used to impute the end date. Otherwise, 
the end date will not be imputed. 
4.3.4. 
Study Treatment Date 
If the first date of dose is completely or partially missing, no imputation will be 
performed. If the last date of study treatment is completely or partially missing, the 


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imputations will be performed as follows (the last date of study treatment will be used 
to impute for the start date of new anti-cancer therapy): 
• 
If the last date of study treatment is completely missing and there is no end date 
of treatment on end of treatment (EOT) eCRF page and no death date, the subject 
should be considered to be ongoing and use the cut-off date for the analysis as the 
last date of study treatment. For active group, end of treatment is all study drugs 
discontinued. 
• 
If the last date of study treatment is completely or partially missing, and an End 
date of Treatment on eCRF page or a death date is available before the cut-off 
date of analysis, then last date of study treatment is imputed as following: 
- 
IF only Year is available and Year < Year of min (EOT date, death date), 
THEN imputed date= 31DECYYYY; 
- 
IF both Year and Month are available and Year = Year of min (EOT date, 
death date) and Month < the month of min (EOT date, death date), THEN 
imputed date= Last day of the month; 
4.3.5. 
Start Date of New Anti-Cancer Therapy 
Start date of new anti-cancer therapy (drug therapy (except traditional Chinese 
medicine), local regional therapy, surgery, radiotherapy) is used for censoring in 
efficacy analyses. The start date of new anti-cancer therapy is the earliest start date of 
anti-cancer therapy recorded in the “Follow-up” eCRF pages (including concomitant 
anti-cancer therapy etc.,) for drug therapy (except traditional Chinese medicine), local 
regional therapy, surgery, radiotherapy after randomization.  
The PD date, last date of study treatment and end date of new anti-cancer therapy will 
be used to impute the start date of new anti-cancer therapy if it is missing. And the 
definitions for the dates as following: 
• 
PD date is PD date by investigator assessment.  
• 
Last date of study treatment (see section 4.3.4). 
• 
End date of new anti-cancer therapy is derived as follows: 
- 
If end date is completely missing, then ignore it 
- 
If only year is present for end date, then set to 31DECYYYY 
- 
If month and year are present for end date, then set to the last day of the 
month for MMMYYYY  
The imputed start date of new anti-cancer therapy is derived as follows: 
- 
If Start date of new anti-cancer therapy is completely missing 


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start date = min [max (PD date + 1, last date of study treatment + 1), end date 
of new anti-cancer therapy] 
- 
If Only year for start of anti-cancer therapy is present 
• 
IF year < year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], THEN start date = 
31DECYYYY; 
• 
IF year = year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], THEN start date = min [max 
(PD date + 1, last date of study treatment + 1), end date of new anti-
cancer therapy] 
• 
IF year > year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], THEN start date = 
01JANYYYY 
- 
If year and month for start of anti-cancer therapy are present 
• 
IF year < year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy],  
Or 
IF year = year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], and month < Month of min 
[max (PD date + 1 day, last dose of study treatment + 1 day), end date of 
new anti-cancer therapy] 
THEN start date = Last day of month for MMM YYYY; 
• 
IF year = year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], and month = month of min 
[max (PD date + 1 day, last dose of study treatment + 1 day), end date of 
new anti-cancer therapy], THEN start date = min [max (PD date + 1 day, 
last date of study treatment + 1 day), end date of new anti-cancer 
therapy]); 
• 
IF year = year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy], and month > month of min 
[max (PD date + 1 day, last date of study treatment + 1 day), end date of 
new anti-cancer therapy] 
Or 
IF year > year of min [max (PD date + 1, last date of study treatment + 
1), end date of new anti-cancer therapy],  
THEN start date = 01 MMM YYYY. 


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4.3.6. 
Death Date 
Last survival date will be used to impute the partial or complete missing death date: 
• 
If year is missing or date is completely missing: death date= the date of last 
survival +1 day 
• 
If only day is missing: death date= max (the first of month and year of death, date 
of last survival + 1) 
• 
If day and month are missing: 
- 
If year = year of the date of last survival, death date= the date of last survival 
+1 day 
- 
If year > the date of last survival, death date= 01JANYYYY 
4.3.7. 
Pharmacokinetics 
For PK concentration summaries and graphical displays, values below the quantitation 
limit (BQL) will be set to zero. If all concentrations at a given time point are BQL 
values, the mean will be presented as zero and both SD and CV% will be reported as 
NA (Not Applicable). BQL values will be presented as “BQL” in data listings. 
If all concentrations at a given time point are missing, then summary statistics will be 
presented as NA.  
If blood sample was collected at a nominal time and dose interruption of SHR-1210 
occurred at the last administration before the nominal time, the concentration at the 
nominal time point will be excluded from the descriptive statistics summary and mean 
concentration-time plotting.  
4.4. 
Analysis Populations 
4.4.1. 
Intent-to-Treat Set (ITT): 
This population will include all randomized subjects. Subjects will be included in the 
treatment group to which they are randomized. 
4.4.2. 
Per-protocol Set (PPS) 
This population is a subset of the ITT population consists of subjects who take at least 
one dose of study drug and have no important protocol deviations during the study that 
do have a significant impact on study results (see Section 4.5 for further detail).  
4.4.3. 
Safety Analysis Set (SS) 
This population will include all treated subjects who receive at least one dose of study 
treatment. Safety data will be analyzed based on the first treatment they actually 
received.  


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4.4.4. 
Anti-drug Antibody Analysis Set (ADAS) 
This population will include all subjects who receive SHR-1210 and had baseline ADA 
measurement and at least one post-baseline ADA measurement. 
4.4.5. 
PK Analysis Set (PKS) 
This population will include all subjects who receive SHR-1210 combined with 
rivoceranib and have at least one measurable drug concentration at any time during the 
study.  
4.4.6. 
PK/QTc Analysis Set (PKQTS) 
This population will include all subjects who have at least 1 pair of post-dose PK 
concentration of rivoceranib and post-dose ΔQTcF data. The PK/QTc Set will be used 
for the concentration-QTc analysis.  
4.4.7. 
Patient Reported Outcomes (PRO) Analysis Set  
Patient reported outcomes analysis set will include subjects who have both a baseline 
PRO assessment and at least one post-baseline PRO assessment, with subjects grouped 
according to the treatment assigned at randomization. 
The analysis sets will be descriptively summarized for each treatment group and total. 
Listing of subjects included/excluded from each of the analysis sets will be provided.   
4.5. 
Protocol Deviations 
All protocol deviations will be identified during study monitoring and important 
protocol deviations related to the study inclusion/exclusion criteria, study conduct, 
subject management or subject assessment will be identified, reviewed and categorized 
prior to database lock for analysis. Important protocol deviations are a subset of 
protocol deviations that may significantly impact the completeness, accuracy, and/or 
reliability of key study data (e.g., the primary study endpoints) or that may significantly 
affect a subject's rights, safety, or well-being. For example, important protocol 
deviations may include enrolling subjects in violation of key eligibility criteria or 
failing to collect data necessary to interpret primary endpoints, as this may compromise 
the scientific value of the trial. The following general protocol deviations will be used 
for study team reviews: 
 
Eligibility 
and Entry 
criteria deviation (e.g., 
subject 
deviated from 
inclusion/exclusion criteria); 
 
Prohibited medication deviation (e.g., subject received other investigational 
products for anti-cancer therapy during the treatment period of this study); 
 
Subjects received incorrect study treatment or dose; 
 
Other categorizations may also be identified during study reviews.  
The following outputs will be provided: 
 
Summary of important protocol deviations by category; 
 
Summary of important deviations, which result in exclusion of subjects from the 
Per Protocol set (PPS) by category. 


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 
Listing of protocol deviations with important deviations identified for exclusion 
of Per Protocol set (PPS) during study reviews; 
 
Summary of important protocol deviations related to COVID-19 epidemic 
measures by category; 
 
Summary of protocol deviations related to COVID-19 epidemic measures by 
category; 
 
Listing of protocol deviations related to COVID-19 epidemic measures with 
important deviations identified; 
 
Listing of important protocol deviations; 
4.6. 
Subject Disposition 
The number of subjects screened, randomized, treated and discontinued will be counted. 
The study drug and/or study discontinuation will be summarized according to the 
categories in the eCRF.  
The end of study status (Physician Decision, Withdrawal by Subject, Lost to Follow-
up, Death, Study Terminated by Sponsor and Other) will be summarized by treatment 
group and total.  
The date of end of study is defined as the death date for subjects who died and the last 
contact date for subjects who were lost to follow-up. 
The primary reasons for study drug discontinuation including AE (subgroup of AE 
(non-COVID-19), AE (COVID-19)), COVID-19 (non-AE), Disease Progression, 
Withdrawal by Subject, Physician Decision, Protocol Deviation, Study Terminated by 
Sponsor, Lost to Follow-Up, Death, Pregnancy, and Other will be summarized for each 
drug component by treatment group. 
Duration of subject follow-up time (months) for each treatment group and total will be 
summarized using descriptive statistics, including 25th and 75th quartiles (Q1 and Q3). 
The results of the randomization according to IRT will be summarized as below: 
 
Number and percentage of randomized subjects by Country and center 
 
Number and percentage of randomized subjects by randomized strata from IRT and 
eCRF, separately 
A subject listing of stratum by IRT and stratum by eCRF will be provided. 
A subject listing for all enrolled subjects will be provided showing the subject’s consent 
data, reason for not being randomized, and reason for not being treated. 
A subject listing for all treated subjects will be provided showing the subject’s 
randomization date, first and last dosing date, date investigator decided to stop the 
treatment and reason for discontinuation. 


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4.7. 
Demographics and Baseline Characteristics 
Demographic and other baseline characteristics captured during screening period will 
be summarized using descriptive statistics. Continuous variables include age, vital signs 
including weight, height, and BMI, etc. History of HCC diagnosis and characteristics 
will be summarized using descriptive statistics for time since initial cancer diagnosis 
(days), time since advanced/metastatic disease diagnosis (days). Categorical variables 
include, gender, ethnicity, ECOG-PS score, country, geographical region (Asia vs. non-
Asia countries), race, race group (Asian vs. non-Asian [White vs. African American vs. 
others] as listed in the eCRF), hepatitis virus, age group (< 65 vs. ≥65 years), weight 
group (<60 vs. ≥60 kg), status of alcohol consumption (absence vs. presence), BMI 
group (<30 vs. ≥30 kg/m2), BCLC stage at Screening, macrovascular invasion status 
(yes vs. no), extrahepatic metastasis status (yes vs. no), macrovascular invasion and/or 
extrahepatic metastasis (yes vs. no) status, root cause of HCC (HBV, HCV and Non-
viral, Non-viral included Alcohol Cirrhosis, Genetic, Metabolic Disorders (such as 
NASH / AFLD) and others), Child-Pugh classification, AFP group (<400 ng/mL vs. ≥
400 ng/mL) as listed in the eCRF. Country and region will be derived from location of 
subject via Subject ID for analysis. PD-L1 category will include PD-L1 categories (TPS 
<1% vs. TPS >=1%, TPS<5% vs. TPS >=5%, and CPS <1 vs. CPS >=1, CPS <5 vs. 
CPS >=5). Height and weight values will be presented in metric units (cm and kg, 
respectively), and BMI is calculated as [weight (kg) / (height (m))2] using the weight 
and height collected during the vital signs at Screening period of the study.  
 
Tabulations by study center, country or subgroup may be repeated, as indicated, 
including additional tables maybe produced to support local registrations such as China, 
USA and Europe. Countries/regions in Asia included in the study are Mainland China, 
Hong Kong, Taiwan and South Korea.  
 
4.8. 
Medical History 
Medical history will be coded using the MedDRA (v 24.0 or higher) for lower level 
term (LLT), preferred term (PT) and primary system organ class (SOC). The medical 
history will be summarized by SOC and PT, and listed. 
4.9. 
Prior and Subsequent Anti-Cancer Therapy 
Prior anti-cancer therapy will be provided in a data listing with data retrieved from 
‘Prior Anti-Cancer Drug Therapy’, ‘Prior Local Regional Therapy’, ‘Prior Anti-Cancer 
Related Radiotherapy’ and ‘Prior Cancer-Related Surgery/Procedure’ eCRF pages. 
Subsequent anti-cancer therapy will be provided in a data listing with data retrieved 
from ‘Follow-up Anti-Cancer Drug Therapy’, ‘Follow-up Local Regional Therapy’, 
‘ Follow-up Anti-Cancer Related Radiotherapy ’  and ‘ Follow-up Cancer-Related 
Surgery/Procedure’ eCRF pages after the last dose date. 
Subjects who received prior anti-cancer drug therapy, prior local regional therapy, prior 
cancer-related surgery/procedure, prior anti-cancer related radiotherapy will be 
summarized using descriptive statistics (n and %) and listed. Similar analysis will also 
be performed for subsequent anti-cancer treatment.  


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4.10. Prior and Concomitant Therapy 
Prior and concomitant therapies collected from Screening to end of safety follow-up 
will be coded using the WHO Drug Dictionary. Prior and concomitant medications will 
be summarized and listed by drug and drug class. Prior medications will be defined as 
medications taken within 28 days of first dose of study drug that were stopped prior to 
study drug administration. Concomitant medications will be defined as medications that 
1) started before the first dose of study drug and continued during the on-treatment 
period, or 2) started during the on-treatment period. Prior and concomitant medications 
will be listed.  
A separate listing for medications related to treatment of COVID-19 infection will also 
be provided.  
4.11. Efficacy Analyses 
The two primary efficacy endpoints for the study are OS and PFS (assessed by BIRC 
base on RECIST v1.1). For the PFS, there is one planned analysis, which is expected 
to occur when approximately 332 PFS events are observed (approximately 19 months 
after first subject enrolled). The OS will be analyzed in the following time points: when 
PFS is analyzed (approximately 19 months after first subject enrolled); when 
approximately 251 OS events (70% are observed at approximately 23 months after first 
subject enrolled) and when 359 OS events are observed (approximately 36 months after 
first subject enrolled), respectively.  
The primary endpoints of PFS assessed by BIRC and OS, key secondary endpoint ORR 
will be analyzed based on ITT and PPS. The primary analysis is based on ITT. The 
sensitivity analysis is based on PPS. Other secondary and exploratory efficacy 
endpoints will be analyzed based on ITT. 
Detail of timing, reasons, number of events and multiplicity adjustment methods for the 
PFS, OS and ORR endpoint analyses can be found in the sections for interim analysis 
and multiplicity. 
Listing of BOR, DoR, PFS assessed by BIRC according to RECIST 1.1 and OS will be 
provided. 
4.11.1. Primary Efficacy Endpoints Analyses 
4.11.1.1. 
Progression-Free Survival by BIRC assessment  
Primary Analysis 
The definition of PFS endpoint by BIRC based on RECIST v1.1 is in section 3.1.2.  
The PFS by BIRC assessment based on ITT will be evaluated by comparing SHR-
1210 plus rivoceranib to sorafenib on PFS events in the intention-to-treat (ITT) 
population using a stratified log-rank test (based on randomization stratification 
factors). The hazard ratio (HR=SHR-1210 plus rivoceranib / sorafenib) and the 
corresponding 95% confidence interval (CI) will be estimated using a stratified Cox 
proportional hazard model with treatment and randomization stratification factors 


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included in the model. The stratification factors are macrovascular invasion and/or 
extrahepatic metastasis (presence vs. absence), geographical region (Asia vs. 
countries outside of Asia) and Baseline AFP (AFP < 400 ng/mL vs. AFP ≥400 
ng/mL). The values of the factors will be obtained from the interactive response 
technology [IRT] system. 
The PFS for each treatment group will be estimated using the Kaplan-Meier (KM) 
product-limit method. The 95% CIs for median PFS and other quartiles will be 
estimated by Brookmeyer-Crowley method for each treatment group. The PFS rates at 
3, 6, 9, 12 months will be estimated by Kaplan-Meier method and their corresponding 
95% CIs will be calculated using the log (-log) transformation (based on normal 
approximation) with back transformation to CIs on the untransformed scale. The 
censoring rule for the primary analysis is described in Table 2 and frequency of subjects 
(n, %) experiencing PFS events and censored by reason will be provided.  
Superiority of SHR-1210 plus rivoceranib over sorafenib in PFS is demonstrated, if 
one-sided p-value obtained from the stratified log-rank test is significant at 0.005 one-
sided in favoring the experimental group. If PFS is non-significant at the 0.005 one-
sided but OS endpoint is significant at the overall 0.020 one-sided, then the PFS can be 
tested again at an updated 0.025 one-sided after alpha re-allocation. No alpha re-
allocation is performed if both PFS and OS endpoints failed to show a significant result 
(see multiplicity section for alpha re-allocation).  
Sensitivity Analyses 
• 
To assess the impact of the randomization stratification factors, the analysis of PFS 
by BIRC assessment will be repeated without the stratification factors included in 
the analysis.  
• 
A sensitivity analyses will be performed using the randomization strata derived 
from the eCRF instead of the randomization strata obtained from the interactive 
response technology (IRT) system. 
• 
A sensitivity analysis will be performed by treating documented PD/death after two 
or more missed disease assessments as an event.  
• 
A sensitivity analysis will be performed by treating documented PD/death 
occurring on or after any new anti-cancer treatment as an event.  
• 
A sensitivity analysis of interval-censored data will be performed in case an 
imbalance between the treatment groups on tumor assessment schedules is 
observed. In this analysis, a Finkelstein’s likelihood-based score test will be used 
to compare the two treatment groups. The interval extends from the date of the last 
disease assessment without documented PD to the date of documented PD or death, 
whichever occurs earlier. Subjects without documented PD or death will be right-
censored according to the censoring rule for the primary PFS analysis. 
• 
The proportional hazards assumption will be checked visually by plotting log (-
log (PFS)) versus log(time) within each randomization stratum. The Schoenfeld 
residuals for the stratified Cox proportional regression model will be plotted to 


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investigate graphically violations of the proportional hazards assumption; a non-
zero slope is evidence of departure from proportional hazards. If it suggests the 
proportional hazard assumption is not met, the PFS by BIRC assessment will be 
analyzed by a Wilcoxon test and the restricted mean survival time (RMST) 
analyses will be performed as follows. 
• 
A sensitivity analysis using a Wilcoxon test will be performed for the PFS by 
BIRC assessment.  
• 
A sensitivity analysis using Restricted Mean Survival time (RMST) method 
will also be performed for the PFS by BIRC assessment. The cut-off point 
(τ) will be used to evaluate the RMST, it should not exceed the minimum of 
the largest observed time for both experiment group and control group. To 
avoid arbitrary selection of cut-off point for both the two groups, two cut-off 
points will be used:  
- 
τ1 = minimum of (largest observed survival time for experimental group, 
largest observed survival time for control group). 
- 
τ2 = minimum of (largest survival event time for experimental group, largest 
survival event time for control group). 
The Impact of COVID-19 
Assessment of the impact of COVID-19 on PFS assessment will be conducted. If 
deemed necessary, the below analyses may be conducted.  
A PFS sensitivity analysis to assess the impacted by COVID-19 pandemic measures 
may be performed. This analysis is the same as the primary analysis except that it 
censors subjects at the time of last tumor assessment prior to the earliest time of study 
treatment discontinuation or interruption (SHR-1210 i. v. ≥ 6 times or rivoceranib ≥ 
28 days, Sorafenib ≥ 28 days in succession) due to COVID-19 (non-AE).  
In addition, a PFS sensitivity analysis to assess the impacted by COVID-19 pandemic 
measures may be performed, by excluding subjects who discontinue or interrupt the 
study drug treatment for certain period of time (SHR-1210 i. v. ≥ 6 times or 
rivoceranib ≥ 28 days, Sorafenib ≥ 28 days in succession) due to COVID-19 (non-
AE). The method of analysis is the same as the primary analysis of PFS. 
4.11.1.2. 
Overall Survival (OS) 
Primary Analysis 
OS will be evaluated by comparing SHR-1210 plus rivoceranib to sorafenib on OS 
events in the ITT population using a stratified Log-rank test (based on randomization 
stratification factors). The hazard ratio (HR=SHR-1210 plus rivoceranib / sorafenib) 
and the corresponding 95% confidence interval (CI) will be estimated using a 
stratified Cox proportional hazard model with treatment and randomization 
stratification factors included in the model. The OS rates for each treatment group will 
be estimated using the Kaplan-Meier (KM) product-limit method. A 95% CI for 
median OS will be estimated by Brookmeyer-Crowley method for each treatment 


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group. The OS rates at 6, 9, 12,18 and 24 months will be estimated by Kaplan-Meier 
method and their corresponding 95% CI will be calculated. The stratification factors 
for randomization are macrovascular invasion and/or extrahepatic metastasis 
(presence vs. absence), geographical region (Asia vs. countries outside of Asia) and 
Baseline AFP (AFP < 400 ng/mL vs. AFP ≥400 ng/mL). The values of the factors 
will be obtained from the interactive response technology [IRT] system.  
Superiority of SHR-1210 plus rivoceranib over sorafenib in OS is demonstrated, if one-
sided p-value obtained from the stratified log-rank test is significant at an overall 
significance level of 0.020 one-sided in favoring the experimental group. If OS is non-
significant at the overall 0.020 one-sided, but PFS endpoint is significant at the 0.005 
one-sided, then OS can be tested again with the efficacy boundaries revised according 
to an updated 0.025 significance level after alpha re-allocation and the actual number 
of events observed. No alpha re-allocation is performed if both PFS and OS endpoints 
failed to show a significant result (see multiplicity section for alpha re-allocation).  
The OS analysis will be performed at the final PFS analysis, at 251 (70%) deaths if 
there are less than 251 deaths at the final PFS analysis at ~23 months, and when ~359 
OS events are observed at ~36 months, if study continued as planned. Detail of 
timing, reasons, number of events and multiplicity adjustment methods for the PFS, 
OS and ORR endpoint analyses can be found in the sections for interim analysis and 
multiplicity.  
Sensitivity Analyses  
 
To assess the impact of the randomization stratification factors, the above primary 
analysis of OS will be repeated without the stratification factors included in the 
analysis.  
 
A sensitivity analyses will be performed using the randomization strata derived 
according to eCRF instead of the randomization strata obtained from the interactive 
response technology (IRT) system. 
 
To account for possible confounding effect due to patients switching to new anti-
cancer treatment (except for traditional Chinese medicine) after the last dose date, 
a sensitivity analysis of OS that censoring subjects at the time of initiation of the 
new anti-cancer therapy after the last dose will be performed.  
 
The assumption of proportionality will be assessed in the same way as for PFS by 
BIRC assessment. If proportional hazard assumption is not met, a sensitivity 
analysis using a Wilcoxon test will be performed for the OS.  
 
If proportional hazard assumption is not met, a sensitivity analysis using Restricted 
Mean Survival time (RMST) method will also be performed for the OS.  
In addition, to further assess the impact of switching to immunotherapy, or targeted 
therapy (Monoclonal Antibodies Therapy, Small Molecules Target Therapy) or other 
treatment after the last dose of study drug on OS results, methods such as Inverse 
Probability of Censoring Weighting (Robins and Finkelstein 2000), and two-stage 
method (Latimer 2017) will be applied as appropriate. The final application of 


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methods will be assessed based on a blinded review of the data and the plausibility of 
the underlying assumptions. 
The Impact of COVID-19 
Assessment of the impact of COVID-19 on OS will be conducted. If deemed 
necessary, the below analyses may be conducted. 
An OS sensitivity analysis to assess the impacted by COVID-19 pandemic measures 
may be performed. This analysis is the same as the primary analysis except that it 
censors subjects at the time of last tumor assessment prior to the earliest time of study 
treatment discontinuation or interruption (SHR-1210 i. v. ≥ 6 times or rivoceranib ≥ 
28 days, Sorafenib ≥ 28 days in succession) due to COVID-19 (non-AE).  
In addition, an OS sensitivity analysis to assess the impacted by COVID-19 pandemic 
measures may be performed by excluding subjects who discontinue or interrupt the 
study drug treatment for certain period of time (SHR-1210 i. v. ≥ 6 times or 
rivoceranib ≥ 28 days, Sorafenib ≥ 28 days in succession) due to COVID-19 (non-
AE). The method of analysis is the same as the primary analysis of OS. 
4.11.2. Secondary and Exploratory Efficacy Endpoints Analyses 
4.11.2.1. 
Progression-Free Survival by Investigator according to RECIST and 
imRECIST, and by BIRC according to mRECIST Assessment 
The method for the below analyses is the same as the primary endpoint PFS assessment 
by BIRC. 
 
The analysis of PFS by investigator assessment according to RECIST 1.1 will be 
performed with the stratification factors included in the analysis. 
 
The analysis of PFS by investigator assessment according to RECIST 1.1 will be 
performed without the stratification factors included in the analysis. 
 
The analysis of PFS by BIRC according to the mRECIST will be performed with 
the stratification factors included in the analysis. 
 
The analysis of PFS by BIRC according to the mRECIST will be performed 
without the stratification factors included in the analysis. 
 
The analysis of PFS by investigator assessment according to the imRECIST will 
be performed with the stratification factors included in the analysis. 
 
The analysis of PFS by investigator assessment according to the imRECIST will 
be performed without the stratification factors included in the analysis. 
4.11.2.2. 
Objective Response Rate (ORR) 
Confirmed BOR and ORR: 


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Frequency (%) of best overall response (BOR) category for each treatment group will 
be provided. The objective response rate (ORR) based on complete response (CR) and 
partial response (PR) as assessed by BIRC according to the RECIST v1.1 will be 
analyzed when 70% OS events are observed. Comparison between treatment groups 
in ORR by BIRC according to RECIST v1.1 will be performed using stratified 
Cochran-Mantel-Haenszel (CMH) test. Difference in proportions (%) for the ORR 
and its 95% CI using normal approximation will be provided. Overall response rates 
and their corresponding 95% exact CIs will be calculated by Clopper-Pearson method 
for each treatment group. Hypothesis testing of ORR will be conducted only if both 
PFS and OS endpoints are significant and when 70% OS events are observed.  
ORR by investigator according to the RECIST v1.1, ORR by BIRC according to 
mRECIST and ORR by investigator according to imRECIST will be evaluated. 
The analyses except for the imRECIST assessment will be repeated in the ITT 
subjects with measurable disease at baseline. 
Unconfirmed BOR and ORR: 
The unconfirmed BOR and ORR by BIRC and Investigator according to RECIST 1.1 
and mRECIST will be summarized as confirmed BOR and ORR.  
The analyses will be repeated in the ITT subjects with measurable disease at baseline. 
Listing of confirmed ORR and unconfirmed ORR will be provided. 
Change in Tumor Size 
The absolute values and percentage change in target lesions (TL) from baseline will 
be summarized using descriptive statistics and presented at each time point by 
treatment group. The best change in TL tumor size will also be presented graphically 
using waterfall plots for each treatment group. 
4.11.2.3. 
Duration of Response (DoR)  
The DoR will be summarized descriptively using Kaplan-Meier (KM) product-limited 
method for median and quartile estimates with 95% CIs estimated using the 
Brookmeyer-Crowley method for each treatment group. DoR rates at 3, 6, 9 and 12 
months obtained from the KM method will also be presented and their respective 95% 
CIs will be calculated. The 95% CIs will be calculated using the log (-log) 
transformation (based on normal approximation) with back transformation to CIs on 
the untransformed scale. 
4.11.2.4. 
 Time-to-Progression (TTP) 
The treatment comparison for TTP will be based on a stratified Log-rank test (based 
on randomization stratification factors). The hazard ratio (HR=SHR-1210 plus 
rivoceranib / sorafenib) and the corresponding 95% confidence interval (CI) will be 
estimated using a stratified Cox proportional hazard model with treatment and 
randomization stratification factors included in the model. The TTP curve for each 
treatment group will be estimated using the Kaplan-Meier (KM) product-limit 


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method. A 95% CI for median TTP will be estimated by the Brookmeyer-Crowley 
method.  
4.11.2.5. 
Disease Control Rate (DCR) 
Disease control rate (DCR in %) will be analyzed using the same methods as ORR.  
4.11.2.6. 
Time to Response (TTR) 
The TTR will be summarized descriptively using n, mean, SD, median, minimum and 
maximum. 
4.12. BIRC versus Investigator Assessment  
The number of discordant assessments between BIRC assessment and investigator 
assessment will be provided. The number of discordant assessments is the number of 
PDs assessed by BIRC but not the investigator, or by investigator not the BIRC, 
timing is not considered. 
4.13. Other Exploratory Endpoints Analyses 
4.13.1. Patient Reported Outcome (PRO) Endpoints Analyses 
For each treatment group and at each time point, the number and percentage of 
patients who complete all questions, complete at least one question and missing 
assessment will be summarized, completion rate (%) over the study for each 
questionnaire will be performed. The completion rate is defined as the proportion of 
total number of questions completed divided by the total number of questions 
attempted. Reasons for not done by analysis visit will also be provided. Reasons for 
missing assessment will be provided in listing.  
The PRO analysis set will be used for descriptive analyses of visit summary and 
change from baseline and proportion analyses. The ITT set will be used for the 
analyses of PRO completion and time-to deterioration. Analyses by visit will be based 
on the Analysis Visit as defined in Section 4.2. Time-to-event analysis will be based 
on all assessments.  
4.13.1.1.1. 
EORTC QLQ-C30 
The linearly transformed score for each of the scales or item will be summarized 
descriptively, including number of missing values and standard error (SE), for 
observed value and change from Baseline by analysis time point (e.g., Baseline, Week 
5, Week 9, etc.) by treatment group. Treatment group comparison in change from 
Baseline will be based on a linear Mixed Model Repeated Measures model (MMRM), 
baseline value as covariate, treatment group, time and treatment-by-time. Subject will 
be included as a random effect. An unstructured (UN) covariance structured for 
repeated measurements over time may be used. If the fit of the unstructured 
covariance structure fails to converge, the Compound Symmetry (CS) covariance 
structures will be used. LSMean and LSMean difference (SHR-1210 plus rivoceranib 
- sorafenib) with corresponding 95% confidence interval (CI) will be estimated and P 


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value will be reported. Plots of LSmean difference (95% CI) for change from Baseline 
over time will be provided. Both raw and linearly transformed scores will be listed.  
For each endpoint of global health status (GHS), physical functioning, role 
functioning and the selected symptom scales / items (Fatigue, Nausea and vomiting, 
Pain, Appetite loss, Diarrhoea), the treatment comparison for Time to Deterioration 
(TTD) will be based on a stratified Log-rank test (based on randomization 
stratification factors). The hazard ratio (HR=SHR-1210 plus rivoceranib / sorafenib) 
and the corresponding 95% confidence interval (CI) will be estimated using a 
stratified Cox proportional hazard model with treatment and randomization 
stratification factors included in the model. Time to deterioration (TTD) curve for 
each treatment group will be estimated using the Kaplan-Meier (KM) product-limit 
method. A 95% CI for median will be estimated by the Brookmeyer-Crowley method. 
For this exploratory analysis, subjects with less than 10 points at Baseline will be 
excluded from the analysis.  
4.13.1.1.2. 
EORTC QLQ-HCC18 
The linearly transformed score for each of the scales or item will be summarized 
descriptively, including number of missing values and standard error (SE), for 
observed value and change from Baseline by analysis time point and treatment group. 
Treatment group comparison in change from Baseline will be based on a linear Mixed 
Model Repeated Measures model (MMRM), baseline value as covariate, treatment 
group, time and treatment-by-time. Subject will be included as a random effect. An 
unstructured (UN) covariance structured for repeated measurements over time may be 
used. If the fit of the unstructured covariance structure fails to converge, the 
Compound Symmetry (CS) covariance structures will be used. LSMean and LSMean 
difference (SHR-1210 plus rivoceranib - sorafenib) with 95% confidence interval (CI) 
and p-value will be calculated. Plots of LSmean difference (95% CI) for change from 
Baseline over time will be provided. Both raw score and linearly transformed scores 
will be listed.  
For the selected (more HCC-related) symptom scales/items including fatigue, 
jaundice, pain, abdominal swelling, the treatment comparison for TTD will be based 
on a stratified Log-rank test (based on randomization stratification factors). The 
hazard ratio (HR=SHR-1210 plus rivoceranib / sorafenib) and the corresponding 95% 
confidence interval (CI) will be estimated using a stratified Cox proportional hazard 
model with treatment and randomization stratification factors included in the model. 
The TTD curve for each treatment group will be estimated using the Kaplan-Meier 
(KM) product-limit method. A 95% CI for median will be estimated by the 
Brookmeyer-Crowley method. 
4.13.1.1.3. 
EQ-5D-5L 
Both UI and EQ-VAS will be summarized descriptively, including number of missing 
values and standard error (SE), for observed value and change from Baseline by 
analysis time point and treatment group. Treatment group comparison in change from 
Baseline will be based on a linear Mixed Model Repeated Measures model (MMRM), 
baseline value as covariate, treatment group, time and treatment-by-time. Subject will 
be included as a random effect. An unstructured (UN) covariance structured for 


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repeated measurements over time will be used. If the fit of the unstructured 
covariance structure fails to converge, the Compound Symmetry (CS) covariance 
structures will be used. LSMean and LSMean difference (SHR-1210 plus rivoceranib 
- sorafenib) and the corresponding 95% confidence interval (CI) will be estimated and 
p-value will be calculated. Plots of LSmean difference (95% CI) for change from 
Baseline over time will be provided.  
Listing of EQ-5D-5L will be provided. 
4.13.2. Biomarker Endpoints Analysis 
Based on the ITT set, the number and overall response rate by BIRC according to 
RECIST v1.1 for each expression level will be provided. The comparison between 
expression levels in ORR will be performed using the Chi-square test. Difference in 
proportions (%) for the ORR and its 95% CI using normal approximation will be 
provided. For PFS assessment by BIRC according to RECIST 1.1 and OS, the hazard 
ratios for the comparisons across expression levels and the corresponding 95% 
confidence intervals (CIs) will be estimated using a Cox proportional hazard model.  
4.14. Pharmacokinetics and Immunogenicity Endpoint Analyses 
4.14.1. Pharmacokinetics  
The PK analysis will be conducted based on the PKS. 
Serum concentrations of SHR-1210 and plasma concentrations of rivoceranib from 
patients in the PKS will be summarized by nominal time descriptively, including n, 
mean, standard deviation, median, minimum, maximum, coefficient of variation 
(CV%), for each drug. Possible stratifications (i.e. age, gender, body weight as 
categorized in subgroup section 4.18) may be applied in summary descriptive 
statistics.  
The plots of mean (SD) concentration per drug over nominal time on linear and log 
scale will also be provided.  
The population PK and exposure to response relationship will be analyzed and 
reported separately. 
4.14.2. Immunogenicity Analysis of SHR-1210 
The Immunogenicity analysis of ADA and Nab will be conducted based on ADAS.  
4.14.2.1. 
Descriptive Summary of Immunogenicity 
The number and percentage of all ADA and Nab classification will be summarized 
descriptively.  
ADA classification: 
(1) Non-treatment emergent ADA positive includes two situations: 
 a) subjects who have baseline positive samples and post-baseline negative samples; 


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 OR 
 b) subjects who have both baseline and post-baseline positive samples, and the titer of 
the post-baseline samples is less than 4-fold of the baseline titer; 
(2) Treatment-enhanced ADA positive: Subjects have both baseline and post-baseline 
positive samples, and the titer of the post-baseline samples is equal or more than 4-fold 
of the baseline titer; 
(3) Treatment-induced ADA positive: subjects have baseline negative and post-baseline 
positive samples.  
The treatment-induced ADA positive will be divided into three categories: transient 
ADA positive, persistent ADA positive and other ADA positive: 
 
Persistent ADA positive:  
a) negative at baseline, there are at least two positive samples post baseline, where the 
first and last ADA-positive samples are separated by a period ≥16 weeks;  
OR 
b) negative at baseline, the last sample of post-baseline is positive or the last sample 
of post-baseline is negative and the second last sample is positive before an ADA-
negative last sample; 
 
Transient ADA positive:  
subjects who are negative at baseline and have only one ADA-positive sample at post-
baseline before the last sample and are not persistent ADA positive; 
 
Other ADA positive:  
subjects who are negative at baseline, have at least two ADA-positive samples post 
baseline, but are not persistent ADA positive, and the last sample is ADA-negative; 
ADA Positive and ADA Negative： 
 
ADA positive (treatment emergent ADA positive): the total subjects who are 
treatment-induced positive and treatment-enhanced positive; 
 
ADA negative: subjects who are not ADA positive will be classified as ADA 
negative; 
Nab Positive and Nab Negative： 
 
Nab positive: subjects who have at least one post-baseline positive Nab sample will 
be classified as Nab positive (Except for subjects with both baseline and post-
baseline positive samples, which will be classified as Nab inconclusive); 


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 
Nab negative: subjects who are not Nab positive and Nab inconclusive will be 
classified as Nab negative. 
Time to and Duration of ADA and Nab response: 
The ADA and Nab analyses described below will include patients with treatment-
induced ADA positive or Nab positive, respectively. 
Time (Weeks) to ADA response is defined as: 
(Date of first ADA positive sample – date of first dosing of SHR-1210 + 1)/7.  
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 
 
the last ADA assessment is positive and patient is ongoing treatment with SHR-
1210; 
 
the last ADA assessment is positive and subject discontinued treatment with SHR-
1210 and the last planned ADA assessment (30 days after the last dose of SHR-
1210) is after the cut-off date. 
Time to ADA response will be summarized using simple descriptive statistics (mean, 
SD, median, min, max. quartiles). 
Time to Nab response and duration of Nab response are defined similarly based on the 
first and the last positive Nab result. 
Duration of ADA response or Nab response will be displayed graphically and 
analyzed using Kaplan-Meier methodology. If the number of patients with ADA 
response or Nab response is small, the Kaplan-Meier method may not provide reliable 
estimates. In this case, only descriptive statistics or listings will be provided 
4.14.2.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics by ADA status (ADA positive and ADA 
negative) will be summarized using descriptive statistics. 
4.14.2.3. 
Impact of Immunogenicity on PK of SHR-1210 
PK trough concentration of SHR-1210 at each visit stratified by ADA status (ADA 
positive and ADA negative) will be summarized using descriptive statistics. Also, the 
plot of mean concentration of SHR-1210 versus time (log and linear scale) stratified 
by ADA status will be drawn. 


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4.14.2.4. 
Impact of Immunogenicity on Efficacy of SHR-1210 
Efficacy endpoints (ORR, PFS assessed by BIRC, OS etc.) stratified by ADA status 
(ADA positive and ADA negative) will be summarized using descriptive statistics, 
including KM estimates and plots, as appropriate. 
4.14.2.5. 
Impact of Immunogenicity on Safety of SHR-1210 
Safety endpoints (drug exposure, TEAEs, treatment related AEs, TEAEs with CTCAE 
grade ≥3, treatment related AE with CTCAE grade ≥3, SAE, treatment related 
SAE, TEAEs leading to discontinuation from any study drug, TEAEs leading to 
discontinuation form SHR-1210, AE leading to dose reduction/interruption of any 
Study drug) stratified by ADA status (ADA positive and ADA negative) will be 
summarized using descriptive statistics.  
Selected AEs including selected AEs and grade ≥3 selected AEs (Grade 3-4, Grade 
5, grade ≥3) for SHR-1210, Serious selected AEs for SHR-1210, Selected AEs for 
SHR-1210 leading to discontinuation from any study drug, selected AEs for SHR-
1210 leading to dose reduction/interruption of any study drug will also be summarized 
by ADA status (ADA positive and ADA negative).  
Drug exposure will also be summarized by ADA status (ADA positive and ADA 
negative). 
ADA and Nab will be assessed as covariates in SHR-1210 population PK analysis and 
maybe in exposure-response analysis to see if ADA positive/ Nab positive has 
significant effect on PK and exposure to response relationship of SHR-1210. The 
population PK and exposure-response analysis will be performed and reported 
separately. 
4.15. Safety Analyses 
All the safety analyses will be based on the safety analysis set. Safety data collected 
during the on-treatment period will be summarized. 
Number and percentage of subjects with missing visits due to COVID-19 (non-AE) 
will be summarized by overall and visit. 
4.15.1. Extent of Exposure 
Exposure will be summarized by cycle and overall for each study drug in each group. 
The following summaries related to study treatment will be produced for the safety 
set: 
• 
Duration of exposure 
• 
Intended duration of treatment 
• 
By cycle actual DI 
• 
Overall actual DI 


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• 
By cycle RDI  
• 
Overall RDI  
• 
Number of SHR-1210 infusions received  
• 
Reasons for SHR-1210 with dose interruption/withdrawn 
• 
Reasons for Rivoceranib/Sorafenib with dose interruption/withdrawn/reduced 
All study drug administration and accountability data will be listed by country, study 
center and subject number. 
Number and percentage of treatment discontinuation or interruption due to COVID-19 
(non-AE) will be summarized. The number and percentage of subjects with 
interruption (<2, 2-6, ≥6 times of SHR-1210, duration of interruption (SHR-1210 ≥ 
6 times, Rivoceranib ≥ 28 days, Sorafenib ≥ 28 days in succession) will also be 
summarized. The duration of interruption for each study drug will be summarized 
using descriptive statistics. Duration (Days) of interruption is defined as interval 
between the last dose date prior to an interruption and the date of first dose given after 
an interruption.  
4.15.2. Adverse Events 
4.15.2.1.1. 
All Adverse Events 
Only TEAEs will be descriptively summarized. All AEs will be presented in subject 
data listings. Any AE occurring before randomized treatment (before the 
administration of the first dose of any drug) will be included in the AE listings and 
period will be referred to as “pre-treatment”. 
Incidence of TEAEs will be reported as number (percentage) of subjects with TEAEs 
by SOC and preferred term. Subjects will be counted only once at the highest severity 
grade per NCI-CTCAE v 4.03 within an SOC and preferred term, even if the subject 
experienced more than one TEAE within a specific SOC and preferred term. The 
number (percentage) of subjects with TEAEs will also be summarized by relationship 
to study drug. Unless specified otherwise, TEAE tables will be ordered by decreasing 
number of subjects in SOC and PT within the SOC for experimental group, and then 
by alphabetically order in SOC and PT within the SOC for tied frequency. Analyses 
will be performed by treatment group and overall. For treatment related analyses, 
results by individual treatment components for the experimental group will also be 
presented as indicated. 
In case a subject has events with non-missing and missing grades, the maximum of 
the non-missing grades will be displayed. No imputation of missing grades will be 
performed. 
Subject incidence of TEAE, Treatment-emergent SAE, TEAE with CTCAE Grade ≥3, 
Treatment-emergent SAE with CTCAE Grade ≥3, drug related TEAE, drug related 
Treatment-emergent SAE, drug related TEAE with CTCAE Grade ≥3, drug related 
Treatment-emergent SAE with CTCAE Grade ≥3, TEAE with incidence ≥5%, drug 


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related TEAE with incidence ≥5%, AE leading to interruption of study treatment, AE 
leading to dose reduction, AE leading to discontinuation of study treatment etc. will 
be tabulated by treatment group.  
Treatment-emergent AE summaries will present the number and percentage of 
subjects with at least one TEAE by treatment group. The following summaries 
include: 
• 
An overview of adverse events with number and percentage of subjects, at subject 
level, by treatment group will be provided for the following categories: 
- 
All TEAEs; 
- 
Treatment related TEAEs with any study drug;  
- 
Treatment related TEAEs with SHR-1210;  
- 
Treatment related TEAEs with Rivoceranib / Sorafenib;  
- 
Grade >=3 TEAEs; 
- 
Grade >=3 TEAEs related to study drug;  
- 
Treatment-emergent SAEs;  
- 
Treatment-emergent SAEs related to study drug; 
- 
TEAEs leading to dose reduction or interruption of any study drug; 
- 
Treatment related TEAEs leading to dose reduction or interruption of any 
study drug; 
- 
TEAEs leading to dose reduction of Rivoceranib / Sorafenib; 
- 
TEAEs leading to interruption of any study drug; 
- 
TEAEs leading to interruption of all study drugs; 
- 
TEAEs leading to interruption of SHR-1210; 
- 
TEAEs leading to interruption of Rivoceranib; 
- 
TEAEs leading to interruption of Sorafenib; 
- 
TEAEs leading to discontinuation of any study drug; 
- 
Treatment related TEAEs leading to discontinuation of any study drug; 
- 
TEAEs leading to discontinuation of all study drugs; 
- 
Treatment related TEAEs leading to discontinuation of all study drugs; 
- 
TEAEs leading to discontinuation of SHR-1210; 


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- 
Treatment related TEAEs leading to discontinuation of SHR-1210; 
- 
TEAEs leading to discontinuation of Rivoceranib; 
- 
Treatment related TEAEs leading to discontinuation of Rivoceranib; 
- 
TEAEs leading to discontinuation of Sorafenib; 
- 
Treatment related TEAEs leading to discontinuation of Sorafenib; 
- 
TEAEs leading to death; 
- 
Treatment-related TEAEs leading to death 
- 
Immun-related TEAEs assessed by investigator 
- 
COVID-19-related TEAEs assessed by investigator 
• 
Summary of TEAEs by SOC and PT; 
• 
Summary of TEAEs by SOC and PT, and by maximum CTCAE grade; 
• 
Summary of treatment-related TEAEs by SOC and PT; 
• 
Summary of treatment-related TEAEs by SOC and PT, and by maximum CTCAE 
grade;  
• 
Summary of treatment-related TEAEs with SHR-1210 by SOC and PT, and by 
maximum CTCAE grade;  
• 
Summary of treatment-related TEAEs with Rivoceranib / Sorafenib by SOC and 
PT, and by maximum CTCAE grade;  
• 
Summary of TEAEs with frequency ≥ 5% in any treatment group by SOC and 
PT; 
• 
Summary of treatment-related TEAEs with frequency ≥ 5% in any treatment 
group by SOC and PT; 
• 
Summary of Grade >=3 TEAEs by SOC and PT, and by maximum grade; 
• 
Summary of Grade >=3 TEAEs related to any study drug by SOC and PT, and by 
maximum grade;  
• 
Summary of Treatment-emergent SAEs by SOC and PT; 
• 
Summary of Treatment-emergent SAEs by SOC and PT, and by maximum 
CTCAE grade; 
• 
Summary of Treatment-emergent SAEs related to study drug by SOC and PT, and 
by maximum CTCAE grade; 


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• 
Summary of Treatment-emergent SAEs related to any study drug by SOC and PT; 
• 
Summary of TEAEs leading to dose reduction or interruption of any study drug 
by SOC and PT; 
• 
Summary of treatment-related TEAEs leading to dose reduction or interruption of 
any study drug by SOC and PT; 
• 
Summary of TEAEs leading to dose reduction of Rivoceranib / Sorafenib by SOC 
and PT; 
• 
Summary of TEAEs leading to study drug interruption of any study drug by SOC 
and PT; 
• 
Summary of TEAEs leading to interruption of SHR-1210 by SOC and PT; 
• 
Summary of TEAEs leading to interruption of Rivoceranib/ Sorafenib by SOC 
and PT; 
• 
Summary of TEAEs leading to dose reduction or interruption of 
Rivoceranib/Sorafenib by SOC and PT;  
• 
Summary of TEAEs leading to discontinuation of any study drug by SOC and PT; 
• 
Summary of treatment-related TEAEs leading to discontinuation of any study 
drug by SOC and PT; 
• 
Summary of TEAEs leading to discontinuation of all study drugs by SOC and PT; 
• 
Summary of treatment-related TEAEs leading to discontinuation of all study 
drugs by SOC and PT; 
• 
Summary of TEAEs leading to discontinuation of SHR-1210 by SOC and PT; 
• 
Summary of treatment-related TEAEs leading to discontinuation of SHR-1210 by 
SOC and PT; 
• 
Summary of TEAEs leading to discontinuation of Rivoceranib/Sorafenib by SOC 
and PT; 
• 
Summary of treatment-related TEAEs leading to discontinuation of 
Rivoceranib/Sorafenib by SOC and PT; 
• 
Summary of TEAEs leading to death by SOC and PT; 
• 
Summary of treatment-related TEAEs leading to death by SOC and PT; 
For overall TEAE, TEAE with CTCAE Grade ≥3, TEAE excluding Hypertension, 
TEAE with CTCAE Grade ≥3 (excluding Hypertension), time-at-risk exposure-
adjusted incidence rate will be summarized descriptively. 


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Time-at-risk (person-months at risk) is calculated as below: 
 
For subjects with events: (start date of the first event – first dose date +1) / 
30.4375 
 
For subject without an event: (end date of on-treatment period– first dose date 
+1) / 30.4375 
The time-at-risk exposure-adjusted incidence rate is calculated as below: 
 number of subjects with events / (total person-months at risk/ 100) 
 
Listings of adverse events, serious adverse events, adverse events leading to study 
drug discontinuation, adverse events leading to dose reduction, adverse events leading 
to interruption, adverse events leading to death will be provided. The listings will 
include at least country/center ID, subject ID, age, sex, race, AE verbatim term, SOC 
and PT term, start/end date (study day), serious flag, CTC-AE grade, relationship to 
study drug, treatment for AEs, action taken, outcome. For SAE listing, reasons 
classified as serious will also be listed. 
4.15.2.1.2. 
irAEs Assessed by Investigator 
The number and percentage of subjects in each of the following categories for 
experimental group (SHR-1210 plus Rivoceranib) will be provided: 
• 
Summary of irAE by SOC and PT, and by Maximum CTCAE grade;  
• 
Summary of irAE leading to discontinuation of SHR-1210 by PT;  
• 
Summary of irAE leading to discontinuation of Rivoceranib by PT;  
• 
Summary of irAE leading to discontinuation of any study drug by PT; 
• 
Summary of irAE leading to discontinuation of all study drugs by PT; 
• 
Summary of serious irAE by PT. 
• 
Summary of irAE leading to death by PT. 
Treatment of irAEs Assessed by Investigator 
 
Number and percentage of subjects with at least one irAE treated with any 
concomitant medication for overall; 
 
Number and percentage of subjects with at least one irAE treated with any 
Systemically Administered Corticosteroids for overall; 
 
Number and percentage of subjects with at least one irAE treated with ≥ 40mg 
Systemically Administered Corticosteroids taken (total daily dose) for overall; 


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 
Number and percentage of subjects with at least one irAE treated with any 
Immunosuppressive regimens for overall. 
 
Number and percentage of subjects with at least one irAE treated with any 
Hormone replacement therapy for overall. 
Listing of irAE assessed by investigator will be provided. The listings will include at 
least country/center ID, subject ID, age, sex, race, AE verbatim term, SOC and PT 
term, date of first study drug administration, start/end date (study day), serious flag, 
CTC-AE grade, relationship to study drug, treatment for AE, Systemically 
Administered Corticosteroids Treatment, high dose systemic corticosteroids used, 
Immunosuppressive treatment, action taken, outcome. 
4.15.2.1.3. Selected Adverse Events 
The selected adverse events will be summarized by medical concept, PT and 
treatment group according to selected AEs for SHR-1210 and rivoceranib, 
respectively. 
The number and percentage of subjects in each of the following categories by 
treatment group will be provided: 
Selected Adverse Events for SHR-1210: 
 
Overview of selected AEs for SHR-1210 by treatment group; 
 
Summary of selected AEs for SHR-1210 by Medical concept and PT by treatment 
group; 
 
Summary of selected AEs for SHR-1210 related to any study drug by Medical 
concept and PT by treatment group; 
 
Summary of selected AEs for SHR-1210 by Medical concept and PT, and by 
maximum CTCAE grade by treatment group; 
 
Summary of selected AEs for SHR-1210 related to any study drug by Medical 
concept and PT, and by maximum CTCAE grade by treatment group; 
 
Summary of serious selected AEs for SHR-1210 by Medical concept and PT; 
 
Summary of serious selected AEs for SHR-1210 related to any study drug by 
Medical concept and PT; 
 
Summary of selected AEs for SHR-1210 leading to discontinuation of any study 
drug by Medical concept and PT; 
 
Summary of selected AEs for SHR-1210 leading to dose reduction or interruption 
of any study drug by Medical concept and PT; 
 
Summary of selected AEs for SHR-1210 leading to death by Medical concept and 
PT. 


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Selected Adverse Events for Rivoceranib: 
 
Overview of selected AEs for Rivoceranib by treatment group; 
 
Summary of selected AEs for Rivoceranib by Medical concept and PT; 
 
Summary of selected AEs for Rivoceranib related to any study drug by Medical 
concept and PT; 
 
Summary of selected AEs for Rivoceranib by Medical concept and PT, and by 
maximum CTCAE grade; 
 
Summary of selected AEs for Rivoceranib related to any study drug by Medical 
concept and PT, and by maximum CTCAE grade; 
 
Summary of serious selected AEs for Rivoceranib by Medical concept and PT; 
 
Summary of serious selected AEs for Rivoceranib related to any study by 
Medical concept and PT; 
 
Summary of selected AEs for Rivoceranib leading to discontinuation of any study 
drug by Medical concept and PT; 
 
Summary of selected AEs for Rivoceranib leading to dose reduction or 
interruption of any study drug by Medical concept and PT; 
 
Summary of selected AEs for Rivoceranib leading to death by Medical concept 
and PT. 
Time to First Onset of Selected AEs for SHR-1210 / Rivoceranib 
Time to first onset of selected AEs and grade 3 or higher selected AEs summarize by 
overall and Grade >=3 within medical concept category descriptively.  
Treatment of Selected AEs for SHR-1210 
 
Number and percentage of subjects with at least one selected AEs for SHR-1210 
treated with any concomitant medication by medical concept category; 
 
Summary of selected AEs for SHR-1210 requiring use of systemic 
Corticosteroids by medical concept and by maximum CTCAE grade; 
 
Summary of selected AEs for SHR-1210 requiring use of immunosuppressive 
treatment other than Corticosteroids by medical concept and by maximum 
CTCAE grade; 
 
Number and percentage of subjects with at least one selected AEs for SHR-1210 
treated with ≥ 40mg systemically administered Corticosteroids taken (total 
daily dose) by medical concept category; 


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 
Duration (total days) of systemically administered Corticosteroids by medical 
concept category for subjects treated with ≥ 40mg/day systemically 
administered Corticosteroids. 
 
Duration (total days) of systemically administered Corticosteroids ≥ 40mg/day 
by medical concept category. 
 
Number and percentage of subjects with at least one selected AEs Thyroid 
disorder and Type 1 Diabetes Mellitus for SHR-1210 treated with any Hormone 
replacement therapy by medical concept category and by maximum CTCAE 
grade; 
Treatment of Selected AEs hepatotoxicity for Rivoceranib will also be 
analyzed with the same content as above: 
 
Number and percentage of subjects with at least one selected AEs hepatotoxicity 
for rivoceranib treated with any concomitant medication by medical concept 
category; 
 
Summary of selected AEs hepatotoxicity for rivoceranib requiring use of 
systemic Corticosteroids by medical concept and by maximum CTCAE grade; 
 
Summary of selected AEs hepatotoxicity for rivoceranib requiring use of 
immunosuppressive treatment other than Corticosteroids by medical concept and 
by maximum CTCAE grade; 
 
Number and percentage of subjects with at least one selected AEs hepatotoxicity 
for rivoceranib treated with ≥ 40mg systemically administered Corticosteroids  
taken (total daily dose) by medical concept category; 
 
Duration (total days) of systemically administered Corticosteroids by medical 
concept category for subjects treated with ≥ 40mg/day systemically 
administered Corticosteroids. 
 
Duration (total days) of systemically administered Corticosteroids ≥ 40mg/day 
by medical concept category. 
Resolution of Selected AEs for SHR-1210 / Rivoceranib 
Time to resolution of selected AEs will be analyzed using K-M method when 
appropriate. The total number of selected AEs, number of selected AEs resolved, 
number of selected AEs ongoing will be provided. The minimum and maximum of 
time to resolution of selected AEs will be denoted by a “+”. 
For the subjects with selected AEs resolved, time to resolution of selected AEs will be 
summarized using mean, SD, median, minimum and maximum. 
For the AE of reactive capillary endothelial proliferation (RCEP), all the summaries 
will include the following summary statistics: 
- 
Location of RCEP 


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- 
Largest lesion numbers  post baseline (<10, 10-19, 20-29, 30-39, 40-49, 
≥50) 
- 
Maximum diameter of lesions after baseline(mm) 
- 
Complications 
- 
Infection 
- 
Ulcer 
- 
Pain 
- 
Sum of bleeding amount post baseline 
- 
Any therapy (medications, laser, surgery, other) 
A listing of selected adverse events for SHR-1210 or Rivoceranib, selected AEs for 
SHR-1210 requiring use of systemic Corticosteroids, selected AEs for SHR-1210 
requiring use of immunosuppressive treatment other Than Corticosteroids will be 
provided with related to study drug, country/center ID, subject ID, age, sex, race, 
cluster, PT term, start/end date (study day), serious flag, CTC-AE grade, relationship 
to study drug, treatment for AE, action taken, outcome. 
4.15.2.1.4. 
COVID-19 Related TEAEs 
 
Summary of COVID-19 related TEAEs by SOC and PT; 
 
Summary of COVID-19 related TEAEs leading to death by SOC and PT; 
 
Summary of COVID-19 related TEAEs leading to any study drug interruption or 
dose reduced by SOC and PT;  
 
Summary of COVID-19 related TEAEs leading to any study drug discontinuation 
by SOC and PT;  
Listing of all COVID-19 related TEAEs will be provided. A complete list of COVID-
19 related TEAEs is described in Appendix 2. 
4.15.2.1.5. 
Deaths 
Summaries of deaths will be provided with number and percentage of subjects by 
treatment group, categorized as following: 
• 
All deaths (throughout the study) 
• 
AE outcome of death only and onset date prior to initiation of new anti-cancer 
therapy. 
• 
Reasons for death 
- 
Adverse Event 


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Disease Progression 
- 
Other 
The date and reason of death will be provided in individual subjects listing together 
with study treatment received, date of first dose, date of last dose. 
4.15.3.  Laboratory Tests Results 
Abnormal laboratory values will be flagged and identified as those above or below the 
normal reference range. The number and percentage of subjects experiencing 
clinically significant laboratory values at Baseline and post-baseline using the worst 
grade will be summarized by shift table. Similar analysis will be performed for fecal 
occult blood parameter, urinalysis, coagulation and HBV serology hepatitis B makers 
(e.g., HBsAg, HBeAg), HBV-DNA and HCV-RNA.     
Laboratory parameters that are graded in NCI-CTCAE v4.03 will be summarized by 
NCI-CTCAE grade. The number and percentage of subjects experiencing toxicity at 
Baseline and post-baseline, using the worst grade, will be summarized by shift table. 
In the summary of laboratory parameters by NCI-CTCAE grade, parameters with 
NCI-CTCAE grading in both high and low directions will be summarized separately.  
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and total bilirubin (TBILI) are used to assess possible drug induced liver 
toxicity. 
Summary of liver function tests will include the following categories. The number 
and percentage of subjects with each of the following categories after first dose 
recorded in eCRF will be summarized by group: 
- 
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
- 
AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
- 
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 
10×ULN, (ALT or AST) ≥ 20×ULN 
- 
Total bilirubin (TBILI) ≥ 2×ULN, ≥ 5×ULN 
- 
Potential Hy’s law (refer to the definition listed in the section 3.3.2).  
Categories will be cumulative, i.e., a subject with an elevation of AST ≥20×ULN 
will also appear in the categories ≥3×ULN, ≥5×ULN and ≥10×ULN. 
AFP evaluated within 14 days of Screening period, Day 1 of each treatment cycle ≥ 
2, End-of-Treatment visit and SFU site visit will be listed. 
Thyroid function, including thyroid stimulating hormone (TSH), FT3, FT4 will be 
listed. 


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A listing of all laboratory data will be provided. The listing includes abnormal 
laboratory values flagged and identified as those outside (above or below) the normal 
reference range, where appropriate. 
A listing of subject’s meeting laboratory criteria for potential Hy’s law will be 
provided. The listing will include the visit, Meet potential Hy’s Criteria, ALT, AST, 
TBIL, ALP. 
4.15.4. ECOG-PS 
Baseline and highest post-baseline ECOG-PS score (0-5) will be descriptively 
summarized using shift table by treatment group. A list of ECOG-PS assessments will 
be provided, which includes at least country/territorial ID, subject ID, date of 
assessment, study day and the scores. 
4.15.5. Child-Pugh 
Baseline and highest post-baseline Child-Pugh (Grade A, Grade B, Grade C) score 
will be descriptively summarized using shift table by treatment group. A list of Child-
Pugh assessments will be provided, which includes at least country/territorial ID, 
subject ID, date of assessment, study day and the scores. 
4.15.6. Vital Signs 
The number and percentage of subjects with clinically significant abnormalities in 
vital signs at post-baseline visits will be provided for each parameter each criterion by 
treatment group. A listing of vital signs assessments will also be provided, which 
includes at least country/territorial, subject ID, date of assessment, study day, results 
and signs of clinically significant abnormalities. The detail of the criteria for clinically 
significant abnormalities is showed in Table 6.  
4.15.7. Physical Examination 
Physical examination collected throughout the study will be descriptively summarized 
by treatment group using a shift table and listed, including any clinical finding results. 
The shift table summarizes the changes in clinical assessment outcome as normal, 
abnormal without clinically significant, abnormal with clinically significant outcome 
between Baseline and worst post-baseline clinically abnormal result. If have OCT 
examinations, listing will be provided. 
4.15.8. 12-Lead ECG 
The overall clinical assessment outcomes are categorized as normal, abnormal 
without clinically significant, abnormal with clinically significant outcome. Baseline 
and worst post-baseline clinically abnormal result will be descriptively summarized 
using shift table.  
Number and percentage of subjects with markedly abnormal value at post-Baseline 
will be provided for each treatment group for PR and QTcF. The detail of the criteria 
can be seen in Table 7.  


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4.15.9. Concentration-QTc Analysis for Rivoceranib 
Concentration-QTc analysis will be performed based on the PKQTS. The post-dose 
rivoceranib plasma concentrations which are below quantifiable limit will be set to 
zero for the analysis.  
A scatter plot of observed concentrations and QTcF changes from baseline (ΔQTcF) 
with a LOESS smooth line with 90% CI and a linear regression line will be provided 
for evaluation of the linearity of the concentration-QTc relationship.  
4.15.10. Echocardiography 
Echocardiography including left ventricular ejection fraction (LVEF) measured at 
investigator discretion during the study will be listed. 
4.16. Interim Analyses 
In this study, there is only one planned PFS analysis, which is planned to occur when 
~332 PFS events are observed (expected at about 19 months). OS analyses will be 
conducted at the following time points: at final PFS analysis, at 251 (70%) deaths if 
there are less than 251 deaths at the final PFS analysis, and when ~359 OS events are 
observed (expected at about 36 months), respectively.  
For the OS analysis, the O’Brien-Fleming alpha-spending function (OBF) will be 
used to adjust alpha except a nominal alpha of 0.001% will be spent at the time of the 
final PFS analysis if there are less than 251 deaths. Since the trial will not stop early if 
there are less than 251 deaths, the 0.001% is considered for administrative purposes to 
avoid trial stop early. 
PFS 
If SHR-1210 in combination with rivoceranib arm demonstrated superiority over 
sorafenib (i.e., one-sided p-value < 0.005), its corresponding alpha level of 0.005 one-
sided will be re-allocated to test the OS hypothesis at 0.025 one-sided with updated 
efficacy boundaries per Lan-DeMets O'Brien-Fleming spending function (see Table 
14).  
OS 
A formal interim analysis (IA) for OS will be conducted after 70% (~251) of the 
target OS events are observed at ~23 months. The OBF was used for calculating 
efficacy boundaries (original 0.020/updated 0.025 alpha level, one-sided). With ~251 
OS events, the SHR-1210 in combination with rivoceranib mesylate will be 
considered superior than the sorafenib at the interim analysis, if the one-sided p-value 
for OS is less than 0.005/0.007, which corresponds to an observed HR of 
approximately 0.725/0.735. The trial will be considered positive at the final analysis, 
if the one-sided p-value for OS is less than 0.018/0.023, which corresponds to an 
observed HR of approximately 0.802/0.810. If the null hypothesis for OS is rejected at 
either the interim (70%) or the final, its corresponding alpha level of 0.020 one-sided 
will be re-allocated to PFS so that the hypothesis for PFS can be tested again at 0.025 


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one-sided. The boundary properties for the planned OS analyses based on the original 
and updated alpha levels can be found in Table 14.  
However, in an anticipation that the number of OS events is < 251 OS events at the 
planned PFS analysis, a nominal alpha of 0.001% will be spent on testing OS at the 
time of the planned PFS analysis. Since the trial will not stop early if there are less 
than 251 deaths, the study will continue to the next planned OS interim analysis 
(70%) and could continue to final analysis after ~251 OS events and ~359 OS events 
are observed, respectively, according to the efficacy boundaries as described in Table 
14. 
4.16.1. Independent Data Monitoring Committee  
The analysis of PFS and the formal interim analysis (IA) of OS will be conducted by a 
Data Monitoring Committee (DMC) that recommends early discontinuation of the 
study for unequivocal efficacy at the formal interim analysis (IA) of OS (~70% 
events), or continuation of the study for final analysis of OS. This committee includes 
independent members of oncologists, independent statistician and a chair person for 
each DMC meeting. The decision to adopt DMC recommendation lies with the 
Sponsor. Further detail regarding role/responsibility and conduct of the interim 
analyses by independent members can be found in the DMC charter. The exact 
analyses, including planned and supplementary analyses as requested by the 
independent members, are to be retained by the DMC members until study ends.  
4.17. Multiplicity 
The two primary endpoints for the study are OS and PFS (assessed by BIRC base on 
RECIST v1.1). There is only one planned PFS analysis, which is expected to occur 
when approximately 332 PFS events are observed at approximately 19 months. OS 
analyses will be conducted at the following time points: at final PFS analysis, at 251 
(70%) deaths if there are less than 251 deaths at the final PFS analysis, and when 
~359 OS events are observed at ~36 months, respectively.  
For the OS analysis, the O’Brien-Fleming alpha-spending function (OBF) will be 
used to adjust alpha except a nominal alpha of 0.001% will be spent at the time of the 
final PFS analysis if there are less than 251 deaths. Since the trial will not stop early if 
there are less than 251 deaths, the 0.001% is considered for administrative purposes to 
avoid trial stop early.   
The Type I error is strongly controlled using the Weighted-Holm procedure with α-
reallocation approach between PFS and OS endpoints as described in Ye et al 2013 
and O’Brien-Fleming alpha-spending function (OBF) within OS. The allocated α 
between two endpoints is α1=0.005 (one-sided) for PFS and α2=0.020 (one-sided) for 
OS. If PFS endpoint is significant at α1=0.005, its α1 level will be re-allocated to 
endpoint OS so that the hypothesis for OS can be tested again using its updated 
efficacy boundaries based on α level 0.025. Similarly, if endpoint OS is significant at 
α2=0.020 according to the efficacy boundaries as determined by OBF, and PFS 
endpoint is not significant at α1=0.005, its α2 level will be re-allocated to PFS so that 
the hypothesis for PFS can be tested again at α level 0.025 (one-sided). In more 


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details, there are three possible scenarios of the testing results for PFS and OS as 
following: 
1) PFS is significant 
• 
If PFS is significant at α1=0.005 and OS is significant at α level 0.005 (1-sided) at 
the time of interim analysis according to the efficacy boundaries as determined by the 
OBF alpha-spending function, alpha re-allocation will not be performed; 
• 
If PFS is significant at α1=0.005 and OS is not significant at α level 0.005 (1-
sided) at the time of interim analysis according to the efficacy boundaries as 
determined by the OBF alpha-spending function, the α1=0.005 will be re-allocated to 
endpoint OS, so that the hypothesis for OS can be tested using its updated efficacy 
boundary at α level 0.007 (1-sided), and the hypothesis for OS can be tested at α level 
0.023 (1-sided) at the time of final analysis; 
2) PFS is not significant and OS is significant  
• 
If endpoint OS is significant at α level 0.005 (1-sided) at the time of formal 
interim analysis, and PFS endpoint is not significant at α1=0.005, the total α2=0.020 
will be re-allocated to PFS so that the hypothesis for PFS can be tested again at α 
level 0.025 (one-sided). 
• 
If endpoint OS is not significant at α level 0.005 (1-sided) at the time of formal 
interim analysis, but is significant at α level 0.018 (1-sided) at the time of final 
analysis, and PFS endpoint is not significant at α1=0.005, the total α2=0.020 will be 
re-allocated to PFS so that the hypothesis for PFS can be tested again at α level 0.025 
(one-sided). 
3) Both PFS and OS are not significant 
• 
If PFS is not significant at α1=0.005 and OS is neither significant at the time of 
interim analysis nor at final analysis at 0.020 according to the efficacy boundaries as 
determined by the OBF alpha-spending function, alpha re-allocation will not be 
performed; 
 The boundary properties for the planned OS analyses based on the original and 
updated alpha levels are summarized in Table 14, below: 
Table 14 Boundary Properties for Planned Analyses of OS 
Analysis 
Value 
α=0.020 
α=0.025 
Interim analysis：~70% 
Z 
-2.549 
-2.440 
Events：251 
p (one-sided) 
0.005 
0.007 


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Months：~23 
HR 
0.725 
0.735 
 
 
 
 
Final analysis 
Z 
-2.089 
-2.000 
Events：359 
p (one-sided) 
0.018 
0.023 
Months：~36 
HR  
0.802 
0.810 
Note: Results were generated using the EAST® 6.4.1. software; HR=Hazard ratio (SHR-1210 + 
Rivoceranib/Sorafenib) less than 1 indicates SHR-1210+rivoceranib group is superior than 
Sorafenib arm. The one-sided nominal significance level and stopping boundary will be determined 
by the actual percentage of events when the interim analysis is conducted. 
The overall type I error will be controlled under 0.025 one sided. If both PFS and OS 
endpoints are not significant, then α-reallocation will not perform. If both the PFS and 
OS endpoints are significant, ORR assessed by BIRC according to RECIST v1.1 at 
the time of 70% OS events observed will be tested at α level of 0.025. The graphical 
approach in Figure 1 shows the α-reallocation strategy for endpoints PFS and OS: 
Figure 1: Type I error reallocation strategy for endpoints PFS and OS. 
 
Above shows the initial one-sided α-allocation for each hypothesis in the ellipse 
representing the hypothesis. The weights for re-allocation from each hypothesis to 
another are represented in the rectangular boxes on the lines connecting hypotheses. 
However, if there are less than 251 OS events at the planned PFS analysis at ~19 
months, a nominal α (0.001%, independent of OBF approach to allocate alpha) will be 
used to test OS, but the trial will not stop based on a positive OS result at the time of 
the PFS analysis. The study will continue to the next planned OS interim analysis 
(70%) and could continue to the final analysis after ~251 OS events and ~359 OS 
events at ~23 and ~36 months, respectively, at the alpha level as determined by the 
OBF boundaries and the actual number of OS events observed. The nominal alpha 
(0.001%) is considered, as this has negligible impact on overall Type I error rate and 
the study will not stop early for a positive OS result at the time of the PFS analysis.  
As cut-off date of 2022-02-08 for the formal OS interim analysis, 262(73%) OS 
events are expected to be observed. A nominal α of 0.0087 using the Lan-DeMets 
procedure with an O’Brien-Fleming boundary is planned to be used to test OS. If one-
sided p-value obtained from the stratified log-rank test is < 0.0087, superiority of 
SHR-1210 plus rivoceranib over sorafenib in OS will be demonstrated. 
PFS 
α1=0.005 
OS  
α2=0.020 
1.0 
1.0 


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4.18. Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, HR 
and 95% CI for the primary endpoints OSand PFS (assessed by BIRC base on 
RECIST v1.1) will be estimated using unstratified Cox proportional hazard model, 
key secondary endpoint ORR (assessed by BIRC base on RECIST v1.1) and 95%CI 
will be calculated, and plotted within each category of the following classification 
variables according to eCRF data:  
• 
Age (<65 years vs. ≥65 years); 
• 
Gender (male vs. female); 
• 
Geographical region (Asia vs. non-Asia countries vs Mainland 
China/HongKong/Taiwan); 
• 
Race (Asian vs. White vs. African American vs. others); 
• 
BCLC stage (Stage B vs. Stage C); 
• 
Macrovascular invasion and/or extrahepatic metastasis (Presence vs. Absence); 
• 
Macrovascular Vascular invasion (Yes vs. No); 
• 
Extrahepatic metastasis (Yes vs. No); 
• 
Root cause of HCC (HBV vs. HCV vs. Non-viral); 
• 
AFP elevation at the baseline (<400ng/mL vs 400ng/mL); 
• 
Involved disease organs assessed by BIRC (≤1 vs. 2 vs. ≥3); 
• 
Previous local therapy (yes vs. no); 
• 
Weight (＜60 kg vs. 60 kg); 
• 
ECOG-PS Score (0 vs. 1); 
• 
PD-L1 category 1 (TPS <1%, TPS ≥1%, unknown) 
• 
PD-L1 category 2 (TPS <5%, TPS ≥5%, unknown) 
• 
PD-L1 category 3 (CPS <1, CPS ≥1, unknown) 
• 
PD-L1 category 4 (CPS <5, CPS≥5, unknown) 
Forest plots of HRs and 95% CIs will be provided for each of the primary endpoints. 
Subgroups with small sample size may reflect in wide confidence intervals, and point 
estimates that may not be estimable will be presented as NE=Not Estimable, or 
indicated otherwise. If any of the analyses was not carried out because the size of any 
category was too small, it will be noted in the relevant section(s) of the CSR. 


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For Geographical region (Asia vs. non-Asia countries vs Mainland 
China/HongKong/Taiwan), demographic and other baseline characteristics will also 
be summarized. For Geographical region of Mainland China/HongKong/Taiwan, the 
HR and 95% CI for the primary endpoint OS and PFS (assessed by BIRC base on 
RECIST v1.1) will also be estimated using stratified Cox proportional hazard model, 
the treatment comparison will be based on a stratified Log-rank test. 
 
 


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5. REFERENCES 
[1] Amit O, et al. Blinded independent central review of progression in cancer clinical 
trials: Results from a meta-analysis and recommendation from a PhRMA working 
group. European Journal of Cancer 47:1772-1778, 2011. 
[2] Fayers P, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC 
Quality of Life Study Group. EORTC QLQ-C30 Scoring Manual: 2nd Edition 1999. 
Available on request.  
[3] Osoba_D, Rodrigues G, Myles J ZEE B, PATER J, Interpreting the significance of 
changes in health-related quality-of-life scores. 1998; J Clin Oncol 16 139-144. 
[4] Devlin NJ, Shah KK, Feng Y, Mulhern B, van Hout B. Valuing health-related quality 
of life: An EQ-5D-5L value set for England, Health Economics. 2018; 27:7–22. 
[5] Robins, J. and Finkelstein, D. Correcting for noncompliance and dependent 
censoring in an AIDS clinical trial with Inverse Probability of Censoring Weighted 
(IPCW) Log-Rank Tests. Biometrics 2000; 56: 779-788. 
[6] Latimer, N., Abrams, K., Lambert, P., Crowther, M., et al. Adjusting for treatment 
switching in randomised controlled trials – A simulation study and a simplified two-
stage method. Statistical Methods in Medical Research 2017; 26(2): 724-751. 
[7] Ye, Yining, et al. "A group sequential Holm procedure with multiple primary 
endpoints." Statistics in medicine 32.7 (2013): 1112-1124. 
 
 
 


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6. APPENDIX 
Appendix 1. Selected Adverse Events defined by Sponsor 
Selected Adverse Events for SHR-1210: 
Category 
SMQs/ PTs 
Pneumonitis (23 PTs) 
PTs: Acute interstitial pneumonitis, Alveolar lung disease, Alveolitis, 
Autoimmune lung disease, Bronchiolitis, Diffuse alveolar damage, 
Eosinophilic pneumonia, Eosinophilic pneumonia acute, Eosinophilic 
pneumonia chronic, Hypersensitivity pneumonitis, Immune-mediated 
lung disease, Interstitial lung disease, Lung opacity, Obliterative 
bronchiolitis, Organising pneumonia, Pneumonitis, Pulmonary fibrosis, 
Pulmonary toxicity, Pulmonary vasculitis, Idiopathic pneumonia 
syndrome, Idiopathic interstitial pneumonia, Lung infiltration, 
Pulmonary sarcoidosis 
Colitis （22 PTs） 
HLT Colitis (excl infective):  Acute haemorrhagic ulcerative colitis, 
Allergic colitis, Autoimmune colitis, Colitis, Colitis erosive, Colitis 
ischaemic, Colitis microscopic, Colitis ulcerative, Crohn's disease, 
Enterocolitis haemorrhagic, Immune-mediated enterocolitis, 
Inflammatory bowel disease, Necrotising colitis, Terminal ileitis 
PT: Enterocolitis, Proctitis haemorrhagic, Proctitis, Diarrhoea 
haemorrhagic, Frequent bowel movements, Enteritis, Vasculitis 
gastrointestinal, Diarrhoea 
Thyroid disorder： 
 
Hypothyroidism (10 PTs) 
HLT Thyroid hypofunction disorders:  Autoimmune hypothyroidism, 
Hypothyroidic goitre, Hypothyroidism, Immune-mediated 
hypothyroidism, Myxoedema, Myxoedema coma, Primary 
hypothyroidism, Secondary hypothyroidism, Tertiary hypothyroidism, 
Thyroid atrophy  
Hyperthyroidism (14 PTs) 
HLT Thyroid hyperfunction disorders: Basedow's disease, Endocrine 
ophthalmopathy, Exophthalmos, Hashitoxicosis, Hyperthyroidism, 
Immune-mediated hyperthyroidism, Marine Lenhart syndrome, Primary 
hyperthyroidism, Secondary hyperthyroidism, Thyroid dermatopathy, 
Thyrotoxic crisis, Thyrotoxic periodic paralysis, Toxic goitre, Toxic 
nodular goitre 
Thyroiditis (10 PTs) 
HLT Acute and chronic thyroiditis:  Atrophic thyroiditis, Autoimmune 
thyroiditis, Immune-mediated thyroiditis, Silent thyroiditis, Thyroiditis, 
Thyroiditis acute, Thyroiditis chronic, Thyroiditis fibrous chronic, 
Thyroiditis subacute 
PTs: Thyroid disorder 
Adrenal Insufficiency (14 PTs) 
HLT Adrenal cortical hypofunctions: Addison's disease, Adrenal 
androgen deficiency, Adrenal atrophy, Adrenal insufficiency, Adrenal 
suppression, Adrenocortical insufficiency acute, Glucocorticoid 
deficiency, Hypoaldosteronism, Mineralocorticoid deficiency, Primary 
adrenal insufficiency, Secondary adrenocortical insufficiency, Steroid 
withdrawal syndrome, Immune-mediated adrenal insufficiency, Blood 
corticotrophin increased 
Type 1 Diabetes Mellitus (11 PTs) 
PTs:  Diabetes mellitus, Diabetic ketoacidosis, Fulminant type 1 
diabetes mellitus, Hyperglycaemia, Ketoacidosis, Latent autoimmune 
diabetes in adults, Type 1 diabetes mellitus, Euglycaemic diabetic 
ketoacidosis, Diabetic ketoacidotic hyperglycaemic coma, Blood 
glucose increased, Ketosis-prone diabetes mellitus 
Hypophysitis (8 PTs) 
PTs:  Hypophysitis, Hypopituitarism, Lymphocytic hypophysitis, 
Immune-mediated hypophysitis, Hypothalamic pituitary adrenal axis 


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suppression, Hypothalamo-pituitary disorder, Adrenocorticotropic 
hormone deficiency, Blood corticotrophin decreased 
Nephritis and renal dysfunction (39 
PTs) 
HLT Nephritis NEC:  Autoimmune nephritis, Immune-mediated 
nephritis, Lupus nephritis, Nephritis, Tubulointerstitial nephritis, 
Nephritis haemorrhagic 
HLT Glomerulonephritis and nephrotic syndrome: Glomerulonephritis, 
Glomerulonephritis acute, Glomerulonephritis membranous, IgA 
nephropathy, Nephritis allergic, Nephrotic syndrome, 
Glomerulonephritis membranoproliferative, Glomerulonephritis 
minimal lesion, Glomerulonephritis proliferative, Glomerulonephritis 
rapidly progressive, Chronic autoimmune glomerulonephritis, 
Mesangioproliferative glomerulonephritis, Fibrillary 
glomerulonephritis, Focal segmental glomerulosclerosis 
HLT Renal failure and impairment: Acute kidney injury, Renal failure, 
Renal impairment, Renal injury, Oliguria, Anuria 
PTs: Renal disorder, Renal tubular disorder, Renal tubular acidosis, 
Renal tubular dysfunction, Renal tubular atrophy, Renal tubular injury, 
Renal tubular necrosis, Nephropathy toxic, Azotaemia, Creatinine renal 
clearance decreased, Glomerular filtration rate decreased, Blood 
creatinine increased, Hypercreatininaemia  
Skin reactions (99 PTs) 
SMQ Severe cutaneous adverse reactions (Narrow search) 
HLT Rashes, eruptions and exanthems NEC: Genital rash, Nodular 
rash, Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash papular, Rash pruritic, Rash vesicular, Administration site rash, 
Anal rash, Application site rash, Butterfly rash, Catheter site rash, 
Eyelid rash, Heliotrope rash, Implant site rash, Incision site rash, 
Infusion site rash, Injection site rash, Instillation site rash, Medical 
device site rash, Mucocutaneous rash, Paraneoplastic rash, Penile rash, 
Perineal rash, Rash maculovesicular, Rash morbilliform, Rash neonatal, 
Rash rubelliform, Rash scarlatiniform, Stoma site rash, Systemic lupus 
erythematosus rash, Vaccination site rash, Vascular access site rash, 
Vessel puncture site rash, Viral rash, Vulvovaginal rash 
HLT Bullous conditions: Autoimmune blistering disease, Blister, 
Bullous impetigo, Dermatitis herpetiformis, Epidermolysis bullosa, 
Pemphigoid, Pemphigus 
HLT Dermatitis and eczema: Autoimmune dermatitis, Dermatitis, 
Dermatitis allergic, Dermatitis atopic, Dermatitis contact, Eczema, 
Eczema infected, Eczema vesicular, Hand dermatitis, Immune-mediated 
dermatitis, Seborrhoeic dermatitis, Urticarial dermatitis 
PTs: Dermatitis acneiform, Drug eruption, Erythema, Keratolysis 
exfoliativa acquired, Macule, Papule, Pruritus, Pruritus genital, Skin 
disorder, Skin exfoliation, Skin lesion, Skin reaction, Skin toxicity, 
Solar dermatitis, Urticaria, Rash papulosquamous, Rash follicular, Rash 
pustular, Southern tick-associated rash illness, Candida nappy rash, 
Septic rash, Vasculitic rash, Lichenoid keratosis 
Pancreatitis (12 PTs) 
PTs: Immune-mediated pancreatitis, Pancreatitis, Pancreatitis acute, 
Haemorrhagic necrotic pancreatitis, Pancreatitis necrotising, Amylase 
increased, Pancreatitis relapsing, Lipase increased, Autoimmune 
pancreatitis, Hyperamylasaemia, Hyperlipasaemia, Pancreatitis 
haemorrhagic 
Nervous system toxicity (60 PTs) 
PTs: Autoimmune demyelinating disease, Chronic inflammatory 
demyelinating polyradiculoneuropathy, Clinically isolated syndrome, 
Concentric sclerosis, Demyelinating polyneuropathy, 
Leukoencephalomyelitis, Myelitis transverse, Neuromyelitis optica 
pseudo relapse, Neuromyelitis optica spectrum disorder, Noninfectious 
myelitis, Noninfective encephalomyelitis, Subacute inflammatory 
demyelinating polyneuropathy, Acute flaccid myelitis, Axonal and 


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demyelinating polyneuropathy, Demyelination, Encephalomyelitis, 
Myelitis, Hypoglossal nerve paresis, IIIrd nerve paresis, IVth nerve 
paresis, Paresis cranial nerve, Trigeminal nerve paresis, VIth nerve 
paresis, Optic neuritis, Encephalitis toxic, Subacute sclerosing 
panencephalitis, Panencephalitis, Encephalitis haemorrhagic, 
Mononeuritis, Neuropathy peripheral, Immune-mediated neurological 
disorder, Multifocal motor neuropathy, Acute polyneuropathy, 
Rasmussen encephalitis, Meningitis aseptic, Encephalitis lethargica, 
Guillain-Barre syndrome, Polyneuropathy idiopathic progressive, 
Lupus encephalitis, Neurotoxicity, Neuritis, Neuromyopathy, 
Neuromuscular toxicity, Miller fisher syndrome, Myasthenic syndrome, 
Encephalitis brain stem, Encephalitis, Meningitis, Autonomic 
neuropathy, Autoimmune neuropathy, Encephalitis autoimmune, 
Axonal neuropathy, Limbic encephalitis, Encephalitis allergic, 
Myasthenia gravis, Myasthenia gravis crisis, Noninfective encephalitis, 
Facial nerve disorder, Immune-mediated encephalitis, Nerve injury 
Ocular toxicity (19 PTs) 
PTs: Visual impairment, Blindness, Episcleritis, Scleritis, Vogt-
Koyanagi-Harada disease, Ocular myasthenia, Ocular sarcoidosis, 
Blepharitis, Cyclitis, Conjunctivitis, Autoimmune uveitis, Uveitis, Iritis, 
Iridocyclitis, Papilloedema, Retinal detachment, Chorioretinitis，
Ulcerative keratitis, Keratitis 
Rheumatoid/ skeletal muscle toxicity 
(28 PTs) 
PTs: Polymyalgia rheumatica, Immune-mediated myositis, Arthritis, 
Arthralgia, Joint swelling, Paraneoplastic dermatomyositis, Inclusion 
body myositis, Eosinophilia myalgia syndrome, Necrotising myositis, 
Polymyositis, Myositis ossificans circumscripta, Infective myositis, 
Rhabdomyolysis, Synovitis, Viral myositis, Dermatomyositis, Myositis-
like syndrome, Rheumatoid arthritis, Sarcoidosis, Myositis, Myopathy, 
Myalgia, Pain in extremity, Pyomyositis, Myositis ossificans, 
Arthropathy, Immune-mediated arthritis, Sjogren's syndrome 
Myocarditis (11 PTs) 
PTs: Myocarditis, Myocarditis infectious, Radiation myocarditis, Lupus 
myocarditis, Viral myocarditis, Myocarditis mycotic, Myocarditis 
bacterial, Myocarditis septic, Autoimmune myocarditis, 
Hypersensitivity myocarditis, Immune-mediated myocarditis 
Reactive Capillary Endothelial 
Proliferation 
PT: Reactive capillary endothelial proliferation 
Infusion-related reaction 
PTs: Infusion related hypersensitivity reaction, Infusion related 
reaction, Hypersensitivity, Drug hypersensitivity, Type I 
hypersensitivity, Anaphylactoid reaction, Anaphylactoid shock, 
Anaphylactic reaction, Anaphylactic shock, Cytokine release syndrome 
（only include the select events with an onset date within one day of 
camrelizumab infusion: start date of AE – injection date of 
SHR1210<=1） 
 
 
Selected Adverse Events for Rivoceranib: 
Category 
SMQs/ PTs 
Hypertension  
SMQ: Hypertension (Narrow search) 
Proteinuria 
SMQ: Proteinuria (Narrow search) 
Palmar-plantar 
erythrodysaesthesia 
syndrome 
PT: Palmar-plantar erythrodysaesthesia syndrome 
Hemorrhage 
SMQ: Haemorrhage terms (excl laboratory terms)  
Hepatotoxicity 
SMQ: Hepatitis, non-infectious (Narrow search)  


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SMQ: Hepatic failure, fibrosis and cirrhosis and other liver damage-
related conditions (Narrow search) 
SMQ: Cholestasis and jaundice of hepatic origin (Narrow search) 
SMQ: Liver related investigations, signs and symptoms (Narrow search) 
QT prolongation 
SMQ: Torsade de pointes/QT prolongation (Narrow search) 
Gastrointestinal perforation  
SMQ: Gastrointestinal perforation 
Thromboembolic events 
SMQ: Embolic and thrombotic events  
Arterial thromboembolic events 
SMQ: Embolic and thrombotic events, arteria 
Venous thromboembolic events 
SMQ: Embolic and thrombotic events, venous 
Posterior reversible encephalopathy 
syndrome 
PTs: 
Posterior 
reversible 
encephalopathy 
syndrome, 
Leukoencephalopathy 
Wound healing impaired 
PTs: Impaired healing, Incisional hernia, Incision site impaired healing, 
Postoperative wound complication 
Appendix 2. COVID-19 related TEAE 
SMQ 
PTs 
COVID-19 
PTs: Asymptomatic COVID-19, Congenital COVID-19，Coronavirus 
infection，Coronavirus test positive，COVID-19，COVID-19 
immunisation，COVID-19 pneumonia，COVID-19 prophylaxis，
COVID-19 treatment，Exposure to SARS-CoV-2，Multisystem 
inflammatory syndrome in children，Occupational exposure to SARS-
CoV-2，Post-acute COVID-19 syndrome，SARS-CoV-2 antibody test 
positive，SARS-CoV-2 carrier，SARS-CoV-2 RNA decreased，
SARS-CoV-2 RNA fluctuation，SARS-CoV-2 RNA increased，
SARS-CoV-2 sepsis，SARS-CoV-2 test false negative，SARS-CoV-2 
test positive，SARS-CoV-2 viraemia，Suspected COVID-19，
Vaccine derived SARS-CoV-2 infection 
 
 
 


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Appendix 3. SAS code for primary analysis of PFS and OS 
 Kaplan-Meier Method and stratified Log-Rank test： 
 
Proc lifetest data=dataset_name; 
Time PFSTIME*censor (1);  /***1 means censored***/ 
Strata strata1 strata2 strata3/Group=TREATMENT; 
Run; 
 
 Stratified Cox Proportional Hazards Model： 
 
Proc phreg data=dataset_name (where= (TREATMENT in (1 2))); 
Class TREATMENT (ref=’2’);    /***1= Experimental group，2=Control group***/ 
model PFSTIME*censor(1)= TREATMENT/ties=discrete; /***1 means censored ***/ 
Strata strata1 strata2 strata3; 
Hazardratio TREATMENT/diff=ref; 
Run; 
Strata1, strata2 and strata3 means stratification factors, which are macrovascular 
invasion and/or extrahepatic metastasis (presence vs. absence), geographical region 
(Asia vs. countries outside of Asia) and Baseline AFP (AFP < 400 ng/mL vs. AFP ≥
400 ng/mL).