A Phase II Study of SHR-1210 in Combination With Apatinib in Advanced Non-Small Cell Lung
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Title: A Phase II Clinical Study of Anti-PD-1 Antibody SHR-1210 Combined with 
Apatinib Mesylate in the Treatment of Advanced Non-Small Cell Lung Cancer  
Clinical trial registration number: NCT03083041  
Version Date: 10 Dec., 2018  
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. Study No.: SHR-1210-APTN-II-202-NSCLC 
Study Protocol 
 
Confidentiality Statement 
This document contains important confidential business information, which is proprietary to Jiangsu Hengrui 
Pharmaceuticals Co., Ltd., and should not be disclosed unless required by current laws or regulations. In any case, 
all personnel receiving this document should be notified of this confidential requirement and should not further 
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and labeled as confidential. 
 
Translated from Original Document 
Registration Classification of Therapeutic Biological Products: Biological Product Category 1 
 
A PHASE II CLINICAL STUDY OF ANTI-PD-1 
ANTIBODY SHR-1210 COMBINED WITH 
APATINIB MESYLATE 
IN THE TREATMENT OF ADVANCED 
NON-SMALL CELL LUNG CANCER 
 
STUDY PROTOCOL 
 
 
Protocol No.: 
SHR-1210-APTN-II-202-NSCLC 
Version No.: 
5.0 
Version Date: 
10 Dec., 2018 
Study Director: 
 
Leading Center of Clinical Study: 
 
Sponsor:  
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. Study No.: SHR-1210-APTN-II-202-NSCLC 
Study Protocol 
Version No.: V5.0 
Version Date: 10 Dec., 2018 
Protocol Signature Page 
Signature of Principal Investigator 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol no.: SHR-1210-APTN-II-202-NSCLC, version no.: 5.0, version date: 10 Dec., 
2018). I agree to fulfill my duties in accordance with applicable Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. In addition, I confirm that any measures is 
subject to approval by the Ethics Committee before implementation, unless they must be taken to 
protect the safety, rights and interests of subjects. 
 
 
 
 
 
Leading Site of Clinical Study:  
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator (signature) 
Signature Date 
(DD/MM/YYYY) 
 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. Study No.: SHR-1210-APTN-II-202-NSCLC 
Study Protocol 
Version No.: V5.0 
Version Date: 10 Dec., 2018 
Protocol Signature Page 
Signature of Investigator 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol no.: SHR-1210-APTN-II-202-NSCLC, version no.: 5.0, version date: 10 Dec., 
2018). I agree to fulfill my duties in accordance with applicable Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. In addition, I confirm that any measures is 
subject to approval by the Ethics Committee before implementation, unless they must be taken to 
protect the safety, rights and interests of subjects. 
 
 
 
 
 
Study Center:  
 
 
 
 
Principal Investigator (print) 
 
 
 
Principal Investigator (signature) 
Signature Date 
(DD/MM/YYYY) 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. Study No.: SHR-1210-APTN-II-202-NSCLC 
Study Protocol 
Version No.: V5.0 
Version Date: 10 Dec., 2018 
Protocol Signature Page 
Sponsor's Signature 
We have read and confirmed this protocol (protocol no.: SHR-1210-APTN-II-202-NSCLC, 
version no.: 5.0, version date: 10 Dec., 2018). I agree to fulfill my duties in accordance with 
Chinese laws, the Declaration of Helsinki, the Chinese GCP, and this study protocol. 
 
 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd.  
 
 
 
 
 
 
 
 
Medical Director (print) 
Medical Director (signature) 
Signature Date 
(DD/MM/YYYY) 
 

Jiangsu Hengrui Pharmaceuticals Co., Ltd. Study No.: SHR-1210-APTN-II-202-NSCLC 
Study Protocol 
Version No.: V5.0 
Version Date: 10 Dec., 2018 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 1 
1 
BACKGROUND ................................................................................................................ 18 
1.1 
Product Name and Physicochemical Properties ...................................................... 20 
1.2 
Pharmacology and Mechanism of Action ................................................................ 21 
1.3 
Pharmacodynamics .................................................................................................. 21 
1.4 
Toxicology Studies ................................................................................................... 22 
1.5 
Pharmacokinetic Study ............................................................................................ 23 
1.6 
Results of Tolerability in the Clinical Studies ......................................................... 24 
1.7 
Progress in Stage I Clinical Studies ......................................................................... 25 
1.7.1 
Progress in the clinical studies of SHR-1210 ............................................ 25 
1.7.2 
Progress in the clinical studies of apatinib ................................................ 28 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 32 
2.1 
Study Objectives ...................................................................................................... 32 
2.2 
Endpoints ................................................................................................................. 33 
3 
STUDY DESIGN ............................................................................................................... 34 
3.1 
Overview of Study Design ....................................................................................... 34 
3.2 
Pharmacokinetic Study ............................................................................................ 36 
3.3 
Collection of Biomarker Samples ............................................................................ 38 
4 
RANDOMIZATION AND BLINDING ........................................................................... 39 
4.1 
Randomization ......................................................................................................... 39 
4.2 
Blinding.................................................................................................................... 39 
5 
SUBJECT SELECTION AND WITHDRAWAL/DISCONTINUATION .................... 39 
5.1 
Inclusion Criteria ..................................................................................................... 39 
5.2 
Exclusion Criteria .................................................................................................... 41 
5.3 
Subject's Withdrawal ................................................................................................ 44 
5.4 
End of Study ............................................................................................................ 45 
5.5 
Termination Criteria ................................................................................................. 45 
6 
STUDY DRUGS ................................................................................................................. 46 
6.1 
Overview of Study Drugs ........................................................................................ 46 
6.2 
Preparation of SHR-1210 ......................................................................................... 48 
6.3 
Administration Regimen .......................................................................................... 49 
6.4 
Dose Modification ................................................................................................... 49 
6.5 
Drug Management, Dispensation and Return .......................................................... 52 
6.6 
Concomitant Medications ........................................................................................ 53 
7 
STUDY PROCEDURES ................................................................................................... 56 

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7.1 
Screening Period (D-21 to D-1) ............................................................................... 56 
7.2 
Treatment Period ...................................................................................................... 59 
7.3 
End of Treatment/Withdrawal .................................................................................. 61 
7.4 
Follow-up Period ..................................................................................................... 61 
8 
SAFETY EVALUATION .................................................................................................. 69 
9 
MANAGEMENT OF ADVERSE EVENTS .................................................................... 78 
10 
EFFICACY EVALUATION ............................................................................................. 85 
11 
STUDY MANAGEMENT ................................................................................................. 85 
11.1 
Ethics and Informed Consent ................................................................................... 85 
11.2 
Protocol Amendments .............................................................................................. 86 
11.3 
Quality Assurance of Clinical Study ........................................................................ 87 
11.4 
Data Management .................................................................................................... 87 
12 
DATA MANAGEMENT AND INTELLECTUAL PROPERTY RIGHTS .................. 89 
12.1 
Data Processing ........................................................................................................ 89 
12.2 
Publication of Study Results .................................................................................... 90 
13 
STATISTICAL ANALYSIS .............................................................................................. 90 
13.1 
Determination of Sample Size ................................................................................. 90 
13.2 
Statistical Hypotheses .............................................................................................. 91 
13.3 
Analysis Sets ............................................................................................................ 91 
13.4 
Statistical Analysis Plan ........................................................................................... 92 
14 
EXPECTED STUDY SCHEDULE .................................................................................. 93 
15 
REFERENCES .................................................................................................................. 93 
Appendix I 
Prohibited Traditional Chinese Medicine (TCM) ........................................ 96 
Appendix II 
Performance Status Criteria (ECOG) .......................................................... 97 
Appendix III 
Calculation of Creatinine Clearance ............................................................. 98 
Appendix IV 
Management Principles for irAEs ................................................................. 99 
Appendix V 
Response Evaluation Criteria in Solid Tumors .......................................... 104 
Appendix VI 
Percent Bone Marrow Content in Human Skeleton ................................... 118 

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PROTOCOL SYNOPSIS 
Study Title 
A Phase II Clinical Study of Anti-PD-1 Antibody SHR-1210 Combined with Apatinib 
Mesylate in the Treatment of Advanced Non-Small Cell Lung Cancer 
Protocol Number 
SHR-1210-APTN-II-202-NSCLC 
Version No. 
5.0 
Version Date 
10 Dec., 2018 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
 
Study Population 
Patients with advanced non-small cell lung cancer (NSCLC) 
Study Objectives 
Primary objective of Stage I study: 
To evaluate the tolerability and safety of anti-PD-1 antibody SHR-1210 plus apatinib 
mesylate in patients with advanced NSCLC 
Secondary objectives of Stage I study: 
1. 
To evaluate the pharmacokinetics of anti-PD-1 antibody SHR-1210 plus 
apatinib mesylate in patients with advanced NSCLC 
2. 
To preliminarily evaluate the efficacy of anti-PD-1 antibody SHR-1210 plus 
apatinib mesylate in patients with advanced NSCLC 
Objectives of Stage II study: 
To observe and evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 plus 
apatinib mesylate in patients with advanced non-small cell lung cancer 
Endpoints 
Primary endpoints: 
Stage I: 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
Stage II: 
Objective response rate (ORR) 
Secondary endpoints: 
Stage I: 
1. Plasma concentrations of SHR-1210 and apatinib 
2. Pharmacokinetic parameters of SHR-1210 and apatinib, including t1/2, Cmax, 
AUC, etc. 
3. Tumor objective response rate (ORR) 
Stage II: 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
Stages I and II: 
1. Clinical benefit rate (CBR): Proportion of subjects with CR, PR, or SD ≥ 
6 months during the study 
2. Duration of response (DoR) 
3. Time to response 
4. Progression free survival (PFS) based on RECIST 1.1 

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5. 12-month survival 
6. Overall survival (OS) 
7. Exploratory analysis of the relationship between biomarkers and efficacy 
Sample Size 
Stage I: 40-60 subjects 
Stage II: about 174 subjects 
Study Design 
Study design of Stage I: 
A multi-arm, multi-center, open-label clinical study 
Inclusion criteria: Patients with advanced NSCLC who have failed standard treatment. 
Three dose groups, i.e., 250 mg apatinib, oral, q.d. + 200 mg SHR-1210, IV, q2W, 
375 mg apatinib, oral, q.d. + 200 mg SHR-1210, IV, q2W, and 500 mg apatinib, oral, 
q.d. + 200 mg SHR-1210, IV, q2W are set up to explore the tolerability of the 
combination therapy. 
Ten to twelve subjects will be enrolled in each dose group (to make sure that at least 
10 subjects will complete the tolerability evaluation), and the first cycle (28 days) of 
continuous treatment will be used as the observation period for tolerability. A dose will 
be considered tolerable if the proportion of subjects with clinically significant toxicities 
is < 0.33. 
After completing the tolerability observation period, subjects will continue the treatment 
until occurrence of any event that meets the criteria for discontinuation. 
After completing the tolerability observation period, the study will enter Stage II for 
further observation of efficacy and safety. 
After the completion of the observation period for tolerability, 10 to 12 subjects will be 
enrolled in each dose group for an expanded pharmacokinetic study. In cycle 1 of the 
expanded PK study, one dose of SHR-1210 will be administered on D1 followed by PK 
blood sampling. Then, apatinib will be started on D22 after the completion of PK blood 
sampling, while another PK blood sampling will be carried out on D28. Starting from 
D1 in cycle 2, SHR-1210 will be administered once every 14 days, while apatinib will 
be administered orally every day. PK blood sampling will be carried out on D1 of cycle 
2 after the administration of SHR-1210 and on D28 after the administration of apatinib. 
After the blood sampling is completed, the subjects will continue to receive the study 
treatment until an event meeting the criteria of study termination occurs. 
Design of Stage II: 
A single-arm/double-arm, multicenter, open-label clinical study 
According to the tolerable doses for combination therapy determined in Stage I, apatinib 
250 mg, q.d. oral + SHR-1210 200 mg, IV, q2W are selected, and patients with 
advanced non-small cell lung cancer who failed first-line chemotherapy or patients with 
non-squamous non-small cell lung cancer with a high tumor mutation burden (TMB) 
confirmed by the central laboratory are planned to be enrolled. According to the 
molecular and pathological classifications, the subjects are divided into: 
Cohort 1. Non-squamous, non-small cell lung cancer with wild-type EGFR and ALK; 
Cohort 2. Non-small cell lung cancer with EGFR mutation or ALK fusion gene 
rearrangement. The subjects harboring sensitive EGFR mutations and ALK fusion gene 
rearrangement must have failed the treatment of at least one EGFR inhibitor or ALK 
inhibitor; 
Cohort 3. Non-central squamous cell lung cancer; 
Cohort 4. Non-squamous and non-small cell lung cancer with wild-type EGFR and ALK 
and with bTMB ≥ 1.54 muts/Mb or tTMB > 10 muts/Mb confirmed by central 
laboratory. 

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The enrolled subjects are treated until the occurrence of any event that meets the criteria 
for discontinuation, so as to further evaluate the efficacy and safety of SHR-1210 in 
combination with apatinib in patients with advanced NSCLC. 
Administration 
Regimen 
SHR-1210 will be administered via intravenous infusion (without prophylactics) with a 
fixed dose of 200 mg given in 30 min (not less than 20 min, no more than 60 min), once 
every 2 weeks. Each cycle contains 4 weeks (the subjects for the expanded PK study 
receive one dose in Cycle 1 of the study) and the longest period of drug use is 2 years; 
Apatinib will be orally administered after meals, once a day through the study (the 
subjects for the expanded PK study will receive the drug orally under fasting conditions 
on D28 of Cycle 1 and D28 of Cycle 2). 
Clinically Significant 
Toxicity 
Definition of clinically significant toxicity: 
1. Grade 4 hematological toxicity or Grade ≥ 3 thrombocytopenia with 
hemorrhage, Grade ≥ 3 neutropenia with fever and infection; 
2. Grade ≥ 3 non-hematological toxicity (except for abnormal laboratory test 
parameters), hypertension, rash, diarrhea, nausea, and vomiting that cannot be 
controlled after symptomatic treatment; 
3. Grade ≥ 3 abnormal laboratory test parameters that lead to medical 
intervention, hospitalization, or lasting for ≥ 7 days; 
4. SHR-1210 interruption for > 14 days due to relevant toxicity (delayed 
administration in Cycle 1 or Cycle 2); 
5. Apatinib interruption for > 7 days due to relevant toxicity. 
Definition of subjects with incomplete tolerance evaluation: 
During the observation period of tolerability, the dose of SHR-1210 is < 90% of the 
prescribed dose due to non-clinically significant toxicity (such as injection reactions). 
Blood Sampling for PK 
Study 
In the expanded PK study, one dose of SHR-1210 will be administered on D1 of Cycle 1 
(28D) via intravenous infusion. PK blood sampling will be performed within 0.5 h 
pre-administration, and at 5 min (± 5 min), 2 h (± 10 min) and 6 h (± 10 min) on D1, D2 
(24 h, ± 1 h), D3 (48 h, ± 1 h), D8 (168 h, ± 1 h), D15 (336 h, ± 1 h) and D22 (504 h, 
± 1 h) post-administration, with 3 mL of blood collected at each time point. After the 
completion of PK blood sampling on D22, the administration of apatinib mesylate 
tablets will be started on the same day and continued once a day. PK blood sampling 
will be performed within 0.5 h pre-administration on D28 and at 0.5 h (± 5 min), 1 h 
(± 5 min), 2 h (± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), 
and 24 h (± 1 h) post-administration, with 3 mL of blood collected at each time point. 
On D1 of Cycle 2, PK blood sampling will be performed within 0.5 h before the 
administration of SHR-1210, and at 5 min (± 5 min), 2h (± 10 min) and 6 h (± 10 min) 
on D1, D2 (24 h, ± 1 h), D3 (48 h, ± 1 h), D8 (168 h, ± 1 h), and D15 (336 h, ± 1 h) 
post-administration, with 3 mL of blood collected at each time point. On D28 of Cycle 
2, PK blood sampling will be performed within 0.5 h before the administration of 
apatinib, and at 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 3 h (± 5 min), 5 h 
(± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h) post-administration, 
with 3 mL of blood collected at each time point. 
There will be a total of 35 blood sampling points. 
Inclusion Criteria 
1. Male and female patients aged 18-70 years old; 
2. Pathologically confirmed advanced (Phase IIIB and IV) non-small cell lung 
cancer with at least one measurable lesion that meets the RECIST v1.1 criteria 
and has not been treated locally; 
3. Able to provide previous tumor samples or agree to cooperate with biopsy 
(Stage II); 

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4. Stage I: Patients who have undergone the second-line and above 
chemotherapy (at least one of the previous chemotherapy regimens is a 
platinum-based chemotherapy doublet regimen) but failed the treatment or 
showed recurrence. The patients harboring EGFR mutations and ALK gene 
abnormalities must have failed the treatment with an EGFR inhibitor or ALK 
inhibitor.  
Stage II: Patients who have undergone only one previous platinum-based 
doublet chemotherapy but failed the treatment or showed recurrence, or 
patients in the stage of palliative treatment who have received no systemic 
treatment (only for cohort 4). 
a. The replacement of platinum drugs due to drug toxicity will be considered 
as one treatment regimen; 
b. Postoperative adjuvant chemotherapy will not be counted as one previous 
chemotherapy regimen if the time from the end of treatment to recurrence 
is > 6 months. 
According to the type of driver gene mutations and pathological classification, 
the subjects will be divided into the following four cohorts: 
Cohort 1. Patients with confirmed absence of mutations in EGFR 18-21 exons 
and ALK fusion genes (the histochemistry result of ALK D5F3 antibody is 
negative); 
Cohort 2. Patients with confirmed presence of mutations in EGFR 18-21 
exons or ALK fusion genes (the histochemistry result of ALK D5F3 antibody 
is positive). Carriers of sensitive EGFR mutations must have received at least 
one targeted treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI) and 
failed the treatment. Carriers of positive ALK fusion genes must have failed 
the treatment of at least one targeted treatment with ALK tyrosine kinase 
inhibitor (ALK-TKI) (treatment failure: progressive disease or intolerable 
toxicity during the treatment); 
Cohort 3. Imaging confirmed non-central squamous cell lung cancer or 
adenosquamous carcinoma primarily consisted of squamous cell carcinoma 
(pathologically confirmed). 
Cohort 4. Non-squamous and non-small cell lung cancer with wild-type EGFR 
and ALK and with bTMB ≥ 1.54 muts/Mb or tTMB > 10 muts/Mb confirmed 
by central laboratory, and patients in the stage of a palliative treatment who 
have received no systemic treatment. 
5. ECOG PS: 0-1; 
6. Life expectancy ≥ 12 weeks;  
7. Major organ functions must meet the following rules (not including any use of 
blood components and cell growth factors within 14 days before the first 
dose): 
 
Absolute neutrophil count ≥ 1.5 × 109/L; 
 
Platelets ≥ 100 × 109/L; 
 
Hemoglobin ≥ 9 g/dL; 
 
Serum albumin ≥ 3 g/dL; 
 
Thyroid stimulating hormone (TSH) ≤ ULN (In the case of abnormalities, 
FT3 and FT4 levels should also be measured. If FT3 and FT4 levels are 
normal, the subject can be enrolled); 
 
Bilirubin ≤ ULN; 
 
ALT and AST ≤ 1.5 × ULN; 

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 
AKP ≤ 2.5 × ULN; 
 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min 
(using the standard Cockcroft-Gault formula, as shown in Appendix 3); 
8. Female patients of a childbearing age who are not surgically sterilized should 
adopt a medically approved contraceptive measure (such as an intra-uterine 
contraceptive device, contraceptive pills or condoms) during the study 
treatment period and within 3 months after the end of the study treatment; 
female patients of a childbearing age who are not surgically sterilized must 
have a negative serum or urine HCG test result within 72 h prior to study 
enrollment, and must not be in the lactation period; male patients should be 
surgically sterilized or agree to use an appropriate contraceptive measure 
during the study period and within 3 months after the last dose of the study 
drug; 
9. Patients must participate voluntarily, sign the informed consent form, have 
good compliance, and cooperate with follow-up visits. 
Exclusion Criteria 
1. Patients with any active autoimmune diseases or a history of autoimmune 
diseases (including but not limited to the following: autoimmune hepatitis, 
interstitial pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, 
nephritis, hyperthyroidism, hypothyroidism; adults with vitiligo or completely 
relieved childhood asthma can be enrolled if they do not require any 
intervention; patients with asthma requiring medical intervention with 
bronchodilators cannot be enrolled); 
2. Patients who are currently using immunosuppressive agents, or systemic or 
absorbable local hormonal therapies for immunosuppression purposes 
(> 10 mg/day prednisone or equivalent) and still use the above drugs within 
2 weeks prior to enrollment; 
3. Patients who have experienced severe allergic reactions to other monoclonal 
antibodies; 
4. Patients with untreated metastases to central nervous system. Patients who 
have received the treatment of metastases to brains or meninges (radiotherapy 
or surgery) may be enrolled if they are clinically stable (MRI) for at least 
1 month and have stopped systemic hormonal therapy (> 10 mg/day 
prednisone or an equivalent dose of other therapeutic hormones) for more than 
2 weeks; 
5. Imaging (CT or MRI) results show that the tumor has invaded the large blood 
vessels or has an unclear boundary with the blood vessels; 
6. Imaging (CT or MRI) results show significant cavitation or necrosis of lung 
tumors; 
Patients with marginal adenocarcinoma with cavity may be considered for 
enrollment after discussion with the principal investigator. 
7. Patients with hypertension which cannot be well controlled by 
antihypertensives (systolic pressure ≥ 140 mmHg or diastolic pressure 
≥ 90 mmHg); 
8. Patients with clinical symptoms or diseases of the heart that are not well 
controlled, such as (1) > NYHA Class II cardiac failure; (2) unstable 
angina;(3) myocardial infarct within past 1 year; (4) clinically significant 
supraventricular or ventricular arrhythmia requiring treatment or intervention; 
9. Patients with abnormal coagulation functions (PT > 16 s, APTT > 43 s,  
TT > 21 s, Fbg < 2 g/L) and hemorrhagic diathesis or those who are currently 
treated by a thrombolytic or anticoagulant therapy; 

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10. Patients with urinalysis results indicating that the urine protein is ≥ ++ and the 
quantitative test of urine protein confirms that the 24-hour urine protein is > 
1.0 g; 
11. Patients who have previously received radiotherapy, chemotherapy or surgery 
that is less than 4 weeks before the study after the end of such treatments (last 
dose), or patients whose last dose of oral targeted drugs is less than 5 drug 
half-lives; Patients with adverse events caused by the previous treatment 
(except for alopecia) that have not returned to CTCAE Grade ≤ 1; 
12. Patients with clinically symptomatic ascites or pleural effusion requiring 
therapeutic paracentesis or drainage; 
13. Patients with obvious hemoptysis or a daily amount of hemoptysis of half a 
teaspoon (2.5 mL) or more within 2 months before randomization; 
14. Patients with clinically significant hemorrhage symptoms or a clear 
hemorrhagic diathesis within 3 months prior to randomization, such as 
hemorrhage of digestive tract, stomach ulcer with hemorrhage, baseline fecal 
occult blood ++ or above, or vasculitis;  
15. Had events of arterial/venous thrombosis within 6 months prior to 
randomization, such as cerebrovascular accidents (including transient 
ischemic attacks, cerebral hemorrhage, brain infarction), deep vein 
thrombosis, and pulmonary embolism; 
16. Known hereditary or acquired hemorrhage and thrombophilia (such as 
hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.); 
17. Patients with active infection or unexplained fever of > 38.5 °C during 
screening or prior to the first dose; 
18. Patients with previous or current objective evidence of pulmonary fibrosis, 
interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced 
pneumonitis, and severe lung function impairment; 
19. Patients with congenital or acquired immunodeficiency, such as patients with 
HIV infection, or active hepatitis (hepatitis B: detection value of HBV DNA > 
ULN; for hepatitis C: HCV viral titre or RNA detection value > ULN); 
20. Those who have used study drugs of other clinical trials within 4 weeks before 
the first dose of this study; 
21. Patients with previous or concurrent malignancies at other sites (except for 
cured skin basal cell carcinoma and cervical carcinoma in situ); 
22. Patients who may receive other systemic anti-tumor treatments during the 
study; 
23. Patients with bone metastasis who have received a palliative radiotherapy in 
an area of > 5% of bone marrow area within 4 weeks prior to the participation 
in this study; 
24. Patients who have previously received other anti-PD-1 antibody therapies or 
other immunotherapies targeting PD-1/PD-L1, or have previously received 
apatinib treatments; 
25. Patients who have received live vaccines within less than 4 weeks before the 
first dose or may receive live vaccines during the study; 
26. Patients who may have other factors leading to the discontinuation of the 
study as judged by the investigator, such as other serious diseases (including 
mental illness) requiring concomitant treatment, serious laboratory test 
abnormalities, or accompanied by family or social factors that can affect the 
safety of the subject or the collection of data and samples. 

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Discontinuation 
Criteria for Subjects 
A Subject must withdraw from/discontinue the treatment when any of the following 
conditions occurs: 
1. The subject withdraws informed consent and requests to withdraw from the 
study; 
2. Imaging examinations show progressive disease; 
Upon the first discovery of progressive disease by imaging examinations, it 
must be confirmed after 4 weeks (except for rapid progression and significant 
clinical progression); 
If a subject shows local progression (1 to 4 lesions show progress) but the 
clinical symptoms are stable, the treatment can be continued according to the 
judgment of the investigator until imaging examinations show progressive 
disease again. 
Definition of clinically stable: a. no clinically significant symptoms or changes 
in laboratory tests; b. no changes in the performance status score 
(deterioration); and c. non-tumor rapid progression and tumor progression not 
involving major organs/sites (e.g., spinal cord compression). 
3. Treated by SHR-1210 for 2 years (no progressive disease as shown by imaging); 
4. Subjects with intolerable toxicity; 
5. Subjects with poor compliance; 
6. Subjects lost to follow-ups or show positive blood HCG results; 
7. Other reasons for which the investigator considers withdrawal as necessary. 
Criteria for Study 
Termination 
The termination criteria of this study include but are not limited to the following: 
1. Discovery of unexpected, important, or unacceptable risks to the subjects; 
2. Major errors in the protocol found during the implementation of the study; 
3. Ineffective study drug/treatment, or meaninglessness to continue the study; 
4. The sponsor decides to terminate the study due to reasons such as serious 
delay in the enrollment of subjects or frequent protocol deviations. 
Safety Endpoints 
The severity of AEs will be determined according to the CTCAE V4.0.3 criteria. The 
adverse event record form should be filled out correctly during the study, including the 
onset time, severity, duration, actions taken, and outcomes of the adverse events. 
Efficacy Evaluation 
The enrolled subjects shall undergo 1 imaging evaluation every 2 cycles (8 weeks). 
After 6 months from the first dose, clinical tumor imaging evaluation will be performed 
once every 12 weeks ± 7 days as appropriate. Tumor efficacy will be evaluated based on 
RECIST 1.1 criteria, and the first evaluation of PR/CR subjects must be confirmed 
4 weeks later. 
Determination of 
Sample Size 
The sample size in Stage I is primarily based on clinical considerations, and the number 
of subjects actually enrolled in each dose group is determined by the number of subjects 
who show clinically significant toxicity during the observation period for tolerability. 
During the expansion stage of PK study, 10-12 subjects are required for each group. The 
sample size in Stage I is 40-60 subjects. 
Stage II: For cohort 1. Assuming that the ORR of the combination therapy is 30% with a 
bilateral alpha of 0.05, enrollment of 62 subjects will have a 80% power to ensure that 
the ORR of the combination therapy has a lower 95% CI limit of > 15%. If the dropout 
rate is 20%, 78 subjects should be enrolled. 
For cohorts 2 and 3, assume that the ORR point estimate of each cohort is 30% and the 
width of the 90% confidence interval is 0.3, 38 subjects are required for each group 
when a 20% dropout rate is considered. 

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For cohort 4, assume that the ORR point estimate is 50% and the width of the 90% 
confidence interval is 0.4, 20 subjects are required to be enrolled. 
In Stage II, the four cohorts require to enroll a total of 174 subjects. 
Statistical Methods 
Study results will mainly be analyzed using descriptive statistics. Numerical data will be 
summarized in means, standard deviations, medians, maximums, and minimums. 
Categorical data will be summarized in frequencies (proportions), percentages, and 
confidence intervals. 
All statistical analyses will be performed using SAS version 9.2 or later. 
Safety analysis: 
Descriptive statistical analysis will be primarily used to analyze the adverse events, 
serious adverse events and adverse reactions in each dose group (the adverse reactions 
are defined as adverse events that are "definitely related, probably related, and 
indeterminable" to the study drug). Laboratory test results will describe the conditions 
that are normal before the study but become abnormal after treatment. 
Efficacy analysis: 
The point estimates of efficacy endpoints such as objective response rate (ORR) and 
clinical benefit rate (CBR) are provided with 95% confidence intervals representing the 
entire population. For survival, the median duration of progression-free survival, the 
12-month survival rate, the median duration of survival, and their 95% confidence 
intervals representing the entire population will be estimated using the Kaplan-Meier 
method. In addition, survival plots will be plotted. Descriptive analysis will be 
performed for other secondary efficacy endpoints. 
PK analysis: 
The PK parameters Cmax, Tmax, AUC, and t1/2 will be statistically described (n, mean, 
standard deviation, median, minimum, and maximum) by dose groups and planed blood 
sampling time points. A mean and/or median-time plot of serum concentration will be 
plotted. Statistical description will be given for the mean, standard deviation, median, 
minimum and maximum values, geometric mean and standard deviation, and %CV and 
95% CI of natural log-transformed parameters (if applicable) by dose groups. Box and 
whisker plots will be drawn for primary parameters. The serum concentration-time plots 
will be drawn for each subject along with a list of serum concentrations and parameter data 
Other analyses: 
SHR-1210-related solid tumor markers, such as expression levels of PD-L1 in tumor 
tissue samples, will also be analyzed using descriptive statistics. 
End of Study 
Stage I: 
The Stage I of this study will end at 3 months after the last dose of the last subject in the 
tolerability observation period if subjects in the PK expansion stage complete the 
specified PK blood sampling; 
Stage II: 
At 6 months after the first dose of the last subject in Stage II, the primary and secondary 
endpoints will be statistically analyzed. 
All subjects will be followed up until 12 to 24 months after the last dose of the last 
subject, and supplemental analysis of the primary and secondary endpoints will be 
performed thereafter. 
After the end of the study, if the subjects may continue to benefit from the study drug, 
the medication may be continued until a criterion for discontinuation is met. The 
occurrence of SAEs will be collected and recorded during the treatment and after the 
last dose according to the protocol. 
Study Period 
Expected to be from Mar. 2017 to Sep. 2019 

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Schedule of Activities 
Item 
Screening Period 
  
Treatment Period (28 
days/cycle) 
Post-Treatment 
Survival 
follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of 
treatment/ 
withdrawal  
(+ 3 d) 
End of 
treatment visit 
(± 3 d) 
Every 2 
months 
(± 3 d)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
Baseline Data 
Signing of Informed Consent 
× 
  
  
  
  
  
  
  
  
Demographics 
× 
  
  
  
  
  
  
  
  
Tumor History/ 
× 
  
Other Medical History[1] 
  
Concomitant Medication[2] 
 × 
 × 
 × 
  
Laboratory tests 
Hematology[3] 
  
× 
 
× 
× 
× 
× 
× 
  
Urinalysis[4] 
  
× 
 
× 
× 
× 
× 
× 
  
Routine Stool Test[5] 
  
× 
  
× 
×  
× 
  
  
Blood biochemistry[6] 
  
× 
× 
× 
× 
× 
× 
  
Coagulation Function Test[7] 
  
× 
  
× 
×  
× 
  
  
T3, FT3, FT4, and TSH[8] 
× 
  
  
  
× 
  
× 
  
  
Pituitary Adrenal Axis Test[9] 
× 
 
 
 
 
 
 
 
 
Myocardial Zymogram[10] 
  
× 
  
  
  
  
× 
  
  
HBV, HCV, and HIV Tests[11] 
× 
  

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Item 
Screening Period 
  
Treatment Period (28 
days/cycle) 
Post-Treatment 
Survival 
follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of 
treatment/ 
withdrawal  
(+ 3 d) 
End of 
treatment visit 
(± 3 d) 
Every 2 
months 
(± 3 d)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
Pregnancy Test[12] 
  
× 
  
  
  
  
× 
  
  
Detection of EGFR Mutations 
and ALK Fusion Genes[13] 
× 
  
  
  
  
  
  
  
  
Clinical Evaluation and Examination 
AEs[14] 
From informed consent to 30 days after the last dose 
  
Vital Signs[15] 
  
× 
× 
× 
× 
× 
× 
× 
  
Physical Examination and 
Weight Measurement[16] 
  
× 
× 
× 
× 
× 
× 
× 
  
ECOG PS 
  
× 
  
  
×  
× 
× 
  
ECG[17] 
  
× 
  
× 
×  
× 
× 
  
  
Echocardiography[18] 
  
× 
  
  
  
  
×  
  
  
Blood Pressure Monitoring[19] 
× 
× 
  
× 
× 
× 
× 
  
  
Pulmonary Function Test[20] 
× 
  
  
  
  
  
  
  
  
STUDY DRUGS 
Administration of SHR-1210[21] 
  
  
× 
× 
× 
× 
  
  
  
Administration of Apatinib[22] 
  
  
Oral administration once a day after 
meal 
  
  
  
Dispensation/Return of 
Apatinib[23] 
  
 
× 
 
×  
 
× 
  
  

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Item 
Screening Period 
  
Treatment Period (28 
days/cycle) 
Post-Treatment 
Survival 
follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of 
treatment/ 
withdrawal  
(+ 3 d) 
End of 
treatment visit 
(± 3 d) 
Every 2 
months 
(± 3 d)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
Imaging Evaluation 
Imaging Examination[24] 
× 
  
Once every 2 cycles in the first 6 
cycles, followed by once every 3 cycles 
× 
  
  
Follow-Up after End of Treatment 
Time to Progression[25] 
  
  
  
  
  
  
Imaging evaluation will be carried out once 
every 3 months (± 7 d) until progressive 
disease or the initiation of other cancer 
treatments (subjects with non-imaging PD) 
Time of Death[26] 
  
  
  
  
  
  
  
  
× 
Blood Sampling and Tumor Tissue Sampling/Sample Collection 
PK Blood Sampling[27] 
  
  
× 
× 
× 
× 
  
  
  
Sampling/Sample Collection 
and Detection of Biomarkers[28] 
× 
  
  
  
  
  
  
  
  
Note: 
[1] 
History of tumor/other diseases: reports of pathological findings, detection of EGFR mutations, and detection of ALK fusion gene; history of tumor 
surgery, chemotherapy, radiotherapy, and other disease treatments; history of tumor other than non-small cell lung cancer. 
[2] 
Concomitant medications and treatments received within 30 days prior to the first dose and during the study period should be recorded. Once the study 
treatment is interrupted, only the concomitant medication and treatment used to solve new or unresolved treatment-related AEs will be recorded 
[3] 
Hematology: Hemoglobin, red blood cell count, white blood cell count, neutrophil count, lymphocyte count, and platelet count will be measured within 7 days 
before enrollment, on Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of treatment. 
[4] 
Urinalysis: Urine protein, urine glucose, and urine occult blood (urine red blood cells and white blood cells). If two consecutive semi-quantitative protein 
tests show urine protein 2-3+, then a quantitative 24-h urine protein test is required. If semi-quantitative protein test shows urine protein > 3+, then a 
quantitative 24-h urine protein test shall be performed. The tests will be carried out within 7 days before the enrollment, on Day 15 of Cycle 1, Day 1 and 
Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of treatment. 

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[5] 
Routine stool test: Occult blood; re-examination is required for fecal occult blood+; if fecal occult blood is confirmed, then a gastroscopy shall be performed. 
The test will be performed within 7 days before enrollment, on Day 15 of Cycle 1 and Day 1 of subsequent cycles, and upon completion of the study. 
[6] 
Blood biochemistry: bilirubin total, bilirubin conjugated, ALT, AST, AKP, γ-GT, protein total, albumin, urea or urea nitrogen, creatinine, uric acid, fasting 
blood glucose, TG, cholesterol, potassium, sodium, chlorine, calcium, phosphorus, blood lipase (only during the screening period and in the case of 
subsequent abdominal pain, abdominal distension and other symptoms of suspected pancreatitis), blood amylase (only during the screening period and 
subsequent abdominal pain, abdominal distension, and other symptoms of suspected pancreatitis). It will be carried out within 7 days before enrollment, 
on Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of treatment. 
[7] 
Coagulation function: INR, APTT, PT, TT, FIB. The test will be performed within 7 days before enrollment, on Day 15 of Cycle 1 and Day 1 of 
subsequent cycles, and upon completion of the study. 
[8] 
Thyroid function test: including serum FT3, FT4 and TSH. The test will be performed 21 days before administration, on Day 1 of Cycle 2, and then once 
every 3 cycles. 
[9] 
Examination of the pituitary adrenal axis: including the test of ACTH, cortisol, and sex hormones, which will be performed during the screening period. 
[10] Myocardial zymogram: Performed once within 7 days before enrollment, then only at the onset of symptoms of precordial pain and palpitations and 
abnormal electrocardiograms, and at the end of treatment/upon withdrawal. 
[11] Hepatitis B, hepatitis C, and HIV tests: hepatitis B panel [If the test results are abnormal, viral replication (HBV DNA) test should be performed]; hepatitis 
C virus antibody (anti-HCV) test (If the test results are abnormal, virus titer should be tested); HIV antibody test. 
[12] Pregnancy test: The urine pregnancy test will be performed 72 h before the first dose for females of a childbearing age. If the result of the urine pregnancy 
test is positive, a serum pregnancy test shall be performed. If necessary, re-tests can be performed for confirmation. 
[13] If the subjects have previously been tested for EGFR mutations and ALK fusion gene, retests are not required; otherwise, the study site will perform 
relevant tests. If the subjects are positive for EGFR mutations, the test of ALK fusion gene will no longer be performed. 
[14] Adverse events: Adverse events will be collected from the time when the subjects sign the informed consent form. AEs unrelated to the study drugs will 
be collected to 30 days after the last dose. Treatment-related AEs will be collected until 90 days after the last dose of SHR-1210 or 30 days after the last 
dose of targeted anti-angiogenic therapy (whichever is longer). See the AE/SAE collection time limit in Section 8.3 for details. 
[15] Vital sign examination: Body temperature, respiration, pulse, blood pressure. The examination will be performed within 7 days before enrollment, on Day 
1 and Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after treatment. 
[16] Physical examination and weight measurement: Examination of major body systems (head and face, skin system, lymph nodes, eyes, ears, nose, throat, 
oral cavity, respiratory system, cardiovascular system, abdomen, urogenital system, musculoskeletal system, nervous system and mental state) will be 
performed within 7 days before enrollment, on D1 and D15 of Cycle 1, D1 and D15 of subsequent cycles, upon completion of the study, and 30 days after 
the end of treatment. Body weight measurement will be started on D1 of Cycle 1 and performed on D1 of subsequent cycles, upon completion of the 
study, and 30 days after the end of treatment. 
[17] 12-Lead ECG: Performed within 7 days before enrollment, on Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, and upon completion of the 
study. Abnormalities in ECG must be confirmed twice via additional ECG tests. 
[18] Echocardiography: Performed within 7 days prior to the enrollment and upon completion of the study, and when clinically significant abnormalities are 
found during the study. 

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[19] Blood pressure monitoring: The blood pressure measurement of subjects will be performed by the investigator during the screening period; during each 
blood pressure measurement, smoking and coffee are prohibited for 30 min before the measurement, and subjects should at least rest for 10 min, and the 
sitting position will be taken during the measurement by placing the elbow at the same level as the heart. Each blood pressure measurement will be taken 
on the same side of the body; during the study, the blood pressure monitoring will be performed by the subjects themselves and recorded in their diary 
card. Blood pressure will be measured at least 3 times a week in the first 2 cycles. If the blood pressure is abnormal, the measurement will be carried out 
every day; If the blood pressure is normal, the blood pressure measurement will be carried out twice a week after 2 cycles; In addition, the blood pressure 
will be measured by the investigator during each follow-up. During each blood pressure measurement, smoking and coffee are prohibited for 30 min 
before the measurement, and subjects should at least rest for 10 min, and the sitting position will be taken during the measurement by placing the elbow at 
the same level as the heart. Each blood pressure measurement will be taken on the same side of the body. 
[20] Pulmonary function test: Maximum vital capacity, the forced expiratory flow at 25-75% of forced vital capacity (FEF25-75), the peak expiratory flow rate 
(PEF), the maximum expiratory volume per second, diffusing capacity of the lungs for carbon monoxide (DLCO) and oxygen saturation. The test will be 
carried out during the screening period and then according to the judgment of the investigator in subsequent cycles. 
[21] SHR-1210 administration: SHR-1210 will be administered via intravenous injection (no prophylactics) with a fixed dose of 200 mg given in 30 min (no 
less than 20 min and no more than 60 min), once every 2 weeks. Each cycle contains 4 weeks (the subjects for the expanded PK study receive one dose 
on D1 of Cycle 1) and the longest period of drug use is 2 years. After 6 cycles of SHR-1210 administration, the treatment can be discontinued if the 
imaging evaluation confirms a CR. 
[22] Apatinib will be taken orally after meals, once a day, and continued throughout the study (the subjects for the expanded PK study receive the drug starting 
on Day 22 of Cycle 1. The administration on Day 28 of Cycle 1 and Day 28 of Cycle 2 will be given orally under fasting conditions). 
[23] Return and dispensation of apatinib. Apatinib will be dispensed on Day 1 of Cycle 1 (dispensed to subjects in the drug expansion study from Day 22 of 
Cycle 1). From Day 1 of Cycle 2, the return and dispensation of apatinib will be performed on Day 1 of each cycle. The remaining drugs will be returned 
first to verify the dose actually taken before new study drugs are dispensed. 
[24] Imaging examination: Including CT or MRI of the chest, abdomen, and brain. The baseline tumor assessment during the screening period can be extended 
to up to 3 weeks before treatment. Qualified CT/MRI scan results obtained before signing the informed consent can be used for tumor assessment during 
the screening period. Bone scan should be performed upon clinically suspected bone metastasis. Absence of cerebral hemorrhage should be confirmed 
within 21 days before randomization for subjects with stable brain metastases. 
During the treatment period, imaging examinations should be performed under the same conditions as those at baseline (layer thickness of the scan, use 
of contrast agent, etc.), and the lesions found at baseline should be checked every 2 cycles in the first 6 cycles of the treatment (bone scan shall be 
performed in the case of suspected bone progression or for CR confirmation). After 6 cycles, imaging examinations can be performed every 3 weeks as 
appropriate and can be performed upon the discovery of suspected new lesions. Initial assessment of PR/CR must be confirmed after 4 weeks; initial 
assessment of PD must be confirmed after 4 to 6 weeks (except for significant changes in the subjects' symptoms or rapid tumor progression). 
The window period for imaging examination schedule is ± 7 days. Unscheduled imaging examinations can be performed when progressive disease is 
suspected (such as worsening of symptoms). 
[25] A tumor assessment is required at the end of treatment for subjects who discontinue study treatment for reasons other than radiographic PD, if not 
performed within 4 weeks prior to study completion. Also, treatment efficacy will be followed up once every 3 months after study completion, until 
documentation of confirmed PD or start of a new anti-tumor treatment. 

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[26] Survival follow-up: After the study treatment is discontinued, the survival status and subsequent anti-tumor treatment can be collected through clinical or 
telephone follow-ups every 2 months until death. 
[27] PK blood sampling: In the stage of expanded PK study, PK blood sampling will be performed within 0.5 h before the administration of SHR-1210, and 
post-dose at 5 min (± 3 min), 2 h (± 10 min), 6 h (± 10 min), 24 h (± 0.5 h), 48 h (± 1 h), 168 h (± 1 h), 336 h (± 1 h), and 504 h (± 1 h) on D1, with 3 mL 
of blood collected at each time point. After the completion of PK blood sampling on D22, the administration of apatinib mesylate tablets will be started on 
the same day and continued at a administration frequency of once a day. PK blood sampling will be performed within 0.5 h pre-dose on D28 and post-dose 
at 0.5 h (± 3 min), 1 h (± 5 min), 2 h (± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h), with 3 mL of blood 
collected at each time point. 
On D1 of Cycle 2, PK blood sampling will be performed within 0.5 h before the administration of SHR-1210, and at 5 min (± 3 min), 2 h (± 10 min), 6 h 
(± 10 min), 24 h (± 0.5 h), 48 h (± 1 h), 168 h (± 1 h), and 336 h (± 1 h) after the administration of SHR-1210, with 3 mL of blood collected at each time 
point. On D28 of Cycle 2, PK blood sampling will be performed within 0.5 h before the administration of apatinib, and at 0.5 h (± 5 min), 1 h (± 5 min), 
2 h (± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h) after the administration of apatinib, with 3 mL of blood 
collected at each time point. 
[28] A total of 14 mL of blood sample will be collected from each subject at baseline and divided into 1 tube of 10 mL and 1 tube of 4 mL. The collected blood 
samples will be transported to the central laboratory at room temperature according to the requirements specified in the central laboratory manual (no 
additional processing by the study center is required). Subjects with CR/PR during the study period shall undergo an additional biomarker blood sampling 
upon the onset of CR/PR and PD, respectively, with 10 mL in 1 tube, and the collection and transport requirements are the same as those in the baseline 
period; archived paraffin-embedded tumor tissue samples or fresh biopsy specimens will be collected. At least 10 slices are required, including 3-5 slices 
of 3-4 μm thickness for PD-L1 detection, and 5-8 slices of 5-8 μm thickness (paraffin blocks may be directly collected without mounting onto slides), 
otherwise fresh biopsy specimens are required for detection of biomarkers such as tumor mutation burden (TMB). 
For cohort 4, the test results of tumor mutation burden (TMB) in the peripheral blood and/or tumor tissues will be verified before the subjects take the 
first dose of the study drug, so the TMB test for cohort 4 must be completed before the first dose. However, the delay in the screening period caused by 
TMB testing is allowed, but other tests (including imaging examinations) must be completed within 21 days prior to the first dose. 
See the laboratory manual for biomarker blood sampling and tumor tissue sampling/sample collection and disposal. 
 

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List of Abbreviations 
Abbreviations and Terms 
Full Name 
ADA 
Anti-drug antibody 
ADRs  
Adverse drug reactions 
AE 
Adverse event 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
B-scan 
- 
Ca  
Calcium 
CFDA 
China Food and Drug Administration (now NMPA) 
Cl  
Chlorine 
Cr 
Creatinine 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBIL 
Direct bilirubin 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data collection 
FAS 
Full analysis set 
FIB 
Fibrinogen 
FDA 
Food and Drug Administration 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
Glu 
Glucose 

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Abbreviations and Terms 
Full Name 
Hb 
Hemoglobin 
IBIL 
ieAE 
Indirect bilirubin 
Immune-related adverse event 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intention to treat 
K  
Potassium 
LLN 
Lower limit of normal 
LVEF  
Left ventricular ejection fraction 
mPFS 
Median progression-free survival 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Na 
Sodium 
NCCN 
National Comprehensive Cancer Network 
NCI-CTC 
National Cancer Institute Common Terminology Criteria 
ORR 
Objective response rate 
OS 
Overall survival 
P  
Phosphorus 
PD 
Progressive disease 
PD-1/PD-L1 
Programmed death 1/programmed death ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PLT 
Platelet 
PPS 
Per-protocol set 
PR 
Partial response 
PT 
Prothrombin time 
QoL 
Quality of life 
RBC 
Red blood cell 
RO 
Receptor occupancy 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAS 
Statistical analysis software 
SD 
Stable disease 
SOP 
Standard operating procedure 
SS 
Safety analysis set 
TB 
Total bilirubin 

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Abbreviations and Terms 
Full Name 
TC 
Total cholesterol 
TCM  
Traditional Chinese medicine 
TG 
Triglyceride 
TP  
Plasma total protein 
TSH 
Thyroid-stimulating hormone 
TT 
Thrombin time 
UA  
Blood uric acid 
UICC  
Union for International Cancer Control 
ULN 
Upper limit of normal 
WBC 
White blood cell 
γ-GT 
γ-Glutamyltransferase 
 

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1 BACKGROUND 
In recent years, significant progress has been made in cancer treatment, and molecular targeted 
therapies inhibiting internal driving factors of tumor angiogenesis and cancer cell growth, as well 
as immunomodulatory therapies enhancing anti-tumor immunity of the patients, have been 
approved by regulatory agencies. With the deepening of the understanding of the body's immune 
system and the rapid development of biotechnology, the immunomodulatory therapy has become 
an important means of cancer treatment, and it is occupying an increasingly important position in 
the comprehensive treatment system of tumors. 
Cancer immunotherapy has been a long-time hot spot in the field of cancer treatment, in which 
the cancer immunotherapy using T cells is at the core position. Cancer immunotherapy fully 
utilizes and mobilizes killer T cells in tumor patients to kill tumors, which may be the most 
effective and safest way to treat tumors. Also, tumor immune escape is a great challenge in 
cancer immunotherapy. Cancer cells' suppressive effect on the immune system promotes 
uncontrolled tumor growth. There is an extremely complex relationship between the immune 
escape mechanism of tumors and the body's anti-tumor immune response. Tumor-specific killer 
T cells have certain biological activities in the early stage of the cancer immunotherapy, but they 
lose their cytotoxicity in the late stage of tumor growth. Therefore, the cancer immunotherapy 
aims to maximize a patient's own immune response against the tumor. It not only activates the 
original immune response in the body, but also maintains the duration and intensity of the 
immune responses which is the key to the cancer immunotherapy. 
A number of multinational pharmaceutical companies are currently developing monoclonal 
antibodies against programmed cell death protein-1 (PD-1, CD279). By blocking the binding 
between PD-L1/PD-1, these monoclonal antibodies maximize a patient’s own immune response 
against the tumor, thereby achieving the purpose of killing tumor cells. BMS and Merck's PD-1 
monoclonal antibodies are currently the most advanced anti-PD-1 antibody drugs. 
In Jul. 2014, Nivoluamb was approved by the Japanese Ministry of Health and Welfare for the 
treatment of advanced melanoma. It was approved by the FDA for the treatment of melanoma in 
Dec. 2014, approved by the FDA for the treatment of non-small cell lung cancer in Mar. 2015, 
and approved by the FDA for the treatment of renal cell carcinoma in Nov. 2015. In 2016, 
indications of Nivoluamb were added by its approval for use in the treatment of classical 
Hodgkin's lymphoma. 
In Sep. 2014, Pembrolizumab was approved by the FDA for the treatment of advanced 
melanoma. In Oct. 2015, Pembrolizumab was approved by the FDA for the treatment of 
non-small cell lung cancer. 

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PD-1/PD-L1 inhibitors, including nivolumab, Atezolizumab, and Avelumab, will play a leading 
role in the combination treatment regimens of cancer patients. These drugs will break through the 
current treatment regimens and become the backbone of the combination therapy. This idea has 
been confirmed in melanoma patients. In a double-blind clinical study of CheckMate-069, the 
combination therapy of nivolumab and a CTLA-4 inhibitor ipilimumab reduced the mortality by 
60% (HR: 0.40; 95%CI: 0.22-0.71; P < .002) compared with the use of ipilimumab alone. For 
melanoma patients harboring wild-type BRAF, the ORR of the combination therapy was 60%, 
while the ORR of ipilimumab alone was 11%. Therefore, FDA accelerated the approval of 
nivolumab in combination with ipilimumab (Yervoy) as a treatment for patients with 
unresectable or metastatic melanoma who harbor wild-type BRAF V600. According to the 
reports in the 2016 Annual Meeting of the American Gastroenterological Association and the 
annual meeting of the American Society of Clinical Oncology, in the Checkmate-032 study for 
Nivolumab, 59 patients with advanced esophageal cancer and gastric cancer were assigned to the 
Nivolumab group, and the overall response rate was 14%. The response rate of PD-L1 positive 
(> 1%) patients was 27%, including a case of complete response, and the 1-year survival rate 
was 36%. 
Anti-angiogenic drugs include mAb targeting the vascular endothelial growth factor (VEGF), 
such as bevacizumab, and multi-targeted TKIs that have been used in the early clinical studies of 
the combination therapy of anti-PD-1/PD-L1 mAb. In metastatic RCC, a phase I study was 
carried out using the combination therapy of Nivolumab + Sunitinib (n = 33), and Nivolumab + 
Pazopanib (n = 20). Grade 3/4 TEAEs were reported in 73% (n = 24/33) patients receiving 
Nivolumab plus Sunitinib and 60% (n = 12/20) patients receiving Nivolumab plus Pazopanib. 
These resulted in treatment discontinuation in 24% (n = 8/33) of patients receiving sunitinib and 
20% (n = 4/20) of patients receiving pazopanib. In addition to anti-angiogenic effects, blockage 
of VEGF has been reported to exert immunomodulatory effects such as promoting the activity of 
effector T-cells, reducing MDSCs, T-regulatory cells, and inhibitory cytokines in the tumor 
microenvironment. The combination of bevacizumab and atezolizumab was studied in the 
metastatic clear-cell RCC and metastatic CRC, and the known AEs of bevacizumab were not 
aggravated. This combination is being studied in a phase II study of RCC (NCT01984242). 
Although this type of therapy has not obtained some data and there are many studies in progress, 
it is not to be overlooked that a large proportion of patients still do not respond to the therapy and 
will increase some adverse reactions. From the current point of view, the combination therapy 
will be one of the inevitable trends in the future development of immunomodulatory therapy of 
tumors. How to carry out the combination therapy is a problem to be solved by the medical 
community. Alternative combination therapies include targeted therapies, 
immunosuppressive/stimulating molecules, vaccines, chemotherapy, and radiation therapy. 

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Currently, there are a large number of ongoing clinical studies that combine targeted molecular 
therapies with tumor immunomodulatory therapies. The rationale supporting these combination 
therapies is that the combination of the two therapies combines different immunological and 
tumor biological mechanisms that enhance the anti-tumor activity; In addition, some evidence 
suggests that targeted molecular therapies can enhance certain aspects of the "cancer-immune 
cycle" (such as tumor antigenicity, T cell initiation/transport/infiltration, etc.) to synergistically 
enhance the efficacy of the immunotherapy. In particular, targeted molecular therapies targeting 
the MAPK and the VEGF pathways, including drugs such as sunitinib and sorafenib, can have a 
direct impact on cancer cell growth and tumor angiogenesis, as well as on tumor antigenicity and 
intratumoral T cell infiltration. Their impact on the patient's immune response is beyond their 
role in tumor biology, providing a strong basis for the combination therapy. 
Some key factors should be considered in the clinical development of combination therapies, 
such as optimizing administration regimens, minimizing treatment-related toxicity, selecting 
appropriate endpoints to assess the efficacy, and so on. 
This clinical study involves recombinant humanized anti-PD-1 monoclonal antibody injection 
(SHR-1210 for injection), a new class 1 therapeutic biological product that has not been 
marketed in China or abroad. Drugs of same class are marketed abroad. Preclinical studies have 
shown that recombinant humanized anti-PD-1 monoclonal antibody injection developed by 
Hengrui has comparable in vivo efficacy and safety compared with those of drugs of same class 
abroad, and may have a better potential in anti-tumor clinical applications. Since 2015, Hengrui 
has carried out the phase I clinical studies of SHR-1210 in several types of tumors in Australia 
and China, and has initially validated the safety, tolerability and efficacy of SHR-1210 
monotherapy in the treatment of advanced solid tumors. 
This study also involves a product with the trade name of apatinib® and generic name of 
apatinib mesylate tablets (English name: Apatinib Mesylas), a small molecule tyrosine kinase 
inhibitor. The National Medical Products Administration has approved the use of apatinib in the 
treatment of advanced gastric cancer on 17 Nov., 2014. Apatinib has also shown efficacy in a 
phase II clinical study of advanced non-small cell lung cancer (NSCLC) by significantly 
prolonging the progression-free survival (PFS) of patients. 
1.1 Product Name and Physicochemical Properties 
[Generic Name] Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Injection 
(SHR-1210) 
[English Name] SHR-1210 for Injection 
[Molecular Weight] About 143 KD 

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[Dosage Form] Lyophilized Powder for Injection 
[Strength] 200 mg/vial 
[Generic Name] Apatinib Mesylate Tablets 
[English Name] Apatinib Mesylate Tablets 
[Molecular Weight] About 493.58 KD 
[Dosage Form] Tablet 
[Strength] 250 mg/tablet; 375mg/tablet 
1.2 Pharmacology and Mechanism of Action 
Programmed Death-1 (PD-1) is a protein receptor located on the surface of T cells and is 
involved in the process of cell apoptosis. PD-1 belongs to the CD28 family and is mainly 
expressed on activated T cells, B cells and myeloid cells. PD-1 has two ligands, PD-L1 and 
PD-L2. PD-L1 is mainly expressed on T cells, B cells, macrophages and dendritic cells, and its 
expression is up-regulated on activated cells. In contrary, the expression of PD-L2 is mainly 
restricted to antigen presenting cells, such as activated macrophages and dendritic cells. 
Humanized anti-PD-1 monoclonal antibody can specifically bind to PD-1 and block the 
interaction between PD-1 and its ligands, allowing T cells to recover tumor-targeting immune 
responses. 
Apatinib is a potent and selective inhibitor of vascular endothelial growth factor receptor-2 
(VEGFR-2). The activity assay showed that its inhibitory effect against VEGFR-2 is stronger 
than that of drugs of same class (sorafenib, sunitinib, pazopanib, etc.); its selectivity for 
VEGFR-2 is ≥ 30 times stronger than that of other targets (VEGFR-1/PDGFR, SRC, etc.). 
Apatinib can effectively inhibit the in vitro lumen formation of Human Umbilical Vein 
Endothelial Cells (HUVEC) and the formation of arterial ring capillaries in rats, and has a strong 
inhibitory effect against neovascularization. 
1.3 Pharmacodynamics 
Studies on the binding affinity of SHR-1210 antibody to human, monkey and rat antigens 
showed that the affinities of SHR-1210 to human and monkey PD1 antigens were quite close at 
6.9 nM and 4.1 nM, respectively, but no binding was detected with rat PD-1 antigens. The 
binding affinity of SHR-1210 to human PD-1 antigen was 3.0 nM, which was similar to those of 
the control antibodies nivolumab and pembrolizumab. 

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Experimental results from inhibition of PD-1/PD-L1 binding by SHR-1210 showed that the in 
vitro binding inhibition activity of SHR-1210 was comparable to those of nivolumab and 
pembrolizumab. The IC50 of inhibition activities of SHR-1210, nivolumab and pembrolizumab 
were 0.70 nM/0.79 nM and 0.79 nM/0.77 nM, respectively. 
Apatinib can effectively inhibit VEGFR2 (KDR) at very low concentrations and can also inhibit 
VEGFR2 (Flt 1), PDGFR, and c-Kit at higher concentrations. Apatinib is also highly selective. 
See the table below for details. The effect of apatinib on VEGFR2 is 13.7-fold higher than 
PTK787; apatinib also inhibits VEGFR2-mediated downstream signaling. Apatinib also inhibits 
the growth of KDR/NIH3T3 cell lines with high-expression of VEGF, inhibits VEGF-induced 
proliferation, migration and lumen formation of HUVEC cells, and inhibits the germination of 
microvessels on rat arterial rings. Apatinib has remarkable anti-tumor effects on a variety of 
human tumors such as colon cancer, lung cancer, and gastric cancer xenografts in nude mice. 
And it exerts obvious synergistic effects on traditional cytotoxic drugs such as oxaliplatin, 5-Fu, 
docetaxel, and doxorubicin. 
1.4 Toxicology Studies 
In a pre-clinical acute toxicity experiment in cynomolgus monkeys, 8 cynomolgus monkeys (half 
male and half female) were randomly divided into 2 groups. The animals in Group 2 were given 
an intravenous injection of SHR-1210 once every other day at doses of 200, 400, and 800 mg/kg, 
respectively, in a dose-escalation manner. No changes in clinical symptoms, body weight, food 
intake, and coagulation related to SHR-1210 were observed. Lymphocytes decreased for both 
female and male animals at doses ≥ 200 mg/kg. Serum globulin increased and albumin decreased 
at doses ≥ 400 mg/kg. Since the magnitude of these changes was small, they were not considered 
harmful effects. The maximum tolerated dose (MTD) of SHR-1210 was ≥ 800 mg/kg. 
In a completed preclinical repeated dose toxicity study in cynomolgus monkeys, continuous 
intravenous administration of SHR-1210 at 20, 50, and 100 mg/kg/dose for 4 weeks (totaling 
5 doses) were well-tolerated in both sexes. Clinical symptoms, including injection site irritation, 
or changes in body weight, food intake, body temperature, ECG, blood pressure, heart rate, and 
respiratory measurements related to SHR-1210 were not observed. No changes in B and T cell 
differentiation, cytokines, immunoglobulins, and complements were observed. No changes in 
organ weight, gross lesions, or histopathological changes associated with SHR-1210 were observed. 
Apatinib primarily caused slight changes in body weight, food intake, liver function, and bone in 
rats. After 4 weeks of drug discontinuation, all other changes were recovered except that the 
bone changes were partially recovered. 15 mg/(kg·d): The safe dose in male and female rats. 
50 mg/(kg·d): The toxicity dose of male and female rats, and female rats are more sensitive. The 
3 months oral application of 30 mg/(kg·d) of apatinib capsules in Beagle dogs showed no 
significant toxicity. 

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1.5 Pharmacokinetic Study 
1.5.1 
PK of SHR-1210 after administration 
For SHR-1210 PK parameters after a single intravenous infusion in cynomolgus monkeys, see 
Table 1. 
Table 1-1. Pharmacokinetic parameters obtained after a single intravenous infusion of 
different doses of SHR-1210 in cynomolgus monkeys 
Dose 
(mg/kg) Gender 
t1/2 
Tmax 
Cmax 
AUClast 
Vz 
Cl 
MRTlast 
(hr) 
(hr) 
(µg/mL) 
(hr·µg/mL) 
(mL/kg) 
(mL/hr/kg) 
(hr) 
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 
Overall 
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 
Overall 
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 
Overall 
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 
1.5.2 
Pharmacokinetic data of apatinib 
1.5.2.1 Pharmacokinetic studies in healthy population 
Previous studies have found that after a single oral administration of apatinib mesylate in healthy 
subjects under fasting conditions, the parent form drug was absorbed fast in the body and time to 
reach the maximum plasma concentration was about 1.7-2.3 h. Its elimination is slow and its 
half-life was 7.9-9.4 h. The time to reach the maximum plasma concentration of three 
hydroxylated metabolites (cis-3-hydroxy apatinib M1-1, trans-3-hydroxy apatinib M1-2, and 
apatinib-25-N-oxide M1-6) and the hydroxylated and glucuronic acid conjugate (the glucuronic 
acid conjugate of M1-1 is M9-2) were quite late (about 2.7-5.8 h), and their elimination 
half-lives were about 9-18 h. In the 250 mg and 500 mg dose groups, the plasma exposure of 
parent form drug and its four metabolites was directly proportional to the dose, but there was no 
further increase in the plasma exposure of parent form drug and its metabolites in the 750 mg 
dose group. The primary pharmacokinetic parameters of apatinib and its metabolites showed no 
significant gender differences in healthy subjects. 

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1.5.2.2 Pharmacokinetic studies in patients with advanced solid tumors 
The single oral doses used in this study included: 500, 750, and 850 mg/person. The low dose 
group enrolled 7 male and 5 female tumor subjects. The medium dose group enrolled 6 males 
and 3 females. The high dose group enrolled 6 males and 6 females. In this study, the drug was 
administered 0.5 h after meals. Blood and urine samples were collected at multiple time points 
within 48 h. The results showed that M1 was a major metabolite produced by apatinib in 
humans. The AUCM1/AUC of apatinib was 1.15-5.06, the Cum.AeM1/Cum.Ae excretion of 
apatinib in 48 h via urine was 24.5-353. The t1/2 of apatinib and M1 was 8.93 ± 0.81 h and 12.5 ± 
1.666 h, respectively. At the same dose, subjects showed greater individual differences in their 
exposure levels of apatinib and M1 (AUC and Cmax), and only the high dose group showed 
statistically significant gender differences (p < 0.05), with the AUC and Cmax in females 
1.96 times and 3.57 times higher than those in males, respectively. The levels of apatinib and M1 
exposure in male and female subjects were not dose-proportional but were positively correlated 
to oral doses. 
1.5.2.3 Food-effect studies 
The food-effect study mainly compared the differences in absorption of a single oral dose of 
apatinib given at 1 h before meals and 0.5 h after meals. The concentrations of M1 were also 
examined. Blood and urine samples were collected at multiple time points within 48 h. The 
results showed that there was no significant difference in the Tmax and Cmax of apatinib in the 
blood of male and female subjects with respect to the order of eating and drug administration 
(P > 0.05). In addition, the AUC, t1/2 and Cum.Ae of apatinib, and relevant pharmacokinetic 
parameters of M1 were not affected by the order of eating and drug administration (P > 0.05). 
1.6 Results of Tolerability in the Clinical Studies 
Based on the modified Fibonacci method, the initially designed doses of apatinib were 250 mg, 
500 mg, 750 mg, 850 mg, and 1000 mg. According to the study design, the Grade 4 hematological 
toxicity and/or Grade ≥ 3 non-hematological toxicity occurring in the first course of treatment 
(28 days) were determined as DLT. A total of 19 patients were evaluable for tolerability, with 
6 patients in the 850 mg dose group and 3 patients each in remaining dose groups. 
The DLT of apatinib appeared in the 1000 mg dose group, which was characterized by Grade 3 
hypertension and Grade 3 hand-and-foot syndrome. Among the 3 patients, 2 patients had Grade 3 
hypertensive toxicity and 1 patient had Grade 3 hand-and-foot syndrome. The toxicity could be 
controlled by delaying the dose and resuming treatment at a reduced dose after the toxicity was 
alleviated. In the additional 850 mg dose group, none of the 6 patients showed DLT. For further 
safety considerations, the observation time of the 850 mg group was extended to two cycles and 
DLT was still not present, thus 850 mg was identified as the maximum tolerated dose. 

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In the first course of apatinib treatment, the primary manifestations of toxicity were: 
Hypertension (10/16), hand-and-foot syndrome (7/16), bone marrow suppression (7/16), oral 
ulcers (5/16), esophagitis (2/16), chest and back pain (2/16), hoarse voice (2/16), asthenia (2/16), 
diarrhea (1/16), and proteinuria (1/16). 
In the 750 mg and lower dose groups, hematological toxicities were all Grade 1-3, including 
leukopenia and thrombocytopenia, while other non-hematological toxicities were all Grade 1-2, 
which could recover to normal after symptomatic treatment. 
1.7 Progress in Stage I Clinical Studies 
1.7.1 
Progress in the clinical studies of SHR-1210 
The phase I clinical study of SHR-1210 was launched in Australia in 2015. Since it was issued 
with the approval for the clinical study of national class I new drug (certificate no. 2016L01455) 
in February 2016, it had been tested in phase I clinical studies at Cancer Hospital Chinese 
Academy of Medical Sciences, Sun Yat-sen University Cancer Center, and Beijing Cancer 
Hospital against multiple types of solid tumors (primarily nasopharyngeal carcinoma, non-small 
cell lung cancer, triple negative breast cancer, melanoma, and various GI cancers). The study 
focused on human safety and tolerability of SHR-1210, and examined the pharmacokinetic 
characteristics and preliminary efficacy of SHR-1210 in humans. The study adopted a classic 
3+3 dose escalation method to investigate the safety and tolerability of SHR-1210 in humans. A 
dose expansion group was set up to investigate the preliminary efficacy and safety of SHR-1210. 
Preliminary results indicated that SHR-1210 was safe and tolerable with a certain preliminary 
efficacy in a variety of solid tumors, including non-small cell lung cancer. 
Up to now (data as of 31 Oct., 2016), 111 subjects with solid tumor have been enrolled in China 
and abroad, including 87 subjects enrolled in China. Tolerability observation showed that 
different doses of SHR-1210 (1 mg/kg, 3 mg/kg, 10 mg/kg and fixed doses of 60 mg, 200 mg, 
and 600 mg) were well tolerated in human, and no DLT was observed in any of the dose groups 
during the observation period, i.e., the maximum tolerated dose (MTD) is greater than 10 mg/kg 
or the fixed dose of 600 mg. 
In terms of safety, the overall incidence of adverse events (AEs) in domestic studies was 77% 
(67/87), which were primarily skin reactions, fever, hypothyroidism, transaminase increased, and 
gastrointestinal reactions. The AEs were mostly related to the mechanism of drug action, and 
were mostly mild to moderate. After symptomatic treatment or interruption of SHR-1210, the 
AEs were resolved or disappeared. 
The investigator determines that the incidence of SHR-1210-related AEs was 59.8% (52/87), and 
the most were mild to moderate as shown in the table below: 

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Treatment-related AEs in three phase I clinical studies of SHR-1210 in China (data as of 
31 Oct., 2016) 
System Organ Class/Preferred Term 
 
 
 
Total 
(N = 67) 
67 (77.0%) 
Number of Subjects with at Least One 
Event 
 
 
 
Investigations 
22 (25.3%) 
Skin and Subcutaneous 
Tissue Disorders 
36 (41.4%) 
Gastrointestinal 
Disorders 
7 (8.0%) 
Alanine 
Aminotransferase 
Increased 
7 (8.0%) 
Hemangioma of skin 
32 (36.8%) 
Nausea 
2 (2.3%) 
Aspartate 
Aminotransferase 
Increased 
7 (8.0%) 
Rash 
7 (8.0%) 
Diarrhea 
2 (2.3%) 
White Blood Cell Count 
Decreased 
3 (3.4%) 
Pruritus 
6 (6.9%) 
Abdominal 
Distension 
1 (1.1%) 
Blood Bilirubin 
Increased 
3 (3.4%) 
Rash Maculo-Papular 
3 (3.4%) 
Mouth 
Ulceration 
1 (1.1%) 
Electrocardiogram QT 
prolonged 
2 (2.3%) 
Flushed skin 
1 (1.1%) 
Vomiting 
1 (1.1%) 
Elevated CR-MB 
2 (2.3%) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
1 (1.1%) 
Constipation 
1 (1.1%) 
Troponin increased 
1 (1.1%) 
Urticaria 
1 (1.1%) 
 
 
White Blood Cell Count 
Increased 
1 (1.1%) 
 
 
Blood and 
Lymphatic 
System 
Disorders 
4 (4.6%) 
Neutrophil count 
decreased 
1 (1.1%) 
General Disorders and 
Administration Site 
Conditions 
18 (20.7%) 
Anemia 
4 (4.6%) 
Blood Thyroid 
Stimulating Hormone 
Increased 
1 (1.1%) 
Pyrexia 
9 (10.3%) 
 
 
Blood prolactin 
increased 
1 (1.1%) 
Asthenia 
5 (5.7%) 
Nervous System 
Disorders 
3 (3.4%) 
Blood myoglobin 
increased 
1 (1.1%) 
Fatigue 
4 (4.6%) 
Insomnia 
1 (1.1%) 
Blood creatine 
phosphokinase increased 
1 (1.1%) 
Chills 
1 (1.1%) 
Headache 
1 (1.1%) 
Blood Creatinine 
Increased 
1 (1.1%) 
 
 
Dizziness 
1 (1.1%) 
Hypokalaemia 
1 (1.1%) 
Endocrine Disorders 
9 (10.3%) 
 
 
 
 
Hypothyroidism 
8 (9.2%) 
Hepatobiliary 
Disorders 
2 (2.3%) 
 
 
Hyperthyroidism 
1 (1.1%) 
Hepatic 
function 
abnormal 
2 (2.3%) 
 
 
 
 
 
 

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System Organ Class/Preferred Term 
 
 
 
Total 
(N = 67) 
67 (77.0%) 
Number of Subjects with at Least One 
Event 
 
 
 
 
 
Metabolism and Nutrition 
Disorders 
7 (8.0%) 
Infections and 
Infestations 
1 (1.1%) 
 
 
Decreased Appetite 
3 (3.4%) 
Conjunctivitis 
1 (1.1%) 
 
 
Hypertriglyceridaemia 
2 (2.3%) 
 
 
 
 
Oedema Peripheral 
1 (1.1%) 
Immune System 
Disorders 
1 (1.1%) 
 
 
Hyperglycaemia 
1 (1.1%) 
Anaphylaxis 
1 (1.1%) 
The incidence of Grade 3 or greater AEs was 10.3%, and the incidence of Grade 3 or greater 
treatment-related AEs was 2.3%. Grade 3 or greater AEs are shown in the table below: 
Grade 3 or greater AEs in three phase I clinical studies of SHR-1210 in China (data as of 
31 Oct., 2016) 
System Organ Class/Preferred Term 
Total (N = 67) 
Number of Subjects with at Least One Event 
67 (77.0%) 
Highlighted are treatment-related AEs as judged by the investigator 
Investigations 
5 (5.7%) 
Gastrointestinal Disorders 
 
2 (2.3%) 
Hypochloraemia 
2 (2.3%) 
Abdominal Pain 
 
1 (1.1%) 
Hyponatraemia 
2 (2.3%) 
Upper Gastrointestinal 
Haemorrhage 
 
1 (1.1%) 
Aspartate Aminotransferase Increased 
2 (2.3%) 
 
 
 
Blood Bilirubin Increased 
1 (1.1%) 
Metabolism and Nutrition 
Disorders 
 
1 (1.1%) 
Hypophosphatemia 
1 (1.1%) 
Hypercalcaemia 
 
1 (1.1%) 
Alanine Aminotransferase Increased 
1 (1.1%) 
 
 
 
Elevated CR-MB 
1 (1.1%) 
Hepatobiliary Disorders 
 
1 (1.1%) 
 
 
Hepatic function abnormal 
 
1 (1.1%) 
General Disorders and Administration 
Site Conditions 
3 (3.4%) 
 
 
 
Pyrexia 
1 (1.1%) 
Musculoskeletal and Connective 
Tissue Disorders 
 
1 (1.1%) 
Progressive disease 
1 (1.1%) 
Back pain 
 
1 (1.1%) 
Death 
1 (1.1%) 
Lumbago 
 
1 (1.1%) 
 
 
 
 
 
Blood and Lymphatic System 
Disorders 
2 (2.3%) 
Endocrine Disorders 
 
1 (1.1%) 
Anemia 
2 (2.3%) 
Hypothyroidism 
 
1 (1.1%) 
Preliminary safety data indicated that the overall safety of the SHR-1210 was acceptable. 

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The assay of PD1 receptor binding rate showed that a single dose of 1 mg/kg of SHR-1210 could 
achieve > 80% PD1 receptor occupancy, and the receptor binding effect of SHR-1210 was 
continuous. This indicates that the clinical dose of SHR-1210 is able to achieve a sustained and 
high binding rate to PD1, so as to play a role in overcoming tumor immune escape. 
The pharmacokinetic study of SHR-1210 in patients with advanced solid tumors showed that the 
in vivo exposure (AUC) and Cmax of SHR-1210 increased proportionally with the increasing dose 
of the drug, and no pharmacokinetic saturation was observed. The elimination half-life (t1/2) of 
SHR-1210 in human is about 3.5 d (1-3 mg/kg), and the t1/2 of a fixed dose of 200 mg is 5.83 ± 
0.91 d, supporting q2w (14 d/dose) administration. 
In terms of efficacy, as of 15 Nov., 2016, clinical studies in China showed a preliminary efficacy 
of SHR-1210 against solid tumors that have failed multiple standard treatments.The overall 
objective response rate (ORR) was 20.8% (10/48); the disease control rate (DCR) was 41.7% 
(20/48). Among them, the objective response rate (ORR) of SHR-1210 in non-small cell lung 
cancer was 9.1% (1/11), and the disease control rate (DCR) was 45.5% (5/11). The efficacy of 
SHR-1210 was also similar to the efficacy data reported by drugs of the same class, and 
SHR-1210 had a longer duration of tumor response/benefit. Subjects with objective tumor 
response or stability had a longer duration of response/benefit (this was an observed trend due to 
ongoing studies and lack of exact data support). 
The phase I clinical studies of SHR-1210 in patients with advanced solid tumors have shown that 
SHR-1210 has excellent safety and tolerability; PK, PD characteristics and worth exploring 
preliminary efficacy. 
1.7.2 
Progress in the clinical studies of apatinib 
1.7.2.1 Stage I tolerability study of apatinib 
According to the modified Fibonacci method, the designed doses of apatinib were 250 mg, 
500 mg, 750 mg, 850 mg, and 1000 mg. According to the study design, the Grade 4 
hematological toxicity and/or Grade ≥ 3 non-hematological toxicity occurring in the first course 
of treatment (28 days) were determined as dose limiting toxicity (DLT). A total of 18 subjects 
were evaluable for tolerability, with 3 subjects in each dose group (6 subjects in the 850 mg dose 
group). DLT appeared in the 1000 mg dose group and was featured as Grade 3 hypertension (2/3) 
and Grade 3 hand and foot skin reactions (1/3). In the additional 850 mg dose group, none of the 
6 patients showed DLT. Therefore, the 850 mg dose was identified as the maximum tolerated 
dose (MTD). 

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The primary AEs in Cycle 1 of the tolerability test included: hand and foot skin reaction, 
hypertension, leukopenia, oral mucositis, fever, thrombocytopenia, asthenia, bilirubin increased, 
headache, abdominal pain, nausea, and transaminases increased. The most AEs were mild to 
moderate. Treatment-related adverse reactions primarily included hand and foot skin reactions, 
leukopenia, hypertension, fever, bilirubin increased, oesophagitis, dermal toxicity, 
thrombocytopenia, nausea, asthenia, headache, transaminases increased, oral mucositis, upper 
abdominal discomfort, tongue pain, hoarseness, stomach discomfort, chest tightness and cough, 
proteinuria, and sinus bradycardia. In groups of 850 mg and lower doses, hematological 
toxicities were Grade 1-3, while other non-hematological toxicities were all Grade 1-2, which 
could recover to normal after symptomatic treatment. 
1.7.2.2 Phase I clinical pharmacodynamic (PD) observation of apatinib 
From May 2007 to Dec. 2008, a phase I clinical study of apatinib was conducted at Fudan 
University Shanghai Cancer Center, including 3 studies, i.e., a tolerability study, a 
pharmacokinetic study, and a phase I supplement clinical study. A total of 81 subjects with 
advanced solid tumors were enrolled. Nine of the subjects were not evaluated, and another 3 
subjects were only administered with a low dose of 250 mg/day. A total of 69 subjects received 
apatinib treatment at doses of 500-1000 mg/day (only 3 subjects received 1000 mg/day), and a 
total of 56 patients were evaluated. Of the 69 subjects included in the statistics, 16 subjects were 
given 500 mg, 37 subjects were given 750 mg, 13 subjects were given 850 mg, and 3 subjects 
were given 1000 mg.  
Table 1. Efficacy of apatinib in the treatment of different solid tumors 
 
Gastric 
Cancer 
Colorectal 
Cancer 
Lung 
Cancer 
Breast 
Cancer 
Nasopharyngeal 
Carcinoma 
Renal 
Cancer 
Esophageal 
Cancer 
Hepatic 
Cancer 
Small 
Intestinal 
Stromal 
Tumor 
Neurilemmoma 
Malignant of 
Left Iliac Fossa 
Not 
Evaluable 
1 
7 
1 
1 
1 
0 
1 
1 
0 
0 
CR 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
PR 
2 
2 
0 
0 
0 
1 
0 
0 
1 
0 
SD 
5 
15 
3 
4 
1 
0 
4 
1 
0 
0 
PD 
1 
7 
1 
2 
0 
0 
0 
0 
0 
1 
Death Without 
Evaluation 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
Objective 
Response 
Rate 
18.1% 
8% 
0 
0 
0 
100% 
0 
0 
100% 
0 
Disease 
control rate 
63.6% 
68% 
75% 
66.7% 
100% 
100% 
100% 
100% 
100% 
0 
Total 
12 
32 
5 
7 
2 
1 
5 
2 
1 
1 

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The results showed that, objective response rate: 1 subject each of renal cancer and small 
intestinal stromal tumor both had efficacy of PR; 11 and 25 evaluable patients were included for 
the gastric cancer and colorectal cancer respectively, and higher response rates of 18.1% and 8%, 
respectively, were achieved. Disease control rate: 1 evaluable subject each for nasopharyngeal 
carcinoma, hepatic cancer, and GIST, respectively, and their efficacy was all SD; the disease 
control rates of evaluable patients of esophageal cancer, lung cancer, and breast cancer were 
100%, 75% and 66.7%, respectively. However, the efficacy is still difficult to determine due to 
the small number of subjects. 
1.7.2.3 Stage I clinical pharmacokinetic studies of apatinib 
A single oral dose study of apatinib was performed at doses of 500, 750, and 850 mg, and all 
drug administration was performed 0.5 h after meals. Blood and urine samples were collected at 
multiple time points within 48 h post-administration. The results showed that M1 was a major 
metabolite produced by apatinib in humans. The AUCM1/AUC of apatinib was 1.15-5.06, and 
the Cum.AeM1/Cum.Ae excretion of apatinib in 48 h via urine was 24.5-353. The t1/2 of apatinib 
and M1 was 8.93 ± 0.81 h and 12.5 ± 1.666 h, respectively. At the same dose, subjects showed 
greater individual differences in their exposure levels of apatinib and M1 (AUC and Cmax), and 
only the high dose group showed statistically significant gender differences (p < 0.05), with the 
AUC and Cmax in females 1.96 times and 3.57 times higher than those in males, respectively. The 
levels of apatinib and M1 exposure in male and female subjects were not dose-proportional but 
were positively correlated to oral doses. 
The multiple-dose study focused on investigating the accumulation of M1 in the body and 
observing the concentration change of apatinib (t1/2: 9.24 ± 1.40 h) during the study. The drug 
was administered once a day for 4 weeks, and blood and urine samples at multiple time points 
within 24 h post-administration were collected on Day 1, 14, and 28 after the start of the study. 
The results of the study showed that M1 and apatinib did not significantly accumulate in the 
subjects based on the comparison of the values obtained on Day 1 and Day 14 after the start of 
the study (P > 0.05). However, the M1 exposure level in male subjects significantly increased on 
Day 28 compared with that on Day 1 (P < 0.05). There was no significant accumulation of 
apatinib and M1 based on the cumulative levels of urinary and renal excretion (P > 0.05). 
Food impact experiment: The results showed that there was no significant difference in the Tmax 
and Cmax of apatinib in the blood of male and female subjects with respect to the order of eating 
and drug administration (P > 0.05). In addition, the AUC, t1/2 and Cum.Ae of apatinib, and 
relevant pharmacokinetic parameters of M1 were not affected by the order of eating and drug 
administration (P > 0.05). 

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1.7.2.4 Phase II clinical study results of apatinib in the treatment of advanced 
non-squamous and non-small cell lung cancer 
The phase II clinical study of apatinib in the treatment of advanced non-squamous non-small cell 
lung cancer enrolled a total of 138 subjects, with 92 subjects in the treatment group and 46 
subjects in the placebo group. A total of 136 subjects completed the study (2 patients obtained 
random numbers but withdrew from the study without using the drug), including 68 males and 
68 females. Among these 136 subjects, 45 subjects were in the placebo group and 91 subjects 
were in the treatment group. There were 4 dropouts in the study and the drop-out rate was 2.94%; 
2 subjects were rejected and the rejection rate was 1.47%. 
The analysis of primary efficacy endpoints showed that in the FAS analysis set, the patients’ 
mPFS in the treatment group was significantly higher than that in the placebo group (4.7 months 
vs. 1.9 months), and the difference was statistically significant (P < 0.0001). The hazard ratio 
between the treatment group and the placebo group was 0.278, and its 95% CI was 0.170-0.455 
(P < 0.0001). In terms of secondary efficacy endpoints, in the FAS analysis set, the apatinib 
group showed a good efficacy by improving the objective response rate and clinical benefit rate 
of the patients compared with the placebo group. The objective response rate was 16.67% in the 
treatment group and 0% in the placebo group. The difference between the two groups was 
statistically significant at P = 0.0158. The objective response rate of the treatment group was 
higher than that of the placebo group. The disease control rate was 68.89% in the treatment 
group and 24.44% in the placebo group. The difference between the two groups was statistically 
significant at P < 0.0001. The disease control rate of the treatment group was higher than that of 
the placebo group. 
The primary adverse reactions were hypertension, proteinuria, thrombocytopenia, leukopenia, 
hand-and-foot syndrome, and bilirubin increased. Most of adverse reactions were mild to 
moderate, and relieved after symptomatic treatment. Apatinib showed a good safety profile. 
Combining the characteristics of two types of drugs, SHR-1210 can achieve sustained effective 
disease response/control in clinical applications by acting as an immunotherapy; it is proven that 
apatinib has significant efficacy in non-small cell lung cancer - it significantly prolongs PFS with 
a high tumor response rate. The combination therapy of SHR-1210 and apatinib may improve the 
short-term objective response rate of tumors while maintaining the sustained efficacy of 
immunotherapy. In addition, previous animal experiments have shown that the combination 
therapy of SHR-1210 and apatinib can show synergy in their anti-tumor efficacy (data to be 
published). In this study, a fixed dose of 200 mg SHR-1210 is selected (studies on drugs of same 
class has confirmed that in the sensitive population, the high dose group had a better efficacy 
than the low dose group); a 500 mg dose of apatinib (q.d.) will be administered in combination 

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(the preliminary results of the study indicated that at a dose of 750 mg apatinib, the rates of 
toxicity-induced dose interruption and reduction were high). At the same time, considering the 
continuity of the efficacy of SHR-1210, the combination therapy will be administered for a long 
time. In order to ensure the tolerability of long-term drug administration, another dose of 250 mg 
of apatinib (q.d.) and a fixed dose of 200 mg of SHR-1210 were chosen for the combination 
therapy. A two-stage design will be used, with safety and tolerability observations carried out in 
Stage I, and efficacy and long-term safety observations carried out in Stage II. The objective is to 
evaluate the safety and efficacy of the combination therapy of SHR-1210 and apatinib in the 
treatment of advanced non-small cell lung cancer. 
This study will investigate the combination therapy of a small molecule drug apatinib mesylate 
targeting the VEGFR signaling pathway and anti-PD-1 antibody SHR-1210 in the treatment of 
advanced non-small cell lung cancer, to meet the urgent needs for new options of clinical 
treatment. The combination therapy has a good basis of study and relatively controllable risk, 
and some patients are expected to benefit from this treatment regimen and help to promote the 
optimization of the regimen. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
Primary objective of Stage I study: 
To evaluate the tolerability and safety of anti-PD-1 antibody SHR-1210 plus apatinib mesylate in 
patients with advanced NSCLC 
Secondary objectives of Stage I study: 
1) To evaluate the pharmacokinetics of anti-PD-1 antibody SHR-1210 plus apatinib mesylate in 
patients with advanced NSCLC 
2) To preliminarily evaluate the efficacy of anti-PD-1 antibody SHR-1210 plus apatinib 
mesylate in patients with advanced NSCLC 
Objectives of Stage II study: 
To observe and evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 plus apatinib 
mesylate in patients with advanced non-small cell lung cancer 

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2.2 Endpoints 
Primary endpoints: 
Stage I: 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
Stage II: 
Tumor objective response rate (ORR) 
Secondary endpoints: 
Stage I: 
Plasma concentrations of SHR-1210 and apatinib 
Pharmacokinetic parameters of SHR-1210 and apatinib, including t1/2; Cmax; AUC, etc. 
Tumor objective response rate (ORR) 
Stage II: 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
Stages I and II: 
Clinical benefit rate (CBR): Proportion of subjects with CR, PR, or SD ≥ 6 months during the 
study 
Duration of response (DoR) 
Time to response 
Progression free survival (PFS) based on RECIST 1.1 
12-month survival 
Overall survival (OS) 
Exploratory analysis of the relationship between biomarkers and efficacy 

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3 STUDY DESIGN 
3.1 Overview of Study Design 
Study design of Stage I: 
A multi-arm, multi-center, open-label clinical study. 
Inclusion criteria: Patients with advanced NSCLC who have failed standard treatment. 
Three dose groups, i.e., 250 mg apatinib, oral, q.d. + 200 mg SHR-1210, IV, q2W, 375 mg 
apatinib, oral, q.d. + 200 mg SHR-1210, IV, q2W, and 500 mg apatinib, oral, q.d. + 200 mg 
SHR-1210, IV, q2W are set up. Ten to twelve subjects will be enrolled in each dose group (to 
make sure that at least 10 subjects will complete the tolerability evaluation), and the first cycle 
(28 days) of continuous treatment will be used as the observation period for tolerability. A dose 
will be considered tolerable if the proportion of subjects with clinically significant toxicity is 
< 0.33. 
Tolerability observation will be performed sequentially from the low dose group to the high dose 
group, and the tolerability observation of a latter dose group can only be carried out after the 
previous dose group is confirmed to be tolerable. 
The first 3 subjects in each dose group will be enrolled on a case-by-case basis with an interval 
of not less than 14 days, and subsequent subjects can be enrolled at the same time. 
After completing the tolerability observation period, subjects will continue the treatment until 
occurrence of any event that meets the criteria for discontinuation. 
After the completion of the tolerability observation in Stage I, the study will enter Stage II for 
further observation of efficacy and safety. 
In addition, after a certain dose group completes the tolerability observation in Stage I and is 
confirmed as tolerable, 10 to 12 subjects will be enrolled into this dose group for an expanded 
pharmacokinetic study. In cycle 1 of the expanded PK study, one dose of SHR-1210 will be 
administered on D1 followed by PK blood sampling. Then, apatinib will be started on D22 after 
the completion of PK blood sampling, while another PK blood sampling will be carried out on 
D28. Starting from D1 in cycle 2, SHR-1210 will be administered once every 14 days, while 
apatinib will be administered orally every day. PK blood sampling will be carried out on D1 of 
cycle 2 after the administration of SHR-1210 and on D28 after the administration of apatinib. 
After the blood sampling is completed, the subjects will continue to receive the study treatment 
until an event meeting the criteria of study termination occurs. 

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Design of Stage II Study: 
A single-arm/double-arm, multicenter, open-label clinical study. 
According to the results of tolerability observation in Stage I and upon the discussion between 
the sponsor and the principal investigators, 250 mg of apatinib, q.d. oral + 200 mg of SHR-1210, 
IV, q2W are selected for the Stage II study. 
Patients of advanced NSCLC who have failed first-line chemotherapy or patients of 
non-squamous and non-small cell lung cancer with a high tumor mutation burden (TMB) 
confirmed by the central laboratory will be enrolled in the Stage II study. According to the 
molecular and pathological classifications, the subjects are divided into: 
Cohort 1. Non-squamous, non-small cell lung cancer with wild-type EGFR and ALK; 
Cohort 2. Non-small cell lung cancer with EGFR mutation or ALK fusion gene rearrangement. 
The subjects harboring sensitive EGFR mutations and ALK fusion gene rearrangement must 
have failed the treatment of at least one EGFR inhibitor or ALK inhibitor; 
Cohort 3. Non-central squamous cell lung cancer; 
Cohort 4. Non-squamous and non-small cell lung cancer with wild-type EGFR and ALK and 
with bTMB ≥ 1.54 muts/Mb or tTMB > 10 muts/Mb confirmed by central laboratory. 
The enrolled subjects are treated until the occurrence of any event that meets the criteria for 
discontinuation, so as to further evaluate the efficacy and safety of SHR-1210 in combination 
with apatinib in patients with advanced NSCLC. 
3.1.1 
Definition of clinically significant toxicity 
1. Grade 4 hematological toxicity or Grade ≥ 3 thrombocytopenia with hemorrhage, 
Grade ≥ 3 neutropenia with fever and infection; 
2. Grade ≥ 3 non-hematological toxicity (except for abnormal laboratory test 
parameters), hypertension, rash, diarrhea, nausea, and vomiting that cannot be 
controlled after symptomatic treatment; 
3. Grade ≥ 3 abnormal laboratory test parameters that lead to medical intervention, 
hospitalization, or lasting for ≥ 7 days; 
4. SHR-1210 interruption for > 14 days due to relevant toxicity (delayed 
administration in Cycle 1 or Cycle 2); 
5. Apatinib interruption for > 7 days due to relevant toxicity. 

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3.1.2 
Definition of subjects with incomplete tolerance evaluation: 
During the observation period of tolerability, the dose of SHR-1210 is < 90% of the prescribed 
dose due to non-clinically significant toxicity (such as injection reactions). 
Subjects who do not complete the tolerability evaluation will not be included in the overall 
number of subjects undergoing tolerability evaluations, and each dose group is required to have 
≥ 10 subjects for the tolerability observation. 
Exemption: If ≥ 7 subjects in a dose group do not develop clinically significant toxicity during 
the tolerability observation period, the dose group is considered to be tolerable and no new 
subjects will be enrolled into this dose group. 
3.1.3 
Follow-up treatment of subjects with clinically significant toxicity 
In the observation period of tolerability, the subjects with clinically significant toxicity may 
receive subsequent combination therapy of SHR-1210 and apatinib based on the investigator's 
judgment after they have recovered from toxicity: interrupt, reduce (for subjects using 500 mg/d 
or 375 mg/d apatinib) or discontinue apatinib administration according to the dose modification 
principles, or discontinue the treatment. Subjects will also be followed up and their data will be 
collected according to the study procedure. 
3.2 Pharmacokinetic Study 
3.2.1 
Study procedure and arrangement of blood sampling points 
After the completion of the tolerability observation, 10 to 12 subjects will be enrolled in each 
dose group for an expanded pharmacokinetic study. In the expanded pharmacokinetic study, 
one dose of SHR-1210 will be administered on D1 of Cycle 1 (28 d) via intravenous infusion. 
Pharmacokinetic blood sampling will be performed within 0.5 h pre-dose, and at 5 min 
(± 5 min), 2 h (± 10 min) and 6 h (± 10 min) after the administration of SHR-1210 on D1, and on 
D2 (24 h, ± 1 h), D3 (48 h, ± 1 h), D8 (168 h, ± 1 h), D15 (336 h, ± 1 h) and D22 (504 h, ± 1 h), 
with 3 mL of blood collected at each time point. After the completion of pharmacokinetic blood 
sampling on D22, the administration of apatinib mesylate tablets (250 mg/tablet·1 tablet, 
375 mg/tablet·1 tablet or 250 mg/tablet·2 tablets) will be started on the same day and continues 
at a administration frequency of once a day. Pharmacokinetic blood sampling will be performed 
within 0.5 h pre-dose on D28 and at 0.5 h (± 5 min), 1 h (± 5 min), 2 h (± 5 min), 3 h (± 5 min), 
5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h) after the administration, with 
3 mL of blood collected at each time point. 

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On D1 of Cycle 2, PK blood sampling will be performed within 0.5 h before the administration 
of SHR-1210, and at 5 min (± 5 min), 2 h (± 10 min) and 6 h (± 10 min) on D1, D2 (24 h, ± 1 h), 
D3 (48 h, ± 1 h), D8 (168 h, ± 1 h), and D15 (336 h, ± 1 h) post-administration, with 3 mL of 
blood collected at each time point. On D28 of Cycle 2, PK blood sampling will be performed 
within 0.5 h before the administration of apatinib, and at 0.5 h (± 5 min), 1 h (± 5 min), 2 h 
(± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h) 
post-administration, with 3 mL of blood collected at each time point. 
There will be a total of 35 blood sampling points. After the blood sampling is completed, the 
subjects will continue to receive the study treatment until an event meeting the criteria of study 
termination occurs. 
If a subject interrupts the administration of apatinib during the period of pharmacokinetic blood 
sampling due to adverse events and if the interruption of apatinib occurs during C1D22-D28, the 
subject will not be subject to pharmacokinetic blood sampling in the future and will be deemed 
as not completing the pharmacokinetic study; if the interruption of apatinib occurs during 
C2D23-C2D28, the pharmacokinetic blood sampling will not be carried out on C2D28. Then, 
after the administration of apatinib is resumed and continued for 7 days, the administration of 
apatinib and the blood sampling will be carried out on D7 according to the administration 
method of apatinib (administration under fasting) and the time points of blood sampling 
specified for C2D28. 
If the administration of SHR-1210 can not be carried out normally during C2D1-C2D28 due to 
adverse events, the pharmacokinetic blood sampling will not be performed starting from C2D1 
and the subject will be deemed as not completing the pharmacokinetic study. 
The administration of SHR-1210 should be performed at the scheduled time on C2D1 of the 
pharmacokinetic study, and no time window for delayed administration is set. The delayed 
administration of SHR-1210 on C2D15 is allowed as long as the time of administration does not 
exceed the planed time by more than 3 days. 
Substitution of subjects is required for those who have not completed the pharmacokinetic study 
to ensure that 10 to 12 subjects can complete the pharmacokinetic study. 
Subjects who have not completed pharmacokinetic blood sampling may continue to receive the 
study drug according to the investigator's judgment until an event meeting the criteria for 
treatment discontinuation occurs. 

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3.2.2 
Blood sample processing and testing 
Blood sampling will be carried out before and after the administration of SHR-1210 on D1-D22 
of Cycle 1 and D1-D15 of Cycle 2, with 3 mL of whole blood collected into an coagulation tube 
at each blood sampling time point, and the coagulation tube should be inverted several times to 
mix the blood sample evenly. After placing the blood sample at room temperature for 30 min, it 
should be centrifuged at 4 °C and 1500 g (centrifugal force) for 10 min; then, the supernatant 
will be aliquoted into 2 tubes (about 500 μL per tube). 
Blood sampling will be carried out before and after the administration of apatinib on D28 of 
Cycle 1 and D28 of Cycle 2, with 3 mL of whole blood collected into an anti-coagulation tube at 
each blood sampling time point, and the anti-coagulation tube should be inverted several times to 
mix the blood sample with the anticoagulant in the tube. Blood samples will be centrifuged 
within 30 min after blood sampling at 4 °C and 1500 g (centrifugal force) for 10 min; the 
supernatant will be aliquoted into 2 tubes (at least 500 μL per tube). 
After being well-marked, the separated plasma/serum samples are temporarily kept in a freezer at 
-20 °C or below, or at -60 °C for a longer period prior to future testing. 
Each sample will be assigned with a unique sample number. The actual date and time of blood 
sampling as well as the exact time of drug administration should be recorded on the PK blood 
sampling page of the eCRF. The problems encountered during blood sampling should be noted in 
the eCRF. 
3.3 Collection of Biomarker Samples 
For all enrolled subjects, their blood samples will be collected at baseline. For subjects showing 
CR/PR during the study, their blood samples will be collected during the first evaluation of 
CR/PR and the first evaluation of PD, with 10 mL of blood samples collected each time (14 mL 
of blood will be collected at baseline and divided into two tubes, with 10 mL in one tube and 
4 mL in the other tube). These blood samples will be sent to the central laboratory for 
blood-based detection of tumor mutation burden (TMB), while the detection of circulating tumor 
cells (CTC) and the detection of PD-L1 based on circulating tumor cells (CTC) will also be 
performed in the baseline period. See the central laboratory manual for blood sampling, disposal, 
and transportation. 
For subjects participating in the Stage II of the study, their tumor tissue samples will be collected 
at baseline. Among these tumor tissue samples, 3-5 slices of 3-4 μm thick paraffin tissue sections 
will be sent to the central laboratory for the detection of levels of PD-L1 and tumor-associated 
macrophages (TAM) in tumor tissues; 5-8 slices of 5-8 μm thick tumor biopsy samples or 
paraffin tissue sections collected before the first dose will also be sent to the central laboratory 

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for the detection of TMB level in tumor tissues. The biopsy samples can be directly sent to the 
central laboratory through cold chain transportation. Paraffin blocks can be directly sent to the 
central laboratory without mounting onto slides. See the central laboratory manual for tissue 
sampling and transportation. 
In order to avoid the impact of previous treatment on tumor mutation burden, the tumor tissue 
samples should be collected from biopsy or surgical resection carried out at a time point closest 
to the first dose for the detection of TMB levels. 
4 RANDOMIZATION AND BLINDING 
4.1 Randomization 
Subjects will not be randomized in the tolerability observation period of Stage I. The tolerability 
observation will be carried out first for the dose group of 250 mg apatinib, oral, q.d. + 200 mg 
SHR-1210, IV, q2W. After it is confirmed that the dose group of 250 mg apatinib, oral, q.d. + 
200 mg SHR-1210, IV, q2W is safe and tolerable, the tolerability observation for the dose groups 
of 375 mg and 500 mg apatinib, oral, q.d. + 200 mg SHR-1210, IV, q2W will be carried out in 
sequence. 
After completing the tolerability observation of a group, 10 to 12 additional subjects will be 
enrolled in each group for an expanded pharmacokinetic (PK) study. 
If two doses are selected for the Stage II, the subjects enrolled in Stage II will be randomized in a 
1:1 ratio using the randomization system provided by Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
into two groups for observation. 
4.2 Blinding 
This study is an open-label study and does not involve blinding. 
5 SUBJECT SELECTION AND WITHDRAWAL/DISCONTINUATION 
5.1 Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for this study: 
1. Male and female patients aged 18-70 years old; 
2. Pathologically confirmed advanced (Phase IIIB and IV) non-small cell lung cancer with 
at least one measurable lesion that meets the RECIST v1.1 criteria and has not been 
treated locally; 
3. Able to provide previous tumor samples or agree to cooperate with biopsy (Stage II); 

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4. Stage I: Patients who have undergone the second-line and above chemotherapy (at least 
one of the previous chemotherapy regimens is a platinum-based chemotherapy doublet 
regimen) but failed the treatment or showed recurrence. The patients harboring EGFR 
mutations and ALK gene abnormalities must have failed the treatment with an EGFR 
inhibitor or ALK inhibitor.  
Stage II: Patients who have undergone only one previous platinum-based doublet 
chemotherapy but failed the treatment or showed recurrence, or patients in the stage of 
palliative treatment who have received no systemic treatment (only for cohort 4). 
a. The replacement of platinum drugs due to drug toxicity will be considered as one 
treatment regimen; 
b. Postoperative adjuvant chemotherapy will not be counted as one previous 
chemotherapy regimen if the time from the end of treatment to recurrence 
is > 6 months. 
According to the type of driver gene mutations and pathological classification, the 
subjects will be divided into the following four cohorts: 
Cohort 1. Patients with confirmed absence of mutations in EGFR 18-21 exons and ALK 
fusion genes (the histochemistry result of ALK D5F3 antibody is negative); 
Cohort 2. Patients with confirmed presence of mutations in EGFR 18-21 exons or ALK 
fusion genes (the histochemistry result of ALK D5F3 antibody is positive). Carriers of 
sensitive EGFR mutations must have received at least one targeted treatment with 
EGFR tyrosine kinase inhibitors (EGFR-TKI) and failed the treatment. Carriers of 
positive ALK fusion genes must have failed the treatment of at least one targeted 
treatment with ALK tyrosine kinase inhibitor (ALK-TKI) (treatment failure: progressive 
disease or intolerable toxicity during the treatment); 
Cohort 3. Imaging confirmed non-central squamous cell lung cancer or adenosquamous 
carcinoma primarily consisted of squamous cell carcinoma (pathologically confirmed). 
Cohort 4. Non-squamous and non-small cell lung cancer with wild-type EGFR and 
ALK and with bTMB ≥ 1.54 muts/Mb or tTMB > 10 muts/Mb confirmed by central 
laboratory, and patients in the stage of a palliative treatment who have received no 
systemic treatment. 
5. ECOG PS: 0-1; 
6. Life expectancy ≥ 12 weeks;  

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7. Major organ functions must meet the following rules (not including the use of blood 
components or cell growth factors during screening): 
 
Absolute neutrophil count ≥ 1.5 × 109/L; 
 
Platelets ≥ 100 × 109/L; 
 
Hemoglobin ≥ 9 g/dL; 
 
Serum albumin ≥ 3 g/dL; 
 
Thyroid stimulating hormone (TSH) ≤ ULN (In the case of abnormalities, FT3 and FT4 
levels should also be measured. If FT3 and FT4 levels are normal, the patient can be 
enrolled); 
 
Total bilirubin ≤ ULN; 
 
ALT and AST ≤ 1.5 × ULN; 
 
AKP ≤ 2.5 × ULN; 
 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min (using the standard 
Cockcroft-Gault formula, as shown in Appendix 3); 
8. Female patients of a childbearing age who are not surgically sterilized should adopt a 
medically approved contraceptive measure (such as an intra-uterine contraceptive 
device, contraceptive pills or condoms) during the study treatment period and within 
3 months after the end of the study treatment; female patients of a childbearing age who 
are not surgically sterilized must have a negative serum or urine HCG test result within 
72 h prior to study enrollment, and must not be in the lactation period; male patients 
should be surgically sterilized or agree to use an appropriate contraceptive measure 
during the study period and within 3 months after the last dose of the study drug; 
9. Patients must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 
5.2 Exclusion Criteria 
Patients meeting any of the following are ineligible to participate in this study: 
1. Patients with any active autoimmune diseases or a history of autoimmune diseases 
(including but not limited to the following: autoimmune hepatitis, interstitial 
pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, 
hyperthyroidism, hypothyroidism; adults with vitiligo or completely relieved childhood 
asthma can be enrolled if they do not require any intervention; patients with asthma 
requiring medical intervention with bronchodilators cannot be enrolled); 

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2. Patients who are currently using immunosuppressive agents, or systemic or absorbable 
local hormonal therapies for immunosuppression purposes (> 10 mg/day prednisone or 
equivalent) and still use the above drugs within 2 weeks prior to enrollment; 
3. Patients who have experienced severe allergic reactions to other monoclonal antibodies; 
4. Patients with untreated metastases to central nervous system. Patients who have 
received treatment for brain or meningeal metastasis can be included if they are 
clinically stable (MRI) for at least 1 month and have stopped systemic hormonal therapy 
(> 10 mg/day prednisone or equivalent) for more than 2 weeks; 
5. Imaging (CT or MRI) results show that the tumor has invaded the large blood vessels or 
has an unclear boundary with the blood vessels; 
6. Imaging (CT or MRI) results show significant cavitation or necrosis of lung tumors; 
Patients with marginal adenocarcinoma with cavity may be enrolled after discussion 
with the leading site. 
7. Patients with hypertension which cannot be well controlled by antihypertensives 
(systolic pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg); 
8. Patients with clinical symptoms or diseases of the heart that are not well controlled, 
such as (1) > NYHA Class II cardiac failure; (2) unstable angina;(3) myocardial infarct 
within past 1 year; (4) clinically significant supraventricular or ventricular arrhythmia 
requiring treatment or intervention; 
9. Patients with abnormal coagulation functions (PT > 16 s, APTT > 43 s, TT > 21 s, Fbg < 
2 g/L) and hemorrhagic diathesis or those who are currently treated by a thrombolytic or 
anticoagulant therapy; 
10. Patients with urinalysis results indicating that the urine protein is ≥ ++ and the 
quantitative test of urine protein confirms that the 24-hour urine protein is > 1.0 g; 
11. Patients who have previously received radiotherapy, chemotherapy or surgery that is 
less than 4 weeks before the study after the end of such treatments (last dose), or 
patients whose last dose of oral targeted drugs is less than 5 drug half-lives; Patients 
with adverse events caused by the previous treatment (except for alopecia) that have not 
returned to CTCAE Grade ≤ 1; 
12. Patients with clinically symptomatic ascites or pleural effusion requiring therapeutic 
paracentesis or drainage; 

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13. Patients with obvious hemoptysis or a daily amount of hemoptysis of half a teaspoon 
(2.5 mL) or more within 2 months before randomization; 
14. Patients with clinically significant hemorrhage symptoms or a clear hemorrhagic 
diathesis within 3 months prior to randomization, such as hemorrhage of digestive tract, 
stomach ulcer with hemorrhage, baseline fecal occult blood ++ or above, or vasculitis;  
15. Had events of arterial/venous thrombosis within 6 months prior to randomization, such 
as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, 
and brain infarction), deep vein thrombosis, and pulmonary embolism; 
16. Known hereditary or acquired hemorrhage and thrombophilia (such as hemophilia, 
coagulopathy, thrombocytopenia, hypersplenism, etc.); 
17. Patients with active infection or unexplained fever of > 38.5 °C during screening or 
prior to the first dose; 
18. Patients with previous or current objective evidence of pulmonary fibrosis, interstitial 
pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced pneumonitis, and 
severe lung function impairment; 
19. Subjects with congenital or acquired immunodeficiency (such as HIV infection), or 
active hepatitis (hepatitis B: HBsAg positive and HBV DNA > upper limit of normal; 
hepatitis C: HCV antibody positive and HCV virus titer > upper limit of normal); 
20. Those who have used study drugs of other clinical trials within 4 weeks before the first 
dose of this study; 
21. Patients with previous or concurrent malignancies at other sites (except for cured skin 
basal cell carcinoma and cervical carcinoma in situ); 
22. Patients who may receive other systemic anti-tumor treatments during the study; 
23. Patients with bone metastasis who have received a palliative radiotherapy in an area 
of > 5% of bone marrow area within 4 weeks prior to the participation in this study; 
24. Patients who have previously received other anti-PD-1 antibody treatments or other 
immunotherapies targeting PD-1/PD-L1; 
25. Patients who have received live vaccines within less than 4 weeks before the first dose 
or may receive live vaccines during the study; 

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26. Patients who may have other factors leading to the discontinuation of the study as 
judged by the investigator, such as other serious diseases (including mental illness) 
requiring concomitant treatment, serious laboratory test abnormalities, or accompanied 
by family or social factors that can affect the safety of the subject or the collection of 
data and samples. 
5.3 Subject's Withdrawal 
5.3.1 
Criteria for withdrawal/treatment discontinuation 
1. The subject withdraws informed consent and requests to withdraw from the study; 
2. Imaging examinations show progressive disease; 
Upon the first discovery of progressive disease by imaging examinations, it must be 
confirmed after 4 weeks (except for rapid progression and significant clinical 
progression); 
If a subject shows local progression (1 to 4 lesions show progress) but the clinical 
symptoms are stable, the treatment can be continued according to the judgment of the 
investigator until imaging examinations show progressive disease again. 
Definition of clinically stable: a. no clinically significant symptoms or changes in 
laboratory tests; b. no changes in the performance status score (deterioration); and c. 
non-tumor rapid progression and tumor progression not involving major organs/sites 
(e.g., spinal cord compression). 
3. Treated by SHR-1210 for 2 years (no progressive disease as shown by imaging); 
4. Subjects with intolerable toxicity; 
5. Subjects with poor compliance; 
6. Subjects lost to follow-ups or show positive blood HCG results; 
7. Other reasons for which the investigator considers withdrawal as necessary. 
Note: Subjects with radiologically confirmed PD may continue the study drug after providing 
informed consent for continuation after PD, if they are judged able to benefit from the study drug 
by the investigator. The treatment may continue until another radiographic PD or they can no 
longer benefit from the treatment. Subjects who continue the medication after PD will undergo 
periodic visits and efficacy evaluations according to the visit procedures specified in the 
protocol. 

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Subjects who agree to continue the treatment after PD should be fully informed of possible 
alternative treatments, potential risks of continuation, etc. 
5.3.2 
Handling of withdrawn subjects 
The efficacy and safety investigations to be completed upon study withdrawal as specified in the 
protocol must be completed as much as possible. In addition, the safety follow-up should be 
completed along with fully collected AEs and their outcomes. The survival follow-up should be 
completed to record subsequent treatment regimens and the survival status of the subjects. The 
investigator can recommend or provide new or alternative treatments to a subject based on the 
condition of the subject. Patients showing no progressive disease need to be continuously 
followed-up for imaging evaluation until the patients begin a new treatment or show progressive 
disease 
5.4 End of Study 
Stage I: 
The Stage I of this study will end at 3 months after the last dose of the last subject in the 
tolerability observation period if subjects in the PK expansion stage complete the specified PK 
blood sampling; 
Stage II: 
At 6 months after the first dose of the last subject in Stage II, the primary and secondary 
endpoints will be statistically analyzed. 
All subjects will be followed up until 12 to 24 months after the last dose of the last subject, and 
supplemental analysis of the primary and secondary endpoints will be performed thereafter. 
After the end of the study, if the subjects may continue to benefit from the study drug, the 
medication may be continued until a criterion for discontinuation is met. The occurrence of SAEs 
will be collected and recorded during the treatment and after the last dose according to the 
protocol. 
5.5 Termination Criteria 
1. Discovery of unexpected, important, or unacceptable risks to the subjects; 
2. Major errors in the protocol found during the implementation of the study; 
3. Ineffective study drug/treatment, or meaninglessness to continue the study; 
4. Extreme difficulties in completing the study due to reasons such as severe delays in 
subject recruitment or frequent protocol deviations. 

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6 STUDY DRUGS 
6.1 Overview of Study Drugs 
6.1.1 
Drug information 
 
SHR-1210: 
Name: SHR-1210 for injection 
Manufacturer: Shanghai Hengrui Pharmaceutical Co., Ltd./Suzhou Suncadia 
Biopharmaceuticals Co., Ltd. 
Dosage Form: Lyophilized powder for injection 
Route of Administration: Intravenous injection 
Strength: 200 mg/20 mL vial. 
Storage and stability: Placed in a 2-8 °C medical refrigerator during storage and the shelf life is 
tentatively set to 2 years. Do not freeze. 
 
Apatinib: 
Name: Apatinib Mesylate Tablets (Apatinib) 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage Form: Tablets 
Route of Administration: Oral 
Strength: 250 mg/tablet; 375 mg/tablet 
Storage and Stability: Away from light, sealed, stored at below 25 °C.Valid for 2 years. 
6.1.2 
Drug packaging and labeling 
Specification and packaging of SHR-1210: 200 mg/20 mL vial, one vial per box, and 20 boxes 
per carton. 
SHR-1210 drug label (for illustration only and the actual label shall prevail), the drug number is 
increased incrementally from 0001. 

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Small Box Label 
 
 
Vial Label 
 
 
SHR-1210 for 
Injection 
Clinical Study Approval  
No.: 2016L01455 
Strength: 
200 mg/vial 
SHR-1210 for 
Injection 
Clinical Study Approval  
No.: 2016L01455 
Strength: 
200 mg/vial 
For Clinical Study Use Only 
For Clinical Study Use Only 
Study Name: A Phase II Clinical Study of Anti-PD-1 Antibody 
SHR-1210 Combined with Apatinib Mesylate in the Treatment 
of Advanced Non-Small Cell Lung Cancer 
Study No.:  SHR-1210-APTN-II-202-NSCLC 
 
Dosage Form: Lyophilized powder 
Study Center: Shanghai Pulmonary Hospital,  
Tongji University 
Usage: 200 mg, Q2W, IVGTT. Note: Prepare as per study 
protocol. 
Drug No._____________________ 
Quantity: 1 vial/box 
Storage Method: Store at 2-8 °C away from light  
Batch No.:  
Expiry Date: DD/MM/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Study Name: A Phase II Clinical Study of Anti-PD-1 Antibody 
SHR-1210 Combined with Apatinib Mesylate in the Treatment 
of Advanced Non-Small Cell Lung Cancer 
Study No.:  SHR-1210-APTN-II-202-NSCLC 
 
Dosage Form: Lyophilized powder 
Study Center: Shanghai Pulmonary Hospital, Tongji University 
Usage: 200 mg, Q2W, IVGTT. Note: Prepare as per study 
protocol. 
Drug No.___________________,  
Preparation Date: __ __/__ __ __/__ __ __ __ 
Storage Method: Store at 2-8 °C away from light  
Batch No.:  
Expiry Date: DD/MM/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
Big Box Label 
 
 
SHR-1210 for 
injection 
Clinical study approval 
No.: 2016L01455 
Strength: 200 mg/vial 
For Clinical Study Use Only 
Study Name: A Phase II Clinical Study of Anti-PD-1 Antibody SHR-1210 Combined with 
Apatinib Mesylate in the Treatment of Advanced Non-Small Cell Lung Cancer 
Study No.: SHR-1210-APTN-II-202-NSCLC  Dosage Form: Lyophilized powder, 200 mg/vial 
Study Center: Shanghai Pulmonary Hospital, Tongji University 
Usage: 200 mg, Q2W, IVGTT. Note: Prepare as per study protocol. 
Quantity: 20 vials per box 
Storage Method: Store at 2-8 °C away from light  
Batch No.:  
Expiry Date: DD/MM/20YY 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Manufacturer: Shanghai Hengrui Pharmaceutical Co., Ltd. 
Packaging specifications and quantity of apatinib: 
The label content includes: 
Label name: Drugs to be used in the phase II clinical study of anti-PD-1 antibody SHR-1210 
combined with apatinib mesylate in the treatment of advanced non-small cell lung cancer 
Strength: 250mg/tablet or 375 mg/tablet 
Indication: For the treatment of advanced non-small cell lung cancer 
Usage: 1 tablet per day (250 mg/d and 375 mg/d dose groups); 2 tablets per day (500 mg/d dose 
group), once a day taken orally after meal 

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Drug number, storage conditions, batch number, expiration date, study site (Jiangsu Hengrui 
Pharmaceuticals Co., Ltd.) 
Precautions: For clinical use only; please return the remaining drug to the physician 
The drug is packaged in aluminum-plastic blister packs with 10 tablets per pack, and each small 
box contains 3 or 6 packs.  
6.2 Preparation of SHR-1210 
SHR-1210 is a lyophilized powder for injection, which needs to be formulated before 
intravenous drip (see the pharmacy manual of SHR-1210 for details). 
Since this product does not contain preservatives, please perform aseptic operations when 
formulating the drug preparation. 
 
Each vial of lyophilized powder is quantitatively reconstituted in 5 mL of distilled 
water for injection. During the operation, the distilled water is slowly added into the 
vial along the vial wall. Please do not directly drop the distilled water onto the surface 
of the lyophilized powder (the post-reconstitution concentration is 40 mg/mL) 
 
Do not vigorously shake the vial during reconstitution. Instead, reconstitute the powder 
in a gentle way with slow vortex. After reconstitution, allow the vial to stand for 6 min 
to allow the foam to disappear. 
 
Visually observe the solution after reconstitution to see whether there are particles and 
discoloration. After reconstitution, the liquid should be colorless or slightly yellowish. 
There may be a small number of light-gray small particles falling into the vial due to 
the puncture of vial stopper by the needle. However, these particles will be filtered by 
the 0.2 μM filter attached to the infusion set and hence will not affect the subsequent 
use of the drug solution. If there are other particles other than the ones mentioned 
above, please do not continue to use this vial of drug. 
 
Draw a corresponding volume of the reconstituted solution from the vial and dilute it in 
100 mL of 5% glucose for injection or 0.9% sodium chloride for injection. Avoid 
generating a large number of air bubbles during the dilution process. After dilution, 
slowly invert the infusion bag several times to mix well. Maintain the final 
concentration at between 0.5 mg/mL and 10 mg/mL. 
 
Within 2 h after the dilution is completed, use an infusion set equipped with an in-line 
filter (0.2 μM) to finish the injection via intravenous drip. After the drug injection is 
completed, use about 20 mL of 5% glucose for injection to flush the remaining drug in 
the infusion line into the body. Do not use this infusion line to administer other drugs. 
Each infusion takes 30 min (not less than 20 min, no more than 60 min) (including the 
final rinse stage). 

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6.3 Administration Regimen 
SHR-1210 will be administered via intravenous drip (without prophylaxis) with a fixed dose of 
200 mg within 30 min (not less than 20 min, no more than 60 min), once every 2 weeks. Each 
cycle contains 4 weeks (the subjects for the expanded PK study will receive one dose on D1 of 
Cycle 1 of the study) and the longest period of drug use is 2 years. 
Apatinib will be orally administered after meals (the subjects for the expanded PK study will 
receive the drug orally under fasting on Day 28 of Cycle 1 and Day 28 of Cycle 2), once a day, 
and one tablet (250 mg/tablet or 375mg/tablet) or 2 tablets (250 mg/tablet, 500 mg dose group) 
each time. The drug administration will be continued through the study. 
Subjects enrolled for the study in the tolerability observation stage and subjects enrolled for the 
Stage II of the study will be given SHR-1210 on D1 and D15 of each cycle from the beginning 
of treatment; apatinib will be given via oral administration once daily. 
Subjects enrolled for the expanded PK study will be given SHR-1210 on D1 in Cycle 1 and on 
D1 and D15 in each cycle starting from Cycle 2. These subjects will also be given daily oral 
administration of apatinib continuously starting from D22 in Cycle 1. 
Definition of postprandial administration: administration within 30 min after the end of a meal. 
The subjects will continue to use the study drugs until the criteria for treatment discontinuation 
specified in the protocol are met. 
6.4 Dose Modification 
The study treatment may be modified according to the toxic side effects appeared. The options 
for treatment modification include: interruption, dose reduction, change in method of 
administration, and discontinuation; 
In this study, only interruptions for up to 12 weeks are permitted for SHR-1210 treatment; A 
SHR-1210 dose delayed by more than 3 days shall be skipped, and the administration may be 
resumed at 200 mg at the next scheduled time point. 
Dose modifications caused by apatinib-related toxicity include: dose interruption, dose reduction 
(500 mg/d or 375 mg/d dose groups), change in method of administration (first modification: 
5 days of drug administration followed by 2 days of dose interruption; re-modification: 1 day of 
drug administration followed by 1 day of dose interruption), and discontinuation. Further 
adjustments will not be allowed after the dose or method of administration of apatinib is 
modified during the study period, unless such adjustments are agreed upon by the investigator 
and the sponsor after discussion. 

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In the event of an apatinib-related adverse reaction, the dose should be interrupted first. After the 
toxicity has returned to an acceptable level, the following options may be selected as appropriate: 
resume administration using the original dose, reduce the dose, modify the method of 
administration or discontinue the drug. Subjects may continue SHR-1210 as monotherapy if 
apatinib treatment is discontinued. 
For immune-related toxicity occurring during the study, such as immune-related pneumonitis, 
hepatitis and colitis, the administration of SHR-1210 and apatinib should be interrupted as 
appropriate. The administration can be resumed when the toxicity returns to Grade ≤ 1 or 
baseline levels (for subjects with abnormal laboratory parameters such as ALT/AST and TBIL at 
baseline). The administration of SHR-1210 should be resumed first. The administration of 
apatinib can be resumed when no significant abnormality is observed within 7 to 14 days after 
SHR-1210 administration. The route of subsequent administration of apatinib should be 
modified. 
Rules for Dose Modifications 
Treatment-Related Toxicity 
Grade 
Whether to Interrupt 
Treatment 
Criteria 
for 
Resuming 
Dose 
Modification 
Method 
Criteria for 
Discontinuation 
SHR-1210 
Apatinib 
Toxicity related 
to SHR-1210 
and apatinib 
Hematologic 
toxicity 
(except for 
decreased 
lymphocyte 
count) 
Grade 1-2 
No 
No 
— 
— 
— 
Grade 3 
No 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 2 
Resume at 
original dose 
Two episodes of 
Grade 4 
hematological 
toxicity 
Grade 4 
Yes 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 2 
Dose reduction 
or modification 
of method of 
administration 
Non- 
hematologic 
toxicity 
Grade 1 
No 
No 
— 
— 
— 
Grade 2 (last 
for ≥ 7 d) 
Yes 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 1 
Resume at 
original dose 
SHR-1210 
interruption for 
more than 
12 weeks 
Grade 3 
Yes 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 1 
Dose reduction 
or modification 
of method of 
administration 
Toxicity 
related to 
SHR-1210 
Reactive 
capillary 
endothelial 
proliferation 
Grade 3 
Yes 
No 
Until the 
toxicity 
returns to 
Grade ≤ 2 
Resume at 
original dose 
SHR-1210 
interruption for 
more than 
12 weeks 

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Treatment-Related Toxicity 
Grade 
Whether to Interrupt 
Treatment 
Criteria 
for 
Resuming 
Dose 
Modification 
Method 
Criteria for 
Discontinuation 
SHR-1210 
Apatinib 
Apatinib- 
Related 
Toxicities 
Hypertension 
Grade 3 (after 
corrective 
treatment) 
No 
Yes 
Wait until 
blood 
pressure 
returns to 
within 
140/90 
mmHg 
Dose reduction 
or modification 
of method of 
administration 
Subjects with 
persistent Grade 
3 hypertension 
after the best 
corrective 
treatment and 
the modification 
of method of 
administration 
of apatinib 
Proteinuria 
(without 
significant 
increase in 
blood 
creatinine) 
Grade 3 
(24 h urine 
protein 
quantification) 
No 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 2 
Dose reduction 
or modification 
of method of 
administration 
Subjects with 
persistent Grade 
3 proteinuria 
after the best 
corrective 
treatment and 
the modification 
of method of 
administration 
of apatinib 
Hand-and-foo
t syndrome 
Grade 3 
No 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 1 
Dose reduction 
or modification 
of method of 
administration 
Subjects with 
persistent Grade 
3 hand-and-foot 
syndrome after 
the best 
corrective 
treatment and 
the modification 
of method of 
administration 
of apatinib 
Headache 
Grade 2 (last 
for ≥ 7 d) or 
Grade 3 
No 
Yes 
Until the 
toxicity 
returns to 
Grade ≤ 1 
Dose reduction 
or modification 
of method of 
administration 
Apatinib 
interruption for 
more than 
28 days 
The investigator may consider interrupting the treatment for subjects who experience significant 
toxicity during the study, such as Grade 3 or greater treatment-related toxicity, or Grade 2 
non-hematological toxicity lasting for 2 weeks and longer (except for asymptomatic Grade 2 
hypertension), abnormal laboratory findings (except < 2 g/24 h proteinuria). After the toxicity 
resolves, the dose of apatinib should be reduced or the method of apatinib administration should 
be adjusted accordingly. 
In the course of the study and based on the above regulations for dose modification, the 
investigator may modify the dose appropriately by comprehensively considering the 
treatment-related toxicity in the subjects (if a subject experiences multiple Grade 2 
treatment-related toxicities and shows poor tolerance to the study drug, the dose of apatinib 
can be reduced or the administration of apatinib can be maintained at the original dose by given 
intermittently with observation after treatment delay and recovery from toxicity). 

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During the study, if a subject has fever (> 38 °C) and needs to use medications for corrective 
treatment; in the case of obvious wheezing, polypnea, symptoms of suffocation or rash, the 
administration of SHR-1210 should be skipped for the current or next scheduled time of 
SHR-1210 administration before the symptoms are recovered. After the symptoms are relieved 
and become stable for more than 7 days, the subjects can be given SHR-1210 according to the 
subsequent administration schedule. For subjects with fever and wheezing, the possibility of 
pneumonitis should be ruled out by imaging examinations before drug administration if 
necessary. 
In the case of hypertensive crisis, cerebral hemorrhage, Grade ≥ 2 pulmonary hemorrhage, other 
Grade ≥ 3 hemorrhage, arterial thrombosis, Grade 4 venous thrombosis, leukoencephalopathy 
syndrome, or gastrointestinal perforation, apatinib should be discontinued, SHR-1210 should be 
interrupted and active symptomatic treatment should be given. The resumption of SHR-1210 
treatment shall depend on the toxicity recovery. 
During the study, in the case of Grade ≥ 3 immune-related pneumonitis, Grade ≥ 3 TBIL 
elevation (recurrent), Grade 4 ALT/AST elevation (recurrent), other Grade 4 immune-related 
toxicities (except for hypothyroidism), Grade 4 injection reactions, or the interruption of 
SHR-1210 administration for more than 12 weeks due to immune-related toxicity but the toxicity 
is still unable to return to Grade ≤ 1 or baseline levels (subjects with baseline abnormality), 
SHR-1210 should be permanently discontinued. 
After discontinuation of SHR-1210 treatment, subjects may continue to receive apatinib 
monotherapy after toxicity recovery if the investigator judges that the subjects can benefit from 
the apatinib monotherapy, until an event meeting the criteria for discontinuation as specified in 
the protocol occurs. 
6.5 Drug Management, Dispensation and Return 
The management, dispensing and return of the study drugs of this study are in the charge of 
designated staff. The investigator must ensure that all the study drugs are only used for the 
subjects participating in this clinical study. The dosage and administration should follow the 
study protocol. The remaining or expired drugs should be returned to the sponsor. The study 
drugs should not be transferred to any non-clinical study participant. 
The study drugs should be stored according to the drug storage conditions detailed in the drug 
information. The drug receipt forms must be signed by two people during drug dispensation. The 
form is in duplicate copies, of which one is for the study center and the other is for the sponsor. 
Remaining drugs and empty boxes will be retrieved at the end of the study and a retrieval form 
will also be signed by both parties. The dispensation and return of every drug should be 
immediately documented on designated forms. 

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The clinical research associate (CRA) is responsible for monitoring the supply, usage, and 
storage of the study drugs, and the management of remaining products. 
6.6 Concomitant Medications 
6.6.1 Medications that are prohibited during the study and medications that should be 
used with caution 
Drugs that may have drug-drug interactions with apatinib: 
In vitro studies have shown that apatinib is prominently metabolized by the liver P450 enzyme 
CYP3A4. Apatinib has a strong inhibitory effect on CYP3A4 and CYP2C9, and has a moderate 
inhibitory effect on CYP2C19.CYP3A4 inducers (dexamethasone, carbamazepine, rifampicin 
and phenobarbital) and inhibitors (ketoconazole, itraconazole, erythromycin and clarithromycin), 
CYP3A4 substrates (simvastatin, cyclosporine and pimozide), and other drugs metabolized via 
CYP3A4 (such as benzodiazepines, dihydropyridine, calcium ion antagonist and HMG-COA 
reductase inhibitors) should be used with caution during the treatment. Omeprazole should be 
used with caution during the treatment (except when omeprazole must be used to treat serious 
adverse drug reactions). 
The substrates of CYP2C9 and CYP2C19 should be used with caution, as shown in the table 
below. 
P450 enzyme 
Substrate 
CYP2C9 
Diclofenac, phenytoin, piroxicam, S-warfarin, and tolbutamide 
CYP2C19 
Diazepam, imipramine, lansoprazole, and S-mephenytoin 
Drugs that prolong the QT interval of the heart 
As tinib drugs may cause toxicities of prolonged QT interval in clinical applications, drugs that 
may prolong the QT interval should be used with caution during the study. These mainly include, 
but are not limited to, the following categories of drugs: 
 
Antibiotics: fluoroquinolones: sparfloxacin, gatifloxacin, levofloxacin, moxifloxacin, 
ofloxacin, ciprofloxacin; macrolides: erythromycin, clarithromycin, telithromycin, 
azithromycin, roxithromycin, and metronidazole 
 
Antiarrhythmics: quinidine, procainamide, disopyramide, flecainide, propafenone, 
amiodarone, dronedarone, sotalol, dofetilide, and ibutilide 
 
Drugs used to relieve angina pectoris: ranolazine, ivabradine 
 
Antipsychotics: risperidone, fluphenazine, droperidol, haloperidol, thioridazine, 
pimozide, olanzapine, and clozapine 

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 
Antifungal drugs: voriconazole, posaconazole 
 
Antimalarial drugs: mefloquine, chloroquine 
 
Antihistamines: terfenadine, astemizole, hydroxyzine 
 
Gastrointestinal drugs: antiemetics: ondansetron, granisetron, dolasetron, droperidol 
(0.625 to 1.25 mg may be a safe dose), hydroxyzine; prokinetics: cisapride, 
domperidone, metoclopramide 
 
Antidepressants: amitriptyline, imipramine, clomipramine, dosulepin, and doxepin 
CYP3A4 substrates prohibited during the study (drugs with narrow safety windows and 
may cause serious adverse reactions when their metabolism is affected) include but are not 
limited to: 
 
Hypoglycemic agents: tolbutamide, chlorpropamide 
 
Ergot derivatives: dihydroergotamine, ergometrine, ergotamine, methyl ergometrine 
(potential risk of ergot poisoning, including severe vasospasm leading to peripheral and 
cerebral ischemia) 
 
Antipsychotic: pimozide (can potentially increase the risk of prolonged QT interval) 
 
Antiarrhythmics: amiodarone (prohibited within 6 months prior to randomization), 
bepridil, flecainide, lidocaine, mexiletine, quinidine, and propafenone 
 
Immunomodulators: cyclosporine, tacrolimus, sirolimus (may potentially increase 
 
the risk of nephrotoxicity and neurotoxicity) 
 
Miscellaneous: quetiapine, risperidone, clozapine, tomoxetine hydrochloride 
If warfarin is used for anticoagulation during the study, a reduced dose should be 
considered with its use being monitored closely, and the use of the study drugs should be 
discontinued if necessary. 
During the treatment period, anti-tumor drugs and adjuvant drugs related to tumor 
treatment, such as anti-tumor traditional Chinese medicine (see Appendix I for a detailed 
list), immunological agents, etc., should be discontinued. 

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6.6.2 Drugs and treatments that may be used as appropriate during the study: 
In Stage I, for subjects enrolled in the tolerability observation study, except that the subjects 
experiencing hypertension, rash, diarrhea, nausea and vomiting can be given symptomatic 
treatments, all other adverse reactions with no clinically significant toxicity occurring during the 
tolerability observation period (Cycle 1 of drug administration) will not be treated in principle, 
so as to observe the possible adverse effects and their extent/reversibility of the study drugs. 
However, in the event of a clinically significant toxicity as specified in the protocol, the 
treatment should be interrupted and a proactive approach should be used to manage the event. 
Used medications should be recorded on the eCRF. For subjects experiencing clinically 
significant toxicity, the treatment can be resumed at the original dose (when the original dose is 
the lowest dose) or the nearest lower level after the toxicity returns to Grade ≤ 1 after 
management. 
In other cases, the subjects should be given an optimal supportive care during the 
treatment.Comorbidities and various adverse reactions, especially immune-related adverse 
reactions, should be actively treated. 
Subjects can receive bisphosphonate for the treatment of bone metastases.If systemic or local 
analgesia is not effective in controlling painful lesions of bone metastases, a small area of 
palliative radiotherapy (the area of the radiotherapy must be < 5% of the bone marrow region, 
and the percent bone marrow content in human skeleton is shown in the figure of Appendix VI) 
is allowed. 
Palliative treatment for lesions outside the lungs and liver is allowed during the study (when the 
treatment of the subjects is needed to improve symptoms upon the onset of PD), including the 
treatments for pleural effusion, ascites, pericardial effusion, and radiotherapy for brain lesions. 
During such treatment, the study drugs should be interrupted until the end of the recovery period 
of palliative treatment. 
All concomitant treatments and medications used within 30 days prior to the first dose and 
during the study should be documented in the eCRF in strict accordance with the GCP 
regulations. Subjects will be closely monitored if adverse reactions occur, and active 
symptomatic treatment will be given if necessary. The drugs used will be documented and 
described in the CRFs. Once the study treatment is interrupted, only the concomitant medication 
and treatment used to solve new or unresolved treatment-related AEs will be recorded. 

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7 STUDY PROCEDURES 
Before the start of the study, subjects must read and sign the current version of informed consent 
form (ICF) approved by the Ethics Committee (EC). All examinations and study procedures will 
be carried out according to the schedule of activities, and will not be affected by the duration of 
drug interruption. However, it is allowed to change within the window period of test items due to 
holidays, weekends or other administrative reasons. 
7.1 Screening Period (D-21 to D-1) 
Unless otherwise stated, the following screening procedures must be completed within 21 days 
prior to the first dose: 
[Signing of ICF] A written ICF must be signed by the subject before any procedures of the 
clinical study are carried out. 
[Demographics] gender, date of birth, ethnicity, height, weight, smoking history. 
[Tumor history] including pathological diagnosis and clinical diagnosis: 
(1) Tumor diagnosis: the date of initial diagnosis of the tumor, histological classification, site of 
primary tumor and metastatic lesions, pathological staging, and clinical staging; 
(2) History of surgery: the surgical history of primary lesions and the surgical history of 
metastatic lesions; 
(3) History of chemotherapy (including new/adjuvant chemotherapy): the history of systemic 
chemotherapy, the history of targeted drug therapy, and the history of local chemotherapy; 
(4) History of radiotherapy: date, dose, and site (systemic/local); 
(5) Results of gene mutation detection (if applicable): whether there are gene mutations, sites of 
mutation, and detection date; 
(6) The date of PD or disease recurrence after the last systemic treatment. 
[Concomitant disease] Concomitant disease and related treatment history (such as diabetes, 
hypertension and other chronic diseases), history of tumors other than non-small cell lung cancer. 
[Concomitant medication] Concomitant medications and treatments received within 30 days 
prior to the first dose and during the study period should be recorded. Once the study treatment is 
interrupted, only the concomitant medication and treatment used to solve new or unresolved 
treatment-related AEs will be recorded; 
[Thyroid function] Including serum FT3, FT4, and TSH; 
[Examination of the pituitary adrenal axis] Including ACTH and cortisol. 

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[Hepatitis B, hepatitis C, and HIV examinations] hepatitis B panel (If the test results are 
abnormal, viral replication [HBV DNA] test should be performed); hepatitis C virus antibody 
(anti-HCV) test (If the test results are abnormal, virus titer should be tested); HIV antibody test. 
[Detection of EGFR mutations and ALK fusion gene] If the subjects have previously been 
tested for EGFR mutations and the ALK fusion gene, they do not need to be tested again. If the 
subjects have not been tested previously, the study site will carry out relevant tests. If the subjects 
are positive for EGFR mutations, the test of ALK fusion gene will no longer be performed. 
[Adverse events] Adverse events will be recorded from the time when the subjects sign the 
informed consent form. AEs unrelated to the study drugs will be recorded to 30 days after the last 
dose. Treatment-related AEs will be collected until 90 days after the last dose of SHR-1210 or 
30 days after the last dose of targeted anti-angiogenic therapy (whichever is longer). See the 
AE/SAE collection time limit in Section 8.3 for details. 
[Blood pressure monitoring] The blood pressure measurement of subjects will be performed by 
the investigator during the screening period; during each blood pressure measurement, smoking 
and coffee are prohibited within 30 min before the measurement, and subjects should rest for at least 
10 min. The sitting position will be taken during the measurement by placing the elbow at the same 
level as the heart. Each blood pressure measurement will be taken on the same side of the body; 
[Pulmonary function test] Maximum vital capacity, the forced expiratory flow at 25-75% of 
forced vital capacity (FEF25-75), the peak expiratory flow (PEF), maximum expiratory volume 
per second, diffusing capacity of the lungs for carbon monoxide (DLCO) and oxygen saturation. 
Carried out during the screening period and then according to the judgment of the investigator in 
subsequent cycles; 
[Imaging examination] Including CT or MRI of the chest, abdomen, and brain. The baseline 
tumor assessment during the screening period can be extended to up to 3 weeks before treatment. 
Qualified CT/MRI scan results obtained before signing the informed consent can be used for 
tumor assessment during the screening period. Bone scan should be performed upon clinically 
suspected bone metastasis. Absence of cerebral hemorrhage should be confirmed within 21 days 
before randomization for subjects with stable brain metastases; 
[Biomarker sampling/sample collection and detection] Archived paraffin-embedded tumor 
samples or fresh biopsy specimens will be collected to make ≥ 10 slices, of which 3-5 slices of 
3-4 μm tumor sections (mounted slides) will be collected for the histochemistry detection of 
biomarkers such as PD-L1, and 5-8 slices of 5-8 μm paraffin sections (paraffin rolls can be 
directly collected without being mounted on the slides) or fresh biopsy specimens will be 
collected for the detection of biomarkers such as tumor mutation burden (TMB). Refer to the 
laboratory manual for details on tumor tissue sampling/sample collection and disposal methods. 

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For cohort 4, the test results of tumor mutation burden (TMB) in the peripheral blood and/or 
tumor tissues will be verified before the subjects take the first dose of the study drug, so the 
TMB test for cohort 4 must be completed before the first dose. However, the delay in the 
screening period caused by TMB testing is allowed, but other tests (including imaging 
examinations) must be completed within 21 days prior to the first dose. 
Unless otherwise stated, the following screening procedures must be completed within 7 days 
prior to the first dose: 
[Hematology] White blood cell count (WBC), absolute neutrophil count (ANC), lymphocyte 
count (LYM), red blood cell count (RBC), hemoglobin (Hb), and platelet count (PLT); 
[Urinalysis] Urine protein (Note: if urine protein ≥ 2+, 24-h urine protein quantification test 
shall be performed), urinary red blood cells, urinary white blood cells, and urine glucose; 
[Routine stool test] Occult blood; re-examination is required for fecal occult blood+; if fecal 
occult blood is confirmed, then a gastroscopy shall be performed. Performed within 7 days 
before enrollment, on Day 15 of Cycle 1 and Day 1 of subsequent cycles, and upon completion 
of the study; 
[Blood biochemistry] bilirubin total, bilirubin conjugated, ALT, AST, AKP, γ-GT, protein total, 
albumin, urea or urea nitrogen, creatinine, uric acid, fasting blood glucose, TG, cholesterol, 
potassium, sodium, chlorine, calcium, phosphorus, blood lipase (only checked in the screening 
period and in the case of subsequent abdominal pain, abdominal distension and other symptoms 
of suspected pancreatitis), blood amylase (only checked in the screening period and subsequent 
abdominal pain, abdominal distension and other symptoms of suspected pancreatitis); 
[Coagulation function] Including INR, APTT, PT, TT, and FIB; 
[Myocardial zymography] 
[Pregnancy test] The urine pregnancy test shall be performed 72 h before the first dose in 
women of childbearing age. If positive, a serum pregnancy test shall be performed. If necessary, 
a re-test can be performed for confirmation; 
[Vital signs] Body temperature, heart rate, respiratory rate, and blood pressure; 
[Physical examinations] General conditions, head and face, skin, lymph nodes, eyes (sclera, 
pupil), ear, nose, throat, respiratory system, cardiovascular system, abdomen (including liver and 
spleen), reproductive-urinary system, musculoskeletal system, nervous system, and mental status; 
[ECOG PS] See Appendix II; 

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[12-Lead ECG] Two additional ECGs or other investigations may be added as determined by 
the investigator if results are abnormal; 
[Echocardiography] 
[Blood sampling for tumor markers] In the baseline period (before drug administration), 
14 mL of blood samples will be collected and divided into two tubes, with 10 mL in one tube and 
4 mL in the other tube. See the laboratory manual for methods of blood sampling and disposal. 
The inclusion and exclusion criteria will be verified again. Subjects must meet all inclusion 
criteria and must not meet any of the exclusion criteria before they can be included in the study. 
7.2 Treatment Period 
 
Stage I study (except for subjects participating in the expanded PK study) and Stage II study 
D1 of Cycle 1 [Vital signs] [Physical examinations and weight measurement] [Intravenous drip 
of SHR-1210] [Dispensation of apatinib] [Administration of apatinib] 
Within 24 h after the first dose, the patients should be closely monitored for acute allergic 
reactions. If an acute allergic reaction occurs, it should be treated according to the medical 
practice of the hospital and relevant guidelines. 
Apatinib is administered continuously from D1 of Cycle 1, and its dose can be interrupted or 
modified according to the occurrence of adverse events. 
D1 of subsequent cycles [Hematology] [Blood biochemistry] [Urinalysis] [Routine stool test] 
[Coagulation function] [Vital signs] [Physical examinations and weight measurement] [ECOG 
PS] [ECG] [Intravenous drip of SHR-1210] [Adverse events] [Concomitant medication] 
[Return/dispensation of apatinib] 
D15 of Cycle 1: [Hematology] [Blood biochemistry] [Urinalysis] [Routine stool test] 
[Coagulation function] [Vital signs] [Physical examinations] [ECG] [Intravenous drip of 
SHR-1210] [Adverse events] [Concomitant medication] 
D15 of subsequent cycles: [Hematology] [Blood biochemistry] [Urinalysis] [Coagulation 
function] [Vital signs] [Physical examinations] [ECG] [Intravenous drip of SHR-1210] [Adverse 
events] [Concomitant medication] 
A window period of ± 3 d is set and the administration of SHR-1210 should be carried out after 
completing the evaluation of examinations and tests specified in the flowchart. 
 
Subjects participating in the expanded PK study 

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D1 of Cycle 1: [Vital signs] [Physical examinations and weight measurement] [Intravenous drip 
of SHR-1210] [PK blood sampling] 
D15 of Cycle 1: [PK blood sampling] [Hematology] [Blood biochemistry] [Urinalysis] [Routine 
stool test] [Coagulation function] [Vital signs] [Physical examinations] [ECG] [Adverse events] 
[Concomitant medication] 
After the blood sampling on D22 of Cycle 1 is completed, continuous oral administration of 
apatinib will be started at a frequency of once a day. 
PK blood sampling will be carried out on D28 of Cycle 1 after the administration of apatinib. 
D1 of Cycle 2: [Hematology] [Blood biochemistry] [Urinalysis] [Routine stool test] 
[Coagulation function] [Vital signs] [Physical examinations and weight measurement] [ECOG 
PS] [ECG] [Adverse events] [Concomitant medication] [Return/dispensation of apatinib] 
[Intravenous drip of SHR-1210] [PK blood sampling] 
D15 of Cycle 2 and subsequent cycles: [Hematology] [Blood biochemistry] [Urinalysis] 
[Coagulation function] [Vital signs] [Physical examinations] [ECG] [Intravenous drip of 
SHR-1210] [Adverse events] [Concomitant medication] 
PK blood sampling will be carried out on D28 of Cycle 2 after the administration of apatinib. 
See the flow chart and "3.3.2 Blood Sample Processing and Testing" for the time points, volume, 
and processing of blood sampling. 
D1 of subsequent cycles [Hematology] [Blood biochemistry] [Urinalysis] [Routine stool test] 
[Coagulation function] [Vital signs] [Physical examinations and weight measurement] [ECOG 
PS] [ECG] [Intravenous drip of SHR-1210] [Adverse events] [Concomitant medication] 
[Return/dispensation of apatinib] 
[Imaging evaluation] During the treatment period, imaging examinations should be performed 
under the same conditions as those at baseline (layer thickness of the scan, use of contrast agent, 
etc.), and the lesions found at baseline should be checked every 2 cycles in the first 6 cycles of 
the treatment (bone scan shall be performed in the case of suspected bone progression or for CR 
confirmation). After 6 cycles, imaging examinations can be performed every 3 weeks as 
appropriate and can be performed upon the discovery of suspected new lesions. Initial 
assessment of PR/CR must be confirmed after 4 weeks; initial assessment of PD must be 
confirmed after 4 to 6 weeks (except for significant changes in the subjects' symptoms or rapid 
tumor progression). 
[Thyroid function test] Performed on Day 1 of Cycle 2 and then once every 3 cycles. 

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[Biomarker collection] For subjects showing CR/PR during the study, an additional collection of 
1 tube of 10 mL blood sample for biomarker detection should be performed upon the onset of 
CR/PR and PD, respectively. The collection requirements are the same as those in the baseline 
period. 
7.3 End of Treatment/Withdrawal 
Subjects shall discontinue study treatment upon the occurrence of an event that meets the "5.3.1 
Criteria for subject withdrawal/treatment discontinuation". At the end of the study treatment or 
upon withdrawal from the study, if a subject has not undergone examinations within 14 days 
prior to the end of the study, the subject should undergo the following examinations: 
[Hematology] [Blood biochemistry] [Urinalysis] [Routine stool test] [Coagulation function] 
[Pregnancy test] [Thyroid function test] [Myocardial zymogram] [Vital signs] [Physical 
examinations and weight measurement] [ECOG PS] [ECG] [Echocardiogram] [Blood pressure 
monitoring] [Adverse events] [Concomitant medication] [Return of apatinib] 
If a subject has not undergone imaging examinations within 4 weeks prior to the end of the study, 
the subject should undergo an imaging examination at the end of the study treatment or upon 
withdrawal from the study. For subjects with PD demonstrated by non-imaging evidence 
(intolerability, other conditions), a tumor evaluation will be carried out every 3 months until PD, 
death, or the initiation of other tumor treatments. 
7.4 Follow-up Period 
30 days after discontinuation/end of treatment 
[Vital signs] [Physical examinations and weight measurement] [ECOG PS] [Hematology] 
[Urinalysis] [Blood biochemistry] [Adverse events] [Concomitant medication] 
Adverse events will be recorded from the time when the subjects sign the informed consent form. 
AEs unrelated to the study drugs will be recorded to 30 days after the last dose. 
Treatment-related AEs will be collected until 90 days after the last dose of SHR-1210 or 30 days 
after the last dose of targeted anti-angiogenic therapy (whichever is longer). See the AE/SAE 
collection time limit in Section 8.3 for details. 
[Survival follow-up] After the study treatment is discontinued, the survival status and subsequent 
anti-tumor treatment can be collected through clinical or telephone follow-ups every 2 months 
until death. 

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Schedule of Activities 
Item 
Screening Period 
Treatment Period (28 days/cycle) 
Post-Treatment 
Survival 
Follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of Treatment/ 
Withdrawal 
(+ 3 d) 
End of 
treatment 
visit 
(± 3 d) 
Every 
2 months 
(± 3)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
Baseline Data 
Signing of Informed 
Consent 
× 
  
  
  
  
  
  
  
  
Demographics 
× 
  
  
  
  
  
  
  
  
Tumor History/ 
× 
  
Other Medical 
History[1] 
  
Concomitant 
Medication[2] 
 × 
 × 
 × 
  
Laboratory Tests 
Hematology[3] 
  
× 
 
× 
× 
× 
× 
× 
  
Urinalysis[4] 
  
× 
 
× 
× 
× 
× 
× 
  
Routine Stool Test[5] 
  
× 
  
× 
×  
× 
  
  
Blood 
biochemistry[6] 
  
× 
 
× 
× 
× 
× 
× 
  
Coagulation 
Function Test[7] 
  
× 
  
× 
×  
 
× 
  
  
T3, FT3, FT4, and 
TSH[8] 
× 
  
  
  
× 
  
× 
  
  
Pituitary Adrenal 
Axis Test[9] 
× 
 
 
 
 
 
 
 
 

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Item 
Screening Period 
Treatment Period (28 days/cycle) 
Post-Treatment 
Survival 
Follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of Treatment/ 
Withdrawal 
(+ 3 d) 
End of 
treatment 
visit 
(± 3 d) 
Every 
2 months 
(± 3)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
Myocardial 
Zymogram[10] 
  
× 
  
  
  
  
× 
  
  
HBV, HCV, and 
HIV Tests[11] 
× 
  
Pregnancy Test[12] 
  
× 
  
  
  
  
× 
  
  
Detection of EGFR 
Mutations and ALK 
Fusion Genes[13] 
× 
  
  
  
  
  
  
  
  
Clinical Evaluation and Examination 
Adverse Events[14] 
From informed consent to 30 days after the last dose 
  
Vital Signs[15] 
  
× 
× 
× 
× 
× 
× 
×  
  
Physical 
Examination 
and Weight 
Measurement[16] 
  
× 
× 
× 
× 
× 
× 
×  
  
ECOG PS 
  
× 
  
  
× 
× 
× 
  
ECG[17] 
  
× 
  
× 
×  
× 
× 
  
  
Echocardiography[18] 
  
× 
  
  
  
  
×  
  
  
Blood Pressure 
Monitoring[19] 
 
 
  
× 
× 
× 
× 
  
  
Pulmonary Function 
Test[20] 
× 
  
  
  
  
  
  
  
  

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Item 
Screening Period 
Treatment Period (28 days/cycle) 
Post-Treatment 
Survival 
Follow-up 
Within 3 
weeks before 
administration 
Within 1 week 
before 
administration 
Cycle 1 
Cycles 2-26 
Day 1 
Day 15 
Day 1 
Day 15 
End of Treatment/ 
Withdrawal 
(+ 3 d) 
End of 
treatment 
visit 
(± 3 d) 
Every 
2 months 
(± 3)  
(± 3 d) 
(± 3 d) 
(± 3 d) 
STUDY DRUGS 
Administration of 
SHR-1210[21] 
  
  
× 
× 
× 
× 
  
  
  
Administration of 
Apatinib[22] 
  
  
Oral administration once a day after meal 
  
  
  
Dispensation/Return 
of Apatinib[23] 
  
× 
× 
× 
×  
× 
× 
  
  
Imaging Evaluation 
Imaging 
Examination[24] 
× 
  
Once every 2 cycles in the first 6 cycles, 
followed by once every 3 cycles 
× 
  
  
Follow-Up After End of Treatment 
Time to 
Progression[25] 
  
  
  
  
  
  
Imaging evaluation will be carried out once 
every 3 months (± 7 d) until progressive disease 
or the initiation of other cancer treatments 
(subjects with non-imaging PD) 
Time of Death[26] 
  
  
  
  
  
  
  
  
× 
Blood Sampling and Tumor Tissue Sampling/Sample Collection 
PK Blood 
Sampling[27] 
  
  
× 
× 
× 
× 
  
  
  
Collection and 
Detection of 
Biomarkers[28] 
× 
  
  
  
  
  
  
  
  

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Note: 
[1] 
History of tumor/other diseases: reports of pathological findings, detection of EGFR mutations, and detection of ALK fusion gene; history of tumor 
surgery, chemotherapy, radiotherapy, and other disease treatments; history of tumor other than non-small cell lung cancer. 
[2] 
Record the concomitant medication and concomitant treatment given within 30 days prior to randomization and during the study period. Once the study 
treatment is interrupted, only the concomitant medication and treatment used to solve new or unresolved treatment-related AEs will be recorded. 
[3] 
Hematology: Hemoglobin, red blood cell count, white blood cell count, neutrophil count, lymphocyte count, and platelet count will be measured within 
7 days before enrollment, on Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of 
treatment. 
[4] 
Urinalysis: Urine protein, urine glucose, and urine occult blood (urine red blood cells and white blood cells). If two consecutive semi-quantitative protein 
tests show urine protein 2-3+, then a quantitative 24-h urine protein test is required. If semi-quantitative protein test shows urine protein > 3+, then a 
quantitative 24-h urine protein test shall be performed. The tests will be carried out within 7 days before the enrollment, on Day 15 of Cycle 1, Day 1 and 
Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of treatment. 
[5] 
Routine stool test: Occult blood; re-examination is required for fecal occult blood+; if fecal occult blood is confirmed, then a gastroscopy shall be 
performed. The test will be performed within 7 days before enrollment, on Day 15 of Cycle 1 and Day 1 of subsequent cycles, and upon completion of the 
study. 
[6] 
Blood biochemistry: bilirubin total, bilirubin conjugated, ALT, AST, AKP, γ-GT, protein total, albumin, urea or urea nitrogen, creatinine, uric acid, fasting 
blood glucose, TG, cholesterol, potassium, sodium, chlorine, calcium, phosphorus, blood lipase (only during the screening period and in the case of 
subsequent abdominal pain, abdominal distension and other symptoms of suspected pancreatitis), blood amylase (only during the screening period and 
subsequent abdominal pain, abdominal distension, and other symptoms of suspected pancreatitis). It will be carried out within 7 days before enrollment, on 
Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after the end of treatment. 
[7] 
Coagulation function: INR, APTT, PT, TT, FIB. The test will be performed within 7 days before enrollment, on Day 15 of Cycle 1 and Day 1 of 
subsequent cycles, and upon completion of the study. 
[8] 
Thyroid function test: including serum FT3, FT4 and TSH. The test will be performed 21 days before administration, on Day 1 of Cycle 2, and then once 
every 3 cycles. 
[9] 
Examination of the pituitary adrenal axis: including the tests of ACTH, cortisol, and sex hormones; carried out during the screening period. 
[10] Myocardial zymogram: Perform once within 7 days before enrollment and retest only upon the onset of symptoms of precordial pain and palpitations, and 
abnormal electrocardiograms hereafter; perform upon completion of the study. 

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[11] Hepatitis B, hepatitis C, and HIV tests: hepatitis B panel [If the test results are abnormal, viral replication (HBV DNA) test should be performed]; hepatitis 
C virus antibody (anti-HCV) test (If the test results are abnormal, virus titer should be tested); HIV antibody test. 
[12] Pregnancy test: The urine pregnancy test will be performed 72 h before the first dose for females of a childbearing age. If the result of the urine pregnancy 
test is positive, a serum pregnancy test shall be performed. If necessary, re-tests can be performed for confirmation. 
[13] If the subjects have previously been tested for EGFR mutations and ALK fusion gene, retests are not required; otherwise, the study site will perform 
relevant tests. If the subjects are positive for EGFR mutations, the test of ALK fusion gene will no longer be performed. 
[14] Adverse events: Adverse events will be collected from the time when the subjects sign the informed consent form. AEs unrelated to the study drugs will 
be collected to 30 days after the last dose. Treatment-related AEs will be collected until 90 days after the last dose of SHR-1210 or 30 days after the last 
dose of targeted anti-angiogenic therapy (whichever is longer). See the AE/SAE collection time limit in Section 8.3 for details. 
[15] Vital sign examination: Body temperature, respiration, pulse, blood pressure. The examination will be performed within 7 days before enrollment, on 
Day 1 and Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, upon completion of the study, and 30 days after treatment. 
[16] Physical examination and weight measurement: Examination of major body systems (head and face, skin system, lymph nodes, eyes, ears, nose, throat, 
oral cavity, respiratory system, cardiovascular system, abdomen, urogenital system, musculoskeletal system, nervous system and mental state) will be 
performed within 7 days before enrollment, on D1 and D15 of Cycle 1, D1 and D15 of subsequent cycles, upon completion of the study, and 30 days after 
the end of treatment. Body weight measurement will be started on D1 of Cycle 2 and carried out on D1 of subsequent cycles, upon completion of the 
study, and 30 days after the end of treatment. 
[17] 12-Lead ECG: Performed within 7 days before enrollment, on Day 15 of Cycle 1, Day 1 and Day 15 of subsequent cycles, and upon completion of the 
study. Abnormalities in ECG must be confirmed twice via additional ECG tests. 
[18] Echocardiography: Performed within 7 days prior to the enrollment and upon completion of the study, and when clinically significant abnormalities are 
found during the study. 
[19] Blood pressure monitoring: The blood pressure monitoring will be performed by the subjects themselves and recorded in their diary card. Blood pressure 
will be measured at least 3 times a week in the first 2 cycles. If the blood pressure is abnormal, the measurement will be carried out every day; If the 
blood pressure is normal, the blood pressure measurement will be carried out twice a week after 2 cycles; In addition, the blood pressure will be measured 
by the investigator during each follow-up. During each blood pressure measurement, smoking and coffee are prohibited for 30 min before the 
measurement, and subjects should at least rest for 10 min, and the sitting position will be taken during the measurement by placing the elbow at the same 
level as the heart. Each blood pressure measurement will be taken on the same side of the body. 

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[20] Pulmonary function test: Maximum vital capacity, the forced expiratory flow at 25-75% of forced vital capacity (FEF25-75), the peak expiratory flow rate 
(PEF), the maximum expiratory volume per second, diffusing capacity of the lungs for carbon monoxide (DLCO) and oxygen saturation. The test will be 
carried out during the screening period and then according to the judgment of the investigator in subsequent cycles. 
[21] SHR-1210 administration: SHR-1210 will be administered via intravenous injection (no prophylactics) with a fixed dose of 200 mg given in 30 min (no 
less than 20 min and no more than 60 min), once every 2 weeks. Each cycle contains 4 weeks (the subjects for the expanded PK study receive one dose 
on D1 of Cycle 1) and the longest period of drug use is 2 years. After 6 cycles of SHR-1210 administration, the treatment can be discontinued if the 
imaging evaluation confirms a CR. 
[22] Apatinib will be taken orally after meals, once a day, and continued throughout the study (the subjects for the expanded PK study receive the drug starting 
on Day 22 of Cycle 1. The administration on Day 28 of Cycle 1 and Day 28 of Cycle 2 will be given orally under fasting conditions). 
[23] Return and dispensation of apatinib. Apatinib will be dispensed on Day 1 of Cycle 1 (dispensed to subjects in the drug expansion study from Day 22 of 
Cycle 1). From Day 1 of Cycle 2, the return and dispensation of apatinib will be performed on Day 1 of each cycle. The remaining drugs will be returned 
first to verify the dose actually taken before new study drugs are dispensed. 
[24] Imaging test: including CT or MRI of the chest, abdomen, and brain. The baseline tumor assessment during the screening period can be extended to up to 
3 weeks before treatment. Qualified CT/MRI scan results obtained before signing the informed consent can be used for tumor assessment during the 
screening period. Bone scan should be performed upon clinically suspected bone metastasis. Absence of cerebral hemorrhage should be confirmed within 
21 days before randomization for subjects with stable brain metastases. 
During the treatment period, imaging examinations should be performed under the same conditions as those at baseline (layer thickness of the scan, use 
of contrast agent, etc.), and the lesions found at baseline should be checked every 2 cycles in the first 6 cycles of the treatment (bone scan shall be 
performed in the case of suspected bone progression or for CR confirmation). After 6 cycles, imaging examinations can be performed every 3 weeks as 
appropriate and can be performed upon the discovery of suspected new lesions. Initial assessment of PR/CR must be confirmed after 4 weeks; initial 
assessment of PD must be confirmed after 4 to 6 weeks (except for significant changes in the subjects' symptoms or rapid tumor progression). 
The window period for imaging examination schedule is ± 7 days. Unscheduled imaging examinations can be performed when progressive disease is 
suspected (such as worsening of symptoms). 
[25] A tumor assessment is required at the end of treatment for subjects who discontinue study treatment for reasons other than radiographic PD, if not 
performed within 4 weeks prior to study completion. Also, treatment efficacy will be followed up once every 3 months after study completion, until 
documentation of confirmed PD or start of a new anti-tumor treatment. 
[26] Survival follow-up: After the study treatment is discontinued, the survival status and subsequent anti-tumor treatment can be collected through clinical or 
telephone follow-ups every 2 months until death. 

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[27] PK blood sampling: In the stage of expanded PK study, PK blood sampling will be performed within 0.5 h before the administration of SHR-1210, and 
post-dose at 5 min (± 3 min), 2 h (± 10 min), 6 h (± 10 min), 24 h (± 0.5 h), 48 h (± 1 h), 168 h (± 1 h), 336 h (± 1 h), and 504 h (± 1 h) on D1, with 3 mL 
of blood collected at each time point. After the completion of PK blood sampling on D22, the administration of apatinib mesylate tablets will be started 
on the same day and continued at administration frequency of once a day. PK blood sampling will be performed within 0.5 h pre-dose on D28 and 
post-dose at 0.5 h (± 3 min), 1 h (± 5 min), 2 h (± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h), with 3 mL of 
blood collected at each time point. 
On D1 of Cycle 2, PK blood sampling will be performed within 0.5 h before the administration of SHR-1210, and at 5 min (± 3 min), 2 h (± 10 min), 6 h 
(± 10 min), 24 h (± 0.5 h), 48 h (± 1 h), 168 h (± 1 h), and 336 h (± 1 h) after the administration of SHR-1210, with 3 mL of blood collected at each time 
point. On D28 of Cycle 2, PK blood sampling will be performed within 0.5 h before the administration of apatinib, and at 0.5 h (± 5 min), 1 h (± 5 min), 
2 h (± 5 min), 3 h (± 5 min), 5 h (± 10 min), 8 h (± 10 min), 12 h (± 10 min), and 24 h (± 1 h) after the administration of apatinib, with 3 mL of blood 
collected at each time point. 
[28] A total of 14 mL of blood sample will be collected from each subject at baseline and divided into 1 tube of 10 mL and 1 tube of 4 mL. The collected blood 
samples will be transported to the central laboratory at room temperature according to the requirements specified in the central laboratory manual (no 
additional processing by the study center is required). Subjects with CR/PR during the study period must be subject to an additional biomarker blood 
sampling upon the onset of CR/PR and PD, respectively, with 10 mL in 1 tube, and the collection and transport requirements are the same as those in the 
baseline period; archived paraffin-embedded tumor tissue samples or fresh biopsy specimens will be collected. At least 10 slices are required, including 
3-5 slices of 3-4 μm thickness for PD-L1 detection, and 5-8 slices of 5-8 μm thickness (paraffin blocks may be directly collected without mounting onto 
slides), otherwise fresh biopsy specimens are required for detection of biomarkers such as tumor mutation burden (TMB). 
For cohort 4, the test results of tumor mutation burden (TMB) in the peripheral blood and/or tumor tissues will be verified before the subjects take the 
first dose of the study drug, so the TMB test for cohort 4 must be completed before the first dose. However, the delay in the screening period caused by 
TMB testing is allowed, but other tests (including imaging examinations) must be completed within 21 days prior to the first dose. 
See the laboratory manual for biomarker blood sampling and tumor tissue sampling/sample collection and disposal.

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8 SAFETY EVALUATION 
8.1 Adverse Events (AEs) 
8.1.1 
Definition of adverse event 
An adverse event (AE) refers to any untoward medical occurrence in a study subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. For the specific period of AE collection in this study, please refer to Section 8.3. 
AEs include the following: 
1) Worsening of pre-existing (prior to entering clinical study) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2) Any new AEs: Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
3) Clinically significant abnormal laboratory findings. 
The investigator should record any AEs that have occurred in detail, including the description of 
the AEs and all relevant symptoms, time of occurrence, severity, causality with the study drugs, 
duration, measures taken, and final results and outcomes. 
8.1.2 
Criteria for severity assessment of adverse events 
The severity of AEs will be determined using NCI-CTCAE v4.03. The following criteria can be 
used as references if an unlisted AE occurs: 
Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
treatment not indicated. 
Grade 2: moderate; minimal, local, or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (e.g., cooking, shopping, using 
the telephone, counting money, etc.); 
Grade 3: severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. Self-care ADL: Refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
Grade 4: life-threatening consequences; urgent intervention indicated. 
Grade 5: death related to AE. 

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8.1.3 
Criteria for the causality between AEs and investigational drug 
AEs include all unexpected clinical manifestations. All the AEs occurring after the signing of the 
ICF must be reported in the form of a clinical report according to AE reporting, regardless of 
whether the AEs are related to the investigational drug, whether the subject is administered with 
the investigational drug, and whether the subject has been administered with drugs. During the 
treatment, any discomfort or abnormal changes in objective laboratory tests should be recorded 
truthfully. The severity, duration, measures taken and outcome of the AE should be indicated. 
The clinical physician should comprehensively assess the causality between the AE and the study 
drugs by considering the timing between the administration of study drug and the occurrence of 
AE, characteristics and toxicology of the study drug, concomitant medications, underlying 
diseases, medical history, family history, etc. The causality assessment will be provided using the 
following five categories "definitely related, possibly related, unlikely related, definitely 
unrelated, and indeterminable". 
Related: The AE has a reasonable correlation with the study drug and can be attributed to the 
study drug from the medical (pharmacological or clinical) point of view. 
Unrelated: The AE has no reasonable correlation with the study drug and cannot be attributed to 
the study drug from the medical (pharmacological or clinical) point of view, and/or there are 
other reasonable reasons to explain the AE, such as underlying diseases, complications, and 
concomitant medications. 
8.2 Serious Adverse Events (SAEs) 
8.2.1 
Definition of serious adverse event 
A serious adverse event (SAE) refers to a medical occurrence during the clinical study that 
results in hospitalization, prolonged hospitalization, disability, incapacity, life-threatening or 
death, or congenital malformation. The following unexpected medical events are included: 
 
Events resulting in death; 
 
Life-threatening events (defined as when the subject is at immediate risk of death at the 
time of the event); 
 
Events resulting in hospitalization or prolonged hospitalization; 
 
Events resulting in permanent or serious disability/incapacity/impairment of work 
ability; 
 
Congenital anomalies or birth defects; 
 
Other important medical events (defined as events that may jeopardize the subject or 
require interventions to prevent any of the above). 

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8.2.2 
Progressive disease and death 
Progressive disease (PD) is defined as the deterioration of the subject's conditions caused by the 
primary tumor targeted by the study drug, including radiological progressions and progressions 
in clinical symptoms and signs. New metastases relative to the primary tumor or progressions of 
the previous metastases are recognized as PD. Life-threatening events, hospitalization or 
prolonged hospitalization, permanent or serious disability/incapacity/impairment of work ability, 
congenital anomalies or birth defects resulting from signs and symptoms of progressive disease 
should not be reported as SAEs on an expedited basis. Death caused by the symptoms and signs 
of PD should be reported as an SAE on an expedited basis. 
Death of a subject during the study, regardless of whether a new anti-tumor treatment is 
administrated, must be reported as an SAE. Deaths caused by symptoms and signs of PD as 
determined by the investigator shall be recorded in the eCRF and reported as SAEs. The term 
"death" shall not be used as an AE or SAE, but an outcome of an event. Events that result in 
death shall be recorded as AEs or SAEs. If the cause of death is unknown and cannot be 
determined at the time of reporting, the AE or SAE term "death of unknown cause" shall be used 
for documentation. 
8.2.3 
Hepatic enzyme abnormalities 
If the levels of AST and/or ALT are abnormal and meet the laboratory test abnormalities shown 
in the table below, such cases of hepatic enzyme abnormalities should be reported as SAEs. The 
investigator is required to strengthen the follow-up of the subjects, who should be followed up 
until their hepatic enzyme levels recover to the normal or baseline level. 
Baseline Period 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT/TBIL) 
Treatment period 
ALT or AST ≥ 3 × ULN  
with TBIL ≥ 2 × ULN 
and ALP ≤ 2 × ULN 
and no hemolysis 
AST or ALT ≥ 2 × baseline level, and ≥ 3 × ULN  
or AST or ALT ≥ 8 × ULN 
with increase in TBIL by ≥ 1 × ULN or TBIL level ≥ 
3 × ULN 
8.2.4 
Other anti-tumor treatments 
If the subjects start other anti-tumor treatments, please refer to Section 8.3 for the period of 
AEs/SAEs reporting.If a death occurs after the end of the study treatment but within the 
reporting period of serious adverse events, it must be reported promptly regardless of whether 
the subject received other treatments. 

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8.2.5 
Hospitalization 
AEs that result in hospitalization (even if for less than 24 h) or prolonged hospitalization during 
the clinical study should be considered as SAEs. 
Hospitalization does not include the following: 
• 
Hospitalization at a rehabilitation institution 
• 
Hospitalization at a sanatorium 
• 
General emergency admission (less than 24 h) 
• 
Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
• 
For social reasons (medical insurance reimbursement, etc.) 
Hospitalization or prolonged hospitalization unrelated to the worsening of an AE is not a SAE. 
For example: 
 
Hospitalization due to the pre-existing disease without new AEs and aggravation of the 
pre-existing disease (e.g., hospitalization to examine laboratory abnormalities that have 
persisted before the study until now); 
 
Hospitalization for management reasons (e.g., annual physical examination); 
 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to the exacerbation of an AE (e.g., elective cosmetic 
surgery); 
 
Scheduled treatment or surgery that should be documented throughout the entire study 
protocol and/or in the subjects' individual baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) or non-invasive procedures should not be 
reported as AEs. However, the disease condition leading to such procedures should be reported if 
it meets the definition of an AE. For example, acute appendicitis during the AE reporting period 
should be reported as an AE, and the resulting appendectomy should be recorded as the treatment 
of the AE. 

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8.2.6 
Reporting of serious adverse events 
In the event of an SAE, whether it is an initial or follow-up report, the investigator must 
complete the "Serious Adverse Event Report Form" immediately with signature and date, and 
notify the sponsor within 24 h of awareness. Relevant authorities must be informed of such an 
SAE in a timely manner according to regulatory requirements. 
The symptoms, severity, causality with the study drug, time of onset, time of treatment, measures 
taken, time and method of follow-up, and outcomes should be documented in detail in the SAE 
report. If the investigator believes that an SAE is not related to the study drug but potentially 
related to the study conditions (such as the discontinuation of past treatment, or comorbidities 
during the study), the causality should be explained in the description section of the SAE report 
form. If the severity of an ongoing SAE or its relationship to the study drug changes, a follow-up 
report should be submitted immediately. If an error is found in a previously reported SAE, such 
SAE may be revised, revoked, or downgraded in follow-up reports and reported in accordance 
with the SAE reporting procedure.  
Email the SAE reports to: hengrui_drug_safety@hrglobe.cn 
8.3 Collection and Follow-Up of AEs/SAEs 
The collection of AEs/SAEs should start from the time when the subjects sign the informed 
consent form and end 90 days after the last dose of SHR-1210 or 30 days after the last dose of 
anti-angiogenic targeted therapy (whichever is longer). SAEs occurring after this period that are 
suspected to be related to the study drug should be collected. See Table 8-1 below for specific 
requirements. Any AE/SAE should be followed-up until the event resolves, returns to the 
baseline level or ≤ Grade 1, reaches a steady state, or is reasonably explained (e.g., lost to 
follow-up, death). The investigator should try to obtain the best outcome and clear causality with 
the study drug. 
During each visit, the investigator should ask about the situation of AEs/SAEs that occur after 
the last visit and provide follow-up information in a timely manner based on the sponsor's query 
request. 

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Table 8-1. Collection period of AEs/SAEs 
Classification 
Collection/Recording Requirements 
AEs Unrelated to the Study Drug 
Up to 30 days after the last dose 
Treatment-Related AEsa  
Up to 90 days after the last dose of SHR-1210 or 30 days after the last dose 
of apatinib (whichever is longer) 
SAEs Unrelated to the Study Druga 
 
Fatal SAEs: up to 90 days after the last dose of SHR-1210 or 30 days 
after the last dose of apatinib (whichever is longer) 
 
Non-fatal SAEs: up to 30 days after the last dose 
Treatment-Related SAEsb 
No time limit 
a Non-serious AEs 
b Including fatal and non-fatal SAEs. 
8.4 Pregnancy 
If a female subject becomes pregnant, she must withdraw from the study. The investigator must 
report to the sponsor within 24 h of being notified of the pregnancy and fill out the "Pregnancy 
Report/Follow-up Form for Hengrui Clinical Studies". If the partner of a male subject becomes 
pregnant, the subject may continue the clinical study. The investigator must report to Hengrui 
within 24 h of being notified of the pregnancy and fill out the "Pregnancy Report/Follow-up 
Form for Hengrui's Clinical Studies". The investigator should follow up the pregnancy until 
1 month after delivery, and report the results to Hengrui. 
A negative pregnancy outcome (stillbirth, spontaneous abortion, or congenital malformation) is 
considered an SAE and should be reported according to the time requirements for SAEs. 
If the subject also meets the criteria for an SAE, an SAE report form should be filled out and the 
SAE should be reported according to the requirements for SAEs as well. 
8.5 Adverse Events of Special Interest 
When an AE of special interest specified in the study protocol occurs, the investigator must fill 
out the "Report of Adverse Event of Special Interest for Hengrui Clinical Studies" and report to 
the sponsor within 24 h of knowing the event. If an AE of special interest is also an SAE, the 
"NMPA Serious Adverse Event Report Form" must also be completed. 
• 
Grade ≥ 3 infusion reaction 
• 
Grade ≥ 2 diarrhea/colitis, uveitis, interstitial pneumonitis 
• 
Other Grade ≥ 3 immune-related AEs 

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• 
Any possible events of hepatic enzyme abnormalities (see 8.2.3, lacking other related 
causes of the abnormalities at the same time, e.g., PD, acute viral hepatitis, cholestasis, 
concomitant medication, concurrent liver disease, etc.) 
• 
Grade 4 amylase or lipase increased 
8.6 Infusion Reactions 
During the course of this study, the investigator should pay close attention to potential infusion 
and/or allergic reactions, especially acute immune-mediated adverse reactions (including 
cytokine storms). 
Generally, there is no need for prophylactics before infusion of SHR-1210. Based on published 
relevant information, an allergic reaction/event is most likely to occur within 24 h after infusion. 
If an allergic reaction/event occurs, the infusion should be slowed or interrupted according to the 
situation, and a supportive treatment should be given. In addition, prophylactics should be given 
before further administration. Possible allergic reactions include fever, chills, shiver, headache, 
rash, pruritus, joint pain, hypotension/hypertension, or bronchospasm. All Grade 3 or 4 infusion 
reactions should be reported in accordance with SAE reporting procedures. 
8.7 Immune-Related Adverse Events (irAEs) 
Immune-related adverse events (irAEs) are clinically significant side effects that are consistent 
with the immunological mechanisms of the study drug.irAEs require further serological, 
immunological and pathological (biopsy) data to support its diagnosis. Also, tumors, infections, 
metabolism, toxins, or other pathogenic factors must be ruled out. 
Management principles for immune-related adverse events (see Appendix IV for details): 
 Immune-related pneumonitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
pneumonia, such as cough and chest discomfort, in the subjects will be strengthened. 
Examinations will be carried out via imaging tests (e.g., X-ray), and a high-dose hormone 
therapy will be given to subjects with a Grade 2 or greater event. Subjects with a Grade 2 event 
can interrupt SHR-1210 and be treated, but subjects with a Grade 3 or 4 event should 
permanently discontinue SHR-1210. 

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 
Immune-related enteritis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
enteritis, such as abdominal pain, diarrhea, and hematochezia, in the subjects will be 
strengthened. A high-dose hormone therapy will be given to subjects with a Grade 2 or greater 
event. Subjects with a Grade 2 or 3 event can interrupt SHR-1210 and be treated, but subjects 
with a Grade 4 event should permanently discontinue SHR-1210. 
 Immune-related hepatitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
hepatitis, such as liver discomfort and abnormally increased transaminase, in the subjects will be 
strengthened. A high-dose hormone therapy will be given to subjects with a Grade 2 or greater 
event. Subjects with a Grade 2 event can interrupt SHR-1210 and be treated, but subjects with a 
Grade 3 or 4 event should permanently discontinue SHR-1210. 
 Immune-related thyroid dysfunction 
Thyroid dysfunction can occur at any time during the study. Therefore, in clinical studies of 
SHR-1210, thyroid functions of subjects will be regularly examined to closely monitor the 
clinical symptoms of thyroid dysfunction. After the occurrence of immune-related 
hyperthyroidism, the subject should be given a high dose of cortisone/prednisone. Hormone 
replacement therapy is used for the treatment of hypothyroidism, but glucocorticoids are not 
applicable. 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
thyroid dysfunction in the subjects will be strengthened. A high-dose hormone therapy will be 
given to subjects with a Grade 3 or greater event, but subjects with a Grade 4 event should 
permanently discontinue SHR-1210. 
 Immune-related nephritis and renal failure 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
nephritis in the subjects will be strengthened. A high-dose hormone therapy will be given to 
subjects with a Grade 2 or greater event. Subjects with a Grade 2 event can interrupt SHR-1210 
and be treated, but subjects with a Grade 3 or 4 event should permanently discontinue 
SHR-1210. 

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 
Immune-related hypophysitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
hypophysitis in the subjects will be strengthened. A high-dose hormone therapy will be given to 
subjects with a Grade 2 or greater event. Subjects with a Grade 2 or 3 event can interrupt 
SHR-1210 and be treated, but subjects with a Grade 4 event should permanently discontinue 
SHR-1210. 
 Other immune-related adverse reactions 
In principle, interruption of SHR-1210 is preferred based on the severity of the adverse reaction. 
The study treatment can be considered to resume when AE returns to Grade ≤ 1. The study 
treatment should be permanently discontinued if severe (Grade 3) or life-threatening (Grade 4) 
adverse reactions occur. 
The treatment of immune-related adverse reactions should be based on the medical practice and 
guidelines of the study center. The treatment recommendations for irAEs are shown in Table 8-2 
for reference. 
Table 8-2. Treatment recommendations for irAEs related to SHR-1210 for injection 
CTCAE Grade 
Clinical Management* 
SHR-1210 Treatment 
Grade 1 (mild) 
- Close observation, especially for diarrhea 
• Supportive care 
Continue 
Grade 2 (moderate) 
 
- Closely monitoring 
• Supportive care 
• Local application of steroids, such as for 
dermatitis/colitis, etc. 
Symptoms persist for ≥ 7 days, start 1 mg/kg of 
prednisone or equivalent 
Symptoms are aggravated, give intravenous or oral 
administration of 1 mg/kg prednisone 
Interrupt, resume when recovers 
to Grade ≤ 1 
Grade ≥ 3 (severe)* 
-2 mg/kg of prednisone or equivalent 
Permanent discontinuation 
* The treatment may not be interrupted for Grade 3 local skin and endocrine disorders, because they can often heal 
(skin) or be treated using an alternative treatment (endocrine) 
(Weber, Jeffrey S. MD, PhD, et al., "Toxicities of immunotherapy for the practitioner," J Clin Oncol, April 2015) 

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9 MANAGEMENT OF ADVERSE EVENTS 
9.1 Immune-Related Adverse Events (irAEs) 
Immune-related adverse events (irAEs) are clinically significant side effects that are consistent 
with the immunological mechanisms of the study drug.irAEs require further serological, 
immunological and pathological (biopsy) data to support its diagnosis. Also, tumors, infections, 
metabolism, toxins, or other pathogenic factors must be ruled out. 
Management principles for immune-related adverse events (see Appendix IV for details): 
The treatment of immune-related adverse reactions should be based on the medical practice and 
guidelines of the study center. The treatment recommendations for irAEs are as follows. The 
details are shown in Appendix IV for reference. 
Subjects using hormones should pay attention to calcium and vitamin D3 supplement, acid 
suppression, and protection of gastric mucosa. 
 Immune-related pneumonitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
pneumonia, such as cough and chest discomfort, in the subjects will be strengthened. A 
high-dose hormone therapy will be given to subjects with a Grade 2 or greater event confirmed 
by chest CT. Subjects with Grade 2 immune-related pneumonitis can interrupt SHR-1210 and be 
treated, but subjects with a Grade 3 or 4 immune-related pneumonitis should permanently 
discontinue SHR-1210. Consultation with the Department of Respiration is recommended. 
For specific operations, refer to the followings: 
Grade 2 event: 1 mg/kg/day of methylprednisolone or equivalent given via intravenous or 
oral administration. The changes in CT should be closely monitored. After the event recovers 
to Grade 1, oral administration of 0.5 mg/kg/day of prednisone can be continued for 2 weeks, 
then the dose of prednisone should be reduced by 5 mg/week until drug discontinuation. 
Grade 3 event: 2-4 mg/kg/day of methylprednisolone or equivalent given via intravenous 
injection. The changes in CT should be closely monitored. After the event recovers to 
Grade 1, the dose of methylprednisolone should be reduced by 50% every 3 days. Oral 
administration of 0.5 mg/kg/day of prednisone can be continued for 2 weeks, then the dose of 
prednisone should be reduced by 5 mg/week until drug discontinuation. 
If the hormone therapy does not improve or deteriorate the condition after 3-5 days, a 
combination therapy with immunosuppressants may be used for the treatment after 
discussion with the sponsor. 

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 Immune-related hepatitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
hepatitis, such as liver discomfort and abnormally increased transaminase, in the subjects will be 
strengthened. A high-dose hormone therapy will be given to subjects with a Grade 2 or greater 
event. For specific operations, refer to the followings: 
Grade 2 hepatitis: 0.5-1 mg/kg/day of methylprednisolone or equivalent given via intravenous or 
oral administration. The changes in liver function parameters should be closely monitored. After 
the event recovers to Grade 1, the dose of hormone should be slowly reduced in a period no less 
than 1 month. 
Grade 3 event: 1-2 mg/kg/day of methylprednisolone or equivalent given via intravenous or oral 
administration. The changes in liver function parameters should be closely monitored. After the 
hepatitis recovers to Grade 1, the dose of hormone should be slowly reduced in a period no less 
than 1 month. 
If the hormone therapy does not improve or deteriorate the condition after 3-5 days, a 
combination therapy with immunosuppressants may be used for the treatment after discussion 
with the sponsor. 
 Immune-related enteritis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
enteritis, such as abdominal pain, diarrhea, and hematochezia, in the subjects will be 
strengthened. A high-dose hormone therapy will be given to subjects with a Grade 2 or greater 
event. Subjects with Grade 2 or 3 immune-related enteritis can interrupt SHR-1210 and be 
treated, but subjects with Grade 4 immune-related enteritis should permanently discontinue 
SHR-1210. 
 Immune-related thyroid dysfunction  
Thyroid dysfunction can occur at any time during the study. Therefore, in clinical studies of 
SHR-1210, thyroid functions of subjects will be regularly examined to closely monitor the 
clinical symptoms of thyroid dysfunction. After the occurrence of immune-related 
hyperthyroidism, the subject should be given a high dose of cortisone/prednisone. Hormone 
replacement therapy is used for the treatment of hypothyroidism, but glucocorticoids are not 
applicable. 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
thyroid dysfunction in the subjects will be strengthened. A high-dose hormone therapy will be 
given to subjects with a Grade 3 or greater event, but subjects with a Grade 4 event should 
permanently discontinue SHR-1210. 

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 Immune-related nephritis and renal failure 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
nephritis in the subjects will be strengthened. A high-dose hormone therapy will be given to 
subjects with a Grade 2 or greater event. Subjects with a Grade 2 event can interrupt SHR-1210 
and be treated, but subjects with a Grade 3 or 4 event should permanently discontinue 
SHR-1210. 
 Immune-related hypophysitis 
In the clinical study of SHR-1210, the monitoring of signs and symptoms of immune-related 
hypophysitis in the subjects will be strengthened. A high-dose hormone therapy will be given to 
subjects with a Grade 2 or greater event. Subjects with a Grade 2 or 3 event can interrupt 
SHR-1210 and be treated, but subjects with a Grade 4 event should permanently discontinue 
SHR-1210. 
 Other immune-related adverse reactions 
In principle, interruption of SHR-1210 is preferred based on the severity of the adverse reaction. 
The study treatment can be considered to resume when AE returns to Grade ≤ 1. The study 
treatment should be permanently discontinued if severe (Grade 3) or life-threatening (Grade 4) 
adverse reactions occur. 
9.2 Infusion Reactions 
As a fully humanized monoclonal antibody, SHR-1210 poses relatively lower risks of infusion 
reactions and prophylactic is therefore not required. Once an infusion reaction occurs, the 
infusion should be slowed or interrupted accordingly, and a supportive treatment should be 
given. Also, prophylactics should be given before further administrations. For acute infusion 
reactions (including cytokine release syndrome, angioedema, anaphylactic shock, allergic 
reactions, please refer to terms and criteria of NCI CTC AE v4.03), their relevant symptoms and 
signs usually occur during drug infusion or shortly after infusion, and usually disappear within 
24 h after the infusion is completed. The signs and symptoms include: allergic 
reaction/hypersensitivity reaction (including drug-induced fever), coughing, chills, rigor, 
dizziness, headache, fatigue (weakness, somnolence), rash/peeling skin, pruritus/itching, 
arthralgia, myalgia, hypotension/hypertension, nausea, vomiting, diaphoresis, tachycardia, cancer 
pain, urticaria, dyspnea (shortness of breath), or bronchospasms. Any Grade 3 or 4 infusion 
reactions must be reported to the sponsor within 24 hours, and should be reported as SAEs if the 
criteria for SAE are met. 
Management of allergic reactions should be based on the medical practice and guidelines of the 
study center. The treatment recommendations for infusion reactions are shown below for 
reference. 

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Table 9-1. Treatment recommendations for infusion reactions 
CTCAE Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade 1 (mild) 
Mild and transient 
reactions;  
Bedside observation and close monitoring until 
recovery. (Prophylactics are recommended for 
subsequent infusion: diphenhydramine 50 mg or 
equivalent, and/or acetaminophen 325-1000 mg, 
at least 30 minutes prior to SHR-1210 
administration) 
Continue 
 
Grade 2 
(moderate) 
Moderate reactions 
requiring treatment 
or interruption; 
rapidly resolve after 
symptomatic 
treatment (such as 
antihistamines, 
non-steroidal 
antiphlogistics, 
anesthetics, 
bronchodilators, 
intravenous fluids, 
etc.) 
Intravenous drip of normal saline, 50 mg of 
diphenhydramine IV or equivalent and/or 
325-1000 mg of acetaminophen; 
Bedside observation and close monitoring until 
recovery. 
Corticosteroids or bronchodilators can be 
considered based on clinical needs; 
The amount of study drug infused should be 
recorded in the original medical record; 
Prophylactics are recommended for subsequent 
infusion: diphenhydramine 50 mg or equivalent, 
and/or acetaminophen 325-1000 mg, at least 
30 minutes prior to SHR-1210 administration. 
Use corticosteroids (equivalent to 25 mg of 
hydrocortisone) when necessary. 
Interrupt. 
Re-administer at 50% 
of the initial rate after 
symptoms resolve. If 
no reaction occurs 
within 30 min, restore 
the original infusion 
rate (100%). Closely 
monitor. If the 
symptoms recur, the 
administration of the 
current SHR-1210 
dose will be 
discontinued. 
Grade ≥ 3 
(severe)  
Grade 3: Severe 
reactions with no 
rapid resolution after 
intervention and/or 
treatment 
interruption; 
symptom recurrence 
after resolution; 
sequelae requiring 
hospitalization. 
Grade 4: 
life-threatening 
Immediately discontinue SHR-1210; 
Administer normal saline by intravenous 
infusion. 
• Bronchodilators are recommended: 0.2-1 mg 
of subcutaneous 1:1000 adrenaline injection or 
slow intravenous injection of 1:10000 
adrenaline solution 0.1-0.25 mg, and/or 
intravenous diphenhydramine 50 mg plus 
methylprednisolone 100 mg or equivalent if 
necessary; 
• Based on the guidelines for anaphylaxis of the 
study center; 
Bedside observation and close monitoring until 
recovery. 
Permanently 
discontinue. 
9.3 Symptomatic Treatment for Apatinib-Related Adverse Reactions 
1) Hand-and-foot syndrome (HFS)  
Hand-and-foot syndrome is skin toxicity with palmar-plantar dysesthesia or acral erythema and 
manifests especially in areas under pressure or force. It may occur in patients with tumor during 
chemotherapy or molecular targeted therapy. HFSR is characterized by numbness, dysesthesia, 
paraesthesia, tingling, no pain or pain, skin swelling, or erythema, desquamation, chapping, 
scleroma-like blisters, and severe pain.  

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HFS grading:  
Grade 1: numbness/dysesthesia/paraesthesia, painless swelling or erythema of the hands and/or 
feet and/or discomforts that does not affect normal activities.  
Grade 2: painful erythema and swelling of the hands and/or feet and/or discomforts affecting 
patients' activities of daily living.  
Grade 3: wet desquamation, ulcers, blisters, or severe pain of hands and/or feet and/or severe 
discomforts that causes the patients to be unable to work or perform activities of daily living. 
Intense pain and loss of skin function, relatively rare.  
Symptomatic treatment and management of HFS:  
Some necessary symptomatic and supportive treatments must be taken, including: strengthen 
skin care, keep skin clean, and avoid secondary infections; avoid pressure or friction; use 
moisturizers or lubricants, topically use lotions or lubricants containing urea and corticosteroids; 
topically use antifungal or antibiotic treatment if necessary.  
Note: If Grade 3 or greater HFS occurs for more than 3 times with an aggravating trend, the 
subject should discontinue the study treatment and withdraw from the study.  
2) Hypertension 
Patients should be strictly screened according to blood pressure requirements in the inclusion and 
exclusion criteria prior to enrollment. Patients with hypertension can control the blood pressure 
by adjusting the dose of or adding new antihypertensive drugs before administering the study 
drug. The blood pressure must be under 140/90 mmHg (average of 2 blood pressure 
measurements taken at least 24 h apart) before randomization.  
Monitoring and handling of such hypertension: Blood pressure should be monitored at least 
3 times a week during the first 2 cycles of the targeted pharmacological treatment.  
If hypertension occurs or aggravates during the administration, 1) give or adjust the dose of 
antihypertensive drugs, and 2) adjust the study drug as per the study protocol.  
Recommended antihypertensive drugs during study: 1) dihydropyridine calcium channel 
antagonists (such as nifedipine sustained release tablets); 2) angiotensin converting enzyme 
inhibitors (ACEIs); 3) angiotensin II receptor blockers (ARBs); 4) Beta blockers.  
Diuretic antihypertensive drugs are not recommended. Antihypertensive drugs with an inhibitory 
effect on CYP3A4, such as nicardipine, diltiazem and verapamil, are prohibited during the 
administration period of the study drug. Subjects with hypertensive crisis should discontinue 
apatinib and withdraw from the study.  

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3) Hemorrhage  
Symptomatic treatment should be actively given for hemorrhage of digestive tract, including 
fecal occult blood (++) or above, hematemesis or bloody stool. Patients with upper 
gastrointestinal hemorrhage should be put under fasting and given acid suppression, gastric 
mucosal protection, hemostasis (transamin, reptilase, etc.), as well as octreotide if necessary; 
patients with lower gastrointestinal hemorrhage should be given hemostasis, blood transfusion 
and supportive care, etc.; for those whose bleeding cannot be controlled, assistance from the 
surgery department should be requested immediately. 
Patients with hemoptysis should be given hemostasis, blood transfusion and supportive care, etc.; 
for those whose bleeding cannot be controlled, assistance from the surgery department should be 
requested. 
Note: The subjects diagnosed with cerebral hemorrhage, pulmonary hemorrhage of Grade 2 or 
greater, and hemorrhage of Grade 3 or greater should discontinue the study treatment, receive 
symptomatic treatment, and withdraw from the study. If hemorrhage and coagulation 
abnormalities (except for cerebral hemorrhage and pulmonary hemorrhage of Grade 2 or greater) 
occur, adjust the dose following the principles below: 
4) Proteinuria 
All subjects should be closely monitored for proteinuria throughout the entire treatment period, 
especially for those with a history of hypertension. For those with a urine protein result of ++ to 
+++ in 2 consecutive tests, a 24-h urine protein assay is required. For those with urine protein of 
++++ or above, a 24-h urine protein assay is required.  
Note: In the case of nephrotic syndrome, the subject should discontinue the treatment 
permanently and withdraw from this clinical study.  
5) Thrombosis  
If any arterial thrombosis (such as cerebral ischemia, stroke, angina pectoris, myocardial 
infarction, etc.) occurs, the subject should discontinue the treatment immediately and withdraw 
from the study. In the case of any symptomatic IV venous thrombosis, the subject should 
discontinue the treatment and withdraw from the study.  
Once the symptoms of thrombosis are observed, symptomatic treatment, surgery, or 
anticoagulants shall be immediately given.  

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6) Reversible posterior leukoencephalopathy syndrome  
Reversible posterior leukoencephalopathy syndrome has not been reported in completed clinical 
studies of apatinib, but has been found in clinical application of newly marketed anti-angiogenic 
macromolecular antibodies and small molecule inhibitors.  
The clinical manifestations are headache, altered consciousness/confusion, abnormal 
vision/blindness, and convulsion, often accompanied by hypertension. The causes of reversible 
posterior leukoencephalopathy syndrome are yet unidentified. Once the symptoms are suspected, 
the study drug should be discontinued immediately, and symptomatic treatment and strict blood 
pressure control should be given. The subject will withdraw from the study once the imaging 
diagnosis is confirmed. 
7) Fatigue and weakness  
Fatigue and weakness are common tumor-related clinical symptoms, the cause of which might be 
electrolyte disturbance, abnormal liver function, abnormal cardiac function, etc. Also, fatigue and 
weakness are common adverse reactions of targeted anti-angiogenic drugs, such as sunitinib, 
pazopanib, and sorafenib. Clinical reports show that targeted anti-angiogenic drugs may increase 
the incidence of fatigue and weakness through hypothyroidism.  
In previously completed clinical studies of apatinib, subjects in the treatment group showed a 
higher incidence of fatigue and weakness than those in the control group, and the mechanism 
behind the increased incidence of fatigue and weakness caused by apatinib is yet unidentified.  
Therefore, close attention should be paid when a patient show and report Grade 2 or greater 
fatigue and weakness. In the case of Grade 3 or greater fatigue and weakness, the patient should 
be admitted to the hospital immediately for detailed examinations to exclude possible reasons 
such as electrolyte disturbance, abnormal liver function, cardiac dysfunction (ECG, 
echocardiography), and abnormal hormone levels (adrenal hormones, thyroid hormones). 
A symptomatic treatment should be given and the dose should be interrupted or modified 
according to the principle of dose modification. 
8) Abdominal pain 
Abdominal pain is not uncommon in the treatment of lung cancer with apatinib, which are 
mostly a concomitant symptom of tumor. Also, gastrointestinal perforation occasionally occurs 
in clinical studies of apatinib and other anti-angiogenic drugs. For subjects with abdominal pain, 
the investigator should be cautious of potential gastrointestinal perforation. Upon the observation 
of gastrointestinal perforation, the drug should be discontinued immediately, and the subject 
should withdraw from the study and be given an active symptomatic treatment.  

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9) Interstitial pulmonary fibrosis  
The clinical physicians should fully understand the conditions of subjects and be familiar with 
the drugs that may lead to pulmonary toxicity. The clinical symptoms and changes in chest X-ray 
or CT should be closely monitored. Once cough, chest tightness, labored breathing, dyspnea, and 
hemoptysis of unknown causes, the drug should be discontinued as soon as other causes (such as 
infection and heart failure) are ruled out. Alveolar lavage fluid analysis and surgical lung biopsy 
are important means to diagnose interstitial lung disease. Currently, no therapy yields a 
satisfactory therapeutic effect on pulmonary fibrosis, and correction of hypoxemia and timely 
administration of corticosteroids are recommended following "Guidelines for Diagnosis and 
Treatment of Idiopathic Pulmonary (Interstitial) Fibrosis" issued by the Chinese Medical 
Association Respiratory Diseases Branch.  
Note: Consult specialists when necessary. 
10 EFFICACY EVALUATION 
The objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), time 
to response, progression-free survival (PFS), 12-month survival, and overall survival (OS) will 
be evaluated. 
The tumor imaging assessment will be performed once every 2 cycles (8 weeks) based on 
RECIST v1.1 (Appendix V). For subjects with CR/PR for the first time, the results should be 
confirmed after 4 weeks. The tumor assessment will be carried out once every 3 cycles 
(12 weeks) 6 months after the first dose of the drug. 
Imaging results (including MRI and CT) of all subjects should be confirmed by blinded 
independent imaging experts. Subjects with efficacy evaluation results of CR, PR, SD, and PD 
should first be reviewed by the Principal Investigator (PI) of each study site, with all imaging 
results of response evaluation saved and finally collectively and independently assessed and 
confirmed by imaging experts. 
11 STUDY MANAGEMENT 
11.1 
Ethics and Informed Consent 
This clinical study must comply with the "Declaration of Helsinki (1996)", NMPA's "Good 
Clinical Practice (GCP)" and relevant regulations. The study can only be initiated after obtaining 
the approval from the IRB/IEC. During the study, amendments to this study protocol must be 
reported to the IRB/IEC and be archived. 

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The clinical investigator must follow all applicable laws and regulations to protect the subjects. 
The informed consent form used in the informed consent process must be approved by the 
IRB/IEC and be readily available for inspection. 
The clinical investigator must inform subjects that participation in the clinical study is voluntary 
and that they have the right to withdraw from the study without being discriminated or retaliated, 
and their medical treatment and right will not be affected, and they can continue to receive other 
therapies. All subjects should be informed that the participation of the study and their personal 
information will be kept confidential. Also, the subjects should be informed of the nature, 
objectives, expected potential benefits, and possible risks and inconvenience of the clinical study, 
other alternative treatment options, and rights and obligations of the subjects in accordance with 
the "Declaration of Helsinki". Subjects should be given sufficient time to consider whether to 
participate in the study and sign the informed consent form. 
Before the implementation of any process required by the study protocol, the subjects must: 
 
Be informed of information relevant to the study and all content and terms in the 
informed consent form. 
 
Be given sufficient time to ask questions and consider whether to participate in the 
study. 
 
Be enrolled in the study voluntarily. 
 
Sign and date the informed consent form approved by the IRB/IEC. 
In the case of major changes during the study, the protocol should be amended. Unless it is 
necessary to eliminate obvious direct harms to subjects, the investigator must not make any 
change to the study without the approval of the IRB/IEC and sponsor.Changes to the study 
protocol intended to eliminate obvious direct risks to subjects can be implemented immediately, 
but the changes must be recorded in protocol amendments, reported to the IRB/IEC, and 
submitted to relevant regulatory authorities within a required period. The process of protocol 
amendment must follow the same process of review and approval of the original protocol. 
11.2 
Protocol Amendments 
The "Clinical Study Protocol" and "Clinical Study Case Report Form" are formulated by the PI, 
agreed upon by Hengrui, which is the study sponsor and study drug provider, and approved by 
the Ethics Committee of the hospital before implementation. During the clinical study, any 
changes to the study protocol must be discussed with Hengrui, and approved by the Ethics 
Committee. 

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11.3 
Quality Assurance of Clinical Study 
To ensure the quality of the study, the sponsor and PI will jointly discuss and formulate a clinical 
study plan before the formal study initiation. All the relevant study staff in the clinical study shall 
be trained for the study protocol and GCP. 
The study drug in the clinical study shall be managed in accordance with the SOP, including 
receiving, storage, dispensing, and returning. 
Hengrui may conduct monitoring and auditing on the request of the PI. The CRA shall follow the 
GCP and SOP, make visits to the study site for clinical monitoring on a regular basis or 
according to the actual conditions, supervise the implementation and progress of the clinical 
study, check and confirm that all data recorded are correct and intact and are consistent with 
source data, and ensure that the clinical study is implemented following the study protocol. The 
investigator should cooperate with the monitor actively. 
According to the GCP guidelines, necessary measures shall be taken at the design and 
implementation stages of the study to ensure that all collected data are accurate, consistent, 
intact, and reliable.All observed results and abnormal findings in the clinical study must be 
verified and recorded in a timely and serious manner to ensure data reliability. All instruments, 
equipment, reagents, and standards used in various tests in the clinical study must have stringent 
specifications and be operated under normal conditions. 
11.4 
Data Management 
Data management is to ensure the reliability, integrity, and accuracy of the data, with an 
objective to obtain authentic data of high quality for statistical analysis. 
Data will be collected and managed using the electronic case report form (eCRF). 
11.4.1 Data collection 
Data will be collected using the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. will provide 
an electronic data capture (EDC) system. Company staff will deliver EDC system training to the 
designated staff of study site. Access to EDC system will only be granted to the study site staff 
who have completed the training. The PI or dedicated data entry person (CRC) should input data 
into the EDC system in accordance with the requirements of the visit procedures and the eCRF 
completion guide. The logic verification program in the system will verify the integrity and logic 
of the clinical study data entered into the EDC system and generate an error message prompt for 
questionable data. The PI or CRC is permitted to modify or explain the problematic data. After 
the database is locked, the investigator will receive a CD-ROM or copy of subject data to archive 
at the study site. 

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Hengrui is the sole owner of all original eCRFs. Aside from Hengrui or the representatives from 
regulatory authorities, no one is allowed to provide any data to a third party. The investigator is 
ultimately responsible for collection and report of all clinical and laboratory data recorded in 
eCRFs and other data collection forms (source records) to ensure the attributability, legibility, 
timeliness, primitiveness, accuracy, durability, integrity, and consistency of the data. 
Signature of the investigator or authorized personnel must sign to confirm the authenticity of the 
data in eCRFs. Any data correction in source record or eCRF should be dated, signed, and given 
with necessary explanations. Source data cannot be covered. 
Source records are usually graphs from a hospital or a physician, In this case, the data collected 
in the eCRF must be consistent with those in the graph. An eCRF can be used as a source record 
under certain circumstances. The study site is required to provide documents to clarify the data 
that should be recorded in eCRF and to use the eCRF as a source record. 
11.4.2 Data management and quality control 
To ensure authenticity and reliability and improve the quality of the clinical data, the CRA will 
monitor the integrity, consistency, and accuracy of the study data in the database, and guide the 
study site staff to add or correct the data whenever necessary. The CRA or data manager will 
send electronic query form to the PI or CRC for problematic data. The PI or CRC must respond 
and provide correction or explanation of the problematic data. Multiple queries may be raised 
when necessary until the problem is solved. The medical director and data manager should 
perform consistency comparison of SAEs periodically. 
At the end of the study, the data manager and medical personnel will conduct a final quality 
control on all data in the database, summarize all protocol deviations and violations during the 
study, and hold a data verification meeting. Database locking and unblinding will be carried out 
after the quality requirements have been met. The data manager will export the data to the 
statistics department for data analysis. 
11.4.3 Data review and study site monitoring 
Before the initiation of the study, a representative from Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. will introduce study protocol and eCRF (Part 2) to the investigator and staff at the initial 
visit to the study site. During the study, the CRA will visit the study center on a regular basis to 
monitor the integrity of the subjects' records and accuracy of the eCRF, compliance with the 
study protocol and GCP, and progress of the enrollment, and to ensure that the storage, 
dispensing, and count of the study drug are performed according to the requirements. During 
these visits, the major research personnel are required to assist the work of CRA. 

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The investigator shall keep the source documents of each subject, including all medical records 
and visit records (outpatient or inpatient record), such as demographic parameters, medical 
information, lab results, ECGs, and result of other examinations and evaluations. All information 
on the eCRF must come from the source documents of the subject. The investigator shall also 
keep the informed consent forms signed by the subjects. 
The investigator must ensure that all source documents are available for monitoring to verify 
their consistency with the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. requires to 
completely monitor the signed informed consent forms, compliance with inclusion/exclusion 
criteria, SAEs records, and all data required for evaluation of primary endpoints and safety 
endpoints. Additional monitoring will be performed on consistency of source data and eCRF 
according to monitoring plan specified by the study. No information related to subjects' identity 
in the source document will be disclosed. 
11.4.4 Record retention 
To fulfill the review and/or audit requirement of regulatory authorities or Hengrui, the 
investigator/study site must agree to keep all relevant records, including all subjects' ID number 
(with sufficient information linked to the records, such as the CRF and medical record), all 
original informed consent forms, all copies of the CRF, safety reports, source records, detailed 
treatment records, and relevant communication documents (such as letters, minutes, and 
telephone reports). The investigator/study site should keep the records according to related 
specifications. 
If the study record cannot be kept for any reasons, the investigator/study site should inform 
Hengrui in advance. Study documents should be kept by the study site for 5 years after 
completion of the clinical study. Hengrui will inform the investigator/study site if the documents 
are no longer required to be retained. 
12 DATA MANAGEMENT AND INTELLECTUAL PROPERTY RIGHTS 
12.1 
Data Processing 
After the completion of the study, data will be processed by the data statistics company 
authorized by the sponsor. Inconsistency in the documents will be discovered via data 
verification. Any inconsistency in the documents should be clarified by the investigator through 
CRA. Database will be locked after the data is verified. No access is allowed without 
authorization. Following database locking, the statistician will unblind the data after applying 
with the sponsor and PI and obtaining agreement from all the three parties. To ensure the safety 
of the data, irrelevant personnel cannot access or modify data. Data should be backed up. Any 
changes to the data should be approved with written agreements by the principal investigator, 
statistician, and data manager before it can be changed. 

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12.2 
Publication of Study Results 
The ownership of the study results belongs to both the PI and Hengrui. Hengrui does not limit 
the publication of any collected or generated data by the investigator, regardless of whether the 
results are beneficial to the study drug. The investigator must promise that no data relevant to the 
study and/or study results should be published on journals and academic or commercial 
conferences without written permission from Hengrui, and also understand that Hengrui will not 
disapprove the publication without reasons. 
However, the investigator should inform Hengrui in advance to review any proposed publication 
or other forms of release before submission or publication to prevent unintentional leakage of 
confidential information or unprotected inventions. The investigator should provide Hengrui with 
the manuscript, abstract, or full text of all planned publications (posters, invited lectures, or guest 
lectures) at least 30 days prior to the submission for publication or other forms of release. 
Hengrui will check the content according to the laws and regulations and intellectual property. To 
protect the intellectual property, especially before the acquisition of patent, the investigator 
should agree to delay or cancel the publication. Before open publication, Hengrui can require the 
investigator to delete any previously unpublished confidential information. 
The investigator is not allowed to mention Hengrui in their promotional materials or publications 
before obtaining written agreement from Hengrui. In the meantime, sponsors are not allowed to 
use the investigator's name in promotional materials or publications before obtaining written 
agreement from the investigator and/or collaborator. 
13 STATISTICAL ANALYSIS 
13.1 
Determination of Sample Size 
The sample size in Stage I is primarily based on clinical considerations, and the number of 
subjects actually enrolled in each dose group is determined by the number of subjects who show 
clinically significant toxicity during the observation period for tolerability. During the expansion 
stage of PK study, 10-12 subjects are required for each group. The sample size in Stage I is 
40-60 subjects. 
In Stage II, for cohort 1, assuming that the ORR of the combination therapy is 30% with a 
bilateral alpha of 0.05, enrollment of 62 subjects will have a 80% power to ensure that the ORR 
of the combination therapy has a lower 95% CI limit of > 15%. If the dropout rate is 20%, 
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For cohorts 2 and 3, assume that the ORR point estimate of each cohort is 30% and the width of 
the 90% confidence interval is 0.3, 38 subjects are required for each group when a 20% dropout 
rate is considered. 
For cohort 4, assume that the ORR point estimate is 50% and the width of the 90% confidence 
interval is 0.4, 20 subjects are required to be enrolled. 
In Stage II, the four cohorts require to enroll a total of 174 subjects. 
13.2 
Statistical Hypotheses 
The primary endpoint in Stage II is ORR. 
Null hypothesis: ORR = 15% 
Alternative hypothesis: ORR ≠ 15% 
13.3 
Analysis Sets 
Full analysis set (FAS) 
All subjects who have received at least one dose of the study drug. 
Evaluable set (ES) 
ES is a subset of FAS, which is defined as the subjects who have received at least one dose of the 
study drug, and have at least one post-baseline imaging assessment for efficacy. Per-protocol set 
All enrolled subjects who have received at least one dose of the study drug without major 
protocol deviation. 
Safety analysis set 
All enrolled subjects who have received at least one dose of the study drug and have safety 
record after administration. This analysis set is used for safety analysis. 
Pharmacokinetic analysis set (PKS):  
1) Concentration analysis set 
PK concentration analysis set is defined as the subjects who have received the study drug and 
have at least one blood concentration observation per cycle. 
2) Parameter analysis set 
PK parameter analysis set is defined as the subjects who have received the study drug and have 
at least one primary PK parameter per cycle. Subjects who have not completed the PK study 
should be excluded. 

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13.4 
Statistical Analysis Plan  
Main part of the study is defined as 6 months after the last subject have received the first dose of 
the drug in Stage I and Stage II. Statistical analysis will be carried out after the completion of the 
main part, and the report will be submitted. At the end of study, which is 12-24 month after the 
first does of the last subject in Stage II, the secondary endpoints, including 12-month survival 
rate and overall survival, will be included in supplementary analysis. 
13.4.1 General analysis 
Study results will mainly be analyzed using descriptive statistics. Numerical data will be 
summarized in means, standard deviations, medians, maximums, and minimums. Categorical 
data will be summarized in frequencies (proportions), percentages, and confidence intervals. 
All statistical analyses will be performed using SAS version 9.2 or later. 
13.4.2 Basic characteristics 
The mean, standard deviation, median, maximum, and minimum of quantitative data such as age, 
height, and weight are calculated, and the frequency and percentage of qualitative data such as 
sex and ECOG PS are listed. 
13.4.3 Efficacy analysis 
Endpoints such as the ORR and CBR will be analyzed using Clopper-Pearson method with 
2-sided 95% CI. For survival, the median duration of progression-free survival, the 12-month 
survival rate, the median duration of survival, and their 95% confidence intervals representing 
the entire population will be estimated using the Kaplan-Meier method. In addition, survival 
plots will be plotted. Descriptive analysis will be performed for other secondary efficacy 
endpoints. 
13.4.4 Safety evaluation 
Descriptive statistical analysis will be primarily used to analyze the adverse events, serious 
adverse events and adverse reactions in each dose group (the adverse reactions are defined as 
adverse events that are "definitely related, probably related, and indeterminable" to the study 
drug). Laboratory test results will describe the conditions that are normal before the study but 
become abnormal after treatment. The mean, standard deviation, median, minimum, and 
maximum of vital signs (blood pressure, pulse, body temperature, and respiratory rate) before 
and after single-dose administration will be respectively calculated by dose group.  

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Besides, irAEs, including immune-related pneumonitis, immune-related enteritis, 
immune-related thyroid dysfunction, immune-related nephritis and renal failure, and 
immune-related hypophysitis will be categorized and summarized using above summary 
analysis of AEs. 
Laboratory parameters, ECG, the number and rate of laboratory parameters "changed from 
normal to abnormal" or "exacerbated", and abnormalities after the study and their clinical 
explanations will be tabulated. 
13.4.5 PK analysis 
The following PK parameters: Cmax, Tmax, AUC and t1/2 will be summarized by dose group and 
planned blood sampling time points and analyzed using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum).A mean and/or median-time plot of serum 
concentration will be plotted. Statistical description will be given for the mean, standard 
deviation, median, minimum and maximum values, geometric mean and standard deviation, 
and %CV and 95% CI of natural log-transformed parameters (if applicable) by dose groups. 
Box-plots will be drawn for primary parameters. The serum concentration-time plots will be 
drawn for each subject along with a list of serum concentrations and parameter data. 
13.4.6 Other analyses 
SHR-1210-related biomarkers of solid tumor, such as PD-L1 expression level and TMB level in 
tumor tissue samples, will also be analyzed using descriptive statistics.  
14 EXPECTED STUDY SCHEDULE 
The study is expected to be carried out from Mar. 2017 to Sep. 2019. 
15 REFERENCES 
1) 
Christian Blank, Andreas Mackensen. Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion: an update on implications for chronic infections and tumor evasion. Cancer 
Immunol Immunother (2007) 56:739–745. 
2) 
Julie R. Brahmer, Charles G. Drake, Ira Wollner, et al. Phase I Study of Single-Agent Anti–
Programmed Death-1(MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, 
Pharmacodynamics, and Immunologic Correlates. J Clin Oncol 2010 Jul. 28:3167-3175. 
3) 
David F. McDermott, Michael B Atkins. PD-1 as a potential target in cancer therapy. Cancer 
Medicine 2013; 2(5): 662–673. 

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4) 
Omid Hamid, Caroline Robert, Adil Daud, et al. Safety and Tumor Responses with 
Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med 2013.DOI: 
10.1056/NEJMoa1305133. 
5) 
Suzanne L. Topalian, F Stephen Hodi, Julie R, Brahmer, et al. Safety, Activity, and Immune 
Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med 2012;366:2443-54. 
6) 
C. Zielinski, S. Knapp, C. Mascaus, et al. Rationale for targeting the immune system 
through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. 
Annals of Oncology 2013. 24: 1170–1179. 
7) 
Jedd D. Wolchok, Axel Hoos, Steven O'Day.Guidelines for the Evaluation of Immune 
Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 
2009;15(23):7412–20 
8) 
Omid Hamid, Richard D Carvajal.Anti-programmed death-1 andanti-programmed 
death-ligand 1 antibodies in cancer therapy.Expert Opin. Biol. Ther. (2013)13(6):847-861 
9) 
Marianne Davies.New modalities of cancer treatment for NSCLC: focus on 
immunotherapy.Cancer Management and Research 2014:6 63–75 
10) Caroline Robert, Antoni Ribas, Jedd D Wolchok. Anti-programmed-death-receptor-1 
treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a phase 1 study. 
http://dx.doi.org/10.1016/S0140-6736(14)60958-2 
11) Chuan-Yong Mu, Jian-An Huang, Ying Chen.High expression of PD-L1 in lung cancer may 
contribute to poorprognosis and tumor cells immune escape through suppressingtumor 
infiltrating dendritic cells maturation. Med Oncol (2011) 28:682–688 
12) Qiang Gao, Xiao-Ying Wang, Shuang-Jian Qiu. Overexpression of PD-L1 Significantly 
Associates with Tumor Aggressiveness and Postoperative Recurrence in Human 
Hepatocellular Carcinoma.Clin Cancer Res 2009;15(3) February 1, 2009 
13) Changping Wu, Yibei Zhu, Jingting Jiang.Immunohistochemical localization of 
programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. 
Acta histochemica108 (2006) 19–24. 
14) Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. 
15) Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer. 
16) Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular 
carcinoma. 

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17) VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. 
18) Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of 
Cancer. 
19) Interactions between immunotherapy and targeted therapy in cancer treatment. doi: 
10.11735/j.issn.1004-0242.2014.11.A013. 
20) http://meetinglibrary.asco.org/content/167136-176 
21) http://meetinglibrary.asco.org/content/163413-176 
22) National Medical Products Administration. Provisions for Drug Registration. 2007. 
23) National Medical Products Administration. Good Clinical Practice. 2003. 

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Appendix I 
Prohibited Traditional Chinese Medicine (TCM) 
Huatan Huisheng tablet 
Brucea Javanica oil soft capsule 
Mandarin melon berry syrup 
Cantharidin 
Cinobufotalin 
Bufotoxin 
Kang'ai injection 
Kanglaite injection 
Zhongjiefeng injection 
Aidi injection 
Awei Huapi ointment 
Kangaiping pill 
Fukang capsule 
Xiaoaiping 
Pingxiao capsule 
Pingxiao tablet 
Shendan Sanjie capsule 
Ankangxin capsule 
Boshengaining 
Zedoary turmeric oil and glucose injection 
Kanglixin capsule 
Cidan capsule 
 
 

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Appendix II Performance Status Criteria (ECOG) 
(Eastern Cooperative Oncology Group) 
Score 
Description 
0 
Asymptomatic, fully active, able to carry on all performance without 
restriction. 
1 
Symptomatic, restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light house work, 
office work. 
2 
Symptomatic, ambulatory and capable of all self-care but unable to carry out 
any physical activities; up and about more than 50% of waking hours 
(confined to bed < 50% of waking hours). 
3 
Symptomatic, capable of only limited self-care; confined to bed or chair more 
than 50% of waking hours, but not totally confined to bed. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair. 
5 
Death. 
 

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Appendix III Calculation of Creatinine Clearance 
Creatinine Clearance Calculation Using the Cockcroft-Gault Formula 
Please choose the appropriate formula corresponding to the unit of serum creatinine test: 
If the unit of serum concentration of creatinine is mg/dL 
Creatinine Clearance in Males (mL/min) = 
(140－Age)×(Weight) 
72×Serum creatinine 
 
Creatinine Clearance in Females (mL/min) 
0.85×(140－Age)×(Weight) 
72×Serum creatinine 
 
If the unit of serum concentration of creatinine is mol/L 
Creatinine Clearance in Males (mL/min) = 
(140－Age)×(Weight) 
0.81×Serum creatinine 
 
Creatinine Clearance in Females (mL/min) 
0.85×(140－Age)×(Weight) 
0.81×Serum creatinine 
 
Note: The unit of age is years old, and the unit of body weight is kilogram (kg). 
 

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Appendix IV Management Principles for irAEs 
1. Management Principles for Gastrointestinal AEs 
 
Non-inflammatory causes of disease should be excluded. Opioids/anesthetics may mask the symptoms of perforation. Do not use 
infliximab in the case of perforation/sepsis. 
Diarrhea/Colitis Grade 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1 
Diarrhea: Increase of < 4 stools  
per day over baseline 
Colitis: No symptom 
Grade 2 
Diarrhea: Increase of 4-6 stools per day 
over baseline; intravenous infusion of 
< 24 h is required; daily living is 
not affected 
Colitis: Abdominal pain; hematochezia 
Grade 3-4 
Diarrhea (Grade 3): Increase of  
≥ 7 stools per day over baseline; fecal 
incontinence; intravenous infusion of 
≥ 24 h is required; daily living is 
affected; 
Colitis (Grade 3): Severe abdominal 
pain, indications for medical 
intervention, peritoneal signs; 
Grade 4: Life-threatening, perforation 
• Continue I-O treatment as per 
study protocol 
• Symptomatic treatment 
• Delay I-O treatment as per study 
protocol 
• Symptomatic treatment 
• Discontinue I-O treatment as per 
study protocol 
• 1.0-2.0 mg/kg/day of 
methylprednisolone IV or 
equivalent IV 
• Add prophylactic antibiotics to 
prevent opportunistic infections 
• Consider lower GI endoscopy 
• Closely monitor aggravated symptoms 
• Educate patients to report aggravated symptoms immediately 
If it is aggravated: 
• Provide treatment according to the method for Grade 2 or Grade 
3/4 situations
If it is improved to Grade 1: 
• Resume I-O treatment as per study protocol 
If it lasts for > 5-7 days or relapses: 
• 0.5-1.0mg/kg/day of methylprednisolone IV or equivalent PO 
• When the symptoms improve to Grade 1, reduce the dose of 
steroids for at least 1 month and consider prophylactic antibiotics to 
prevent opportunistic infections, then resume I-O treatment as per 
study protocol 
If the symptoms are aggravated or persisted after >3-5 days of oral 
administration of steroids: 
• Provide treatment according to the method for Grade 3/4 situations 
If symptoms improve: 
• Continue steroid treatment until the symptoms return to Grade 1, 
then gradually reduce the dose of steroids for at least 1 month 
If it lasts for > 3-5 days or relapses after improvement: 
• Add 5 mg/kg infliximab (if there are no contraindications)./ 
Note: Do not use infliximab in the case of perforation/sepsis. 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose, it should be considered that the 
bioavailability of oral corticosteroids is relatively low. 

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2. Management Principles for Pulmonary AEs 
 
Grade of Pneumonitis 
(NCI CTCAE V4) 
Handling 
Follow-Up 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause,  
a symptomatic treatment should be given while the I-O therapy should be continued. Imaging evaluation and 
consultations with the respiratory department should be performed. 
Grade 1 
Only radiographic 
changes 
Grade 2 
Mild to moderate new 
symptoms 
Grade 3-4 
Severe new symptoms; 
new onset/aggravation of 
hypoxia; life-threatening. 
• Consider delaying the I-O treatment 
• Monitor symptoms every 2-3 days 
• Consider consulting with respirologist and 
infectious diseases specialist 
• Delay I-O treatment as per study protocol 
• Consult with respirologist and infectious 
diseases specialist 
• Monitor symptoms daily and consider 
hospitalization 
• 1.0 mg/kg/day of methylprednisolone IV or 
equivalent PO 
• Consider bronchoscopy and lung biopsy 
• Discontinue I-O treatment as per study 
protocol 
• Hospitalization 
• Consult with respirologist and infectious 
diseases specialist 
• 2-4 mg/kg/day of methylprednisolone IV or 
equivalent IV 
• Add prophylactic antibiotics to prevent 
opportunistic infections 
• Consider bronchoscopy and lung biopsy 
• Repeat imaging examinations at least every 3 weeks 
If it is aggravated: 
• Provide treatment according to the method for Grade 2 or Grade 3-4 
situations 
• Repeat imaging examinations every 1-3 days 
If symptoms improve: 
• When symptoms return to near baseline levels, reduce the dose of 
steroids for at least 1 month and then resume the I-O treatment as per 
study protocol while considering prophylactic antibiotics 
If the symptoms are not improved or aggravated after 2 weeks: 
• Provide treatment according to the method for Grade 3 or Grade 4 situations 
If symptoms improve to the baseline level: 
• Gradually reduce the dose of steroids for at least 6 weeks 
If the symptoms are not improved or aggravated after 48 h: 
• Add other immunosuppressants (e.g., infliximab, cyclophosphamide, 
intravenous immunoglobulin or mycophenolate mofetil) 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose, it should be considered that 
the bioavailability of oral corticosteroids is relatively low. 

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3. Management Principles for Hepatic Adverse Events 
 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause,  
a symptomatic treatment should be given while the I-O therapy should be continued. Consider imaging examinations to rule out 
obstruction/tumor progression. 
Elevation Grade in the 
Hepatic Function Test 
(NCI CTCAE V4) 
Handling 
Follow-Up 
Grade 1 
AST or ALT > 1.0-3.0 × 
ULN and/or T.bili > 1.0- 
1.5 × ULN  
• Continue I-O treatment as per study protocol 
Grade 2 
AST or ALT > 3.0 to ≤ 5 × 
ULN and/or T.bili > 1.5 to 
≤ 3 × ULN 
Grade 3-4 
ALT or AST > 5 × ULN 
and/or T. bili > 3 × ULN  
• Delay I-O treatment as per study protocol 
• Increase the monitoring frequency to once 
every 3 days 
• Discontinue I-O treatment* 
• Increase monitoring frequency to once every 
1-2 days 
• 1.0-2.0 mg/kg/day of methylprednisolone IV or 
equivalent IV** 
• Add prophylactic antibiotics to prevent 
opportunistic infections 
• Consultation with the gastroenterology 
department 
• Continue hepatic function monitoring as per study protocol 
If it is aggravated: 
• Provide treatment according to the method for Grade 2 or Grade 3/4 
situations 
If it returns to the baseline level: 
• Resume routine monitoring and resume I-O treatment as per study protocol 
If elevation persists for > 5-7 days or aggravates: 
• Intravenous administration of 0.5-1 mg/kg/day of methylprednisolone 
IV or equivalent orally administrated dose. If LFT returns to Grade 1 or 
baseline, reduce the dose of steroid for at least 1 month, and consider 
prophylactic antibiotics to prevent opportunistic infection, and then 
resume I-O treatment according to study protocol 
If it returns to Grade 2: 
• Reduce the dose of steroids for at least 1 month 
 
If there is no improvement within > 3-5 days, or if the symptoms are 
aggravated or deteriorated: 
• Add 1 g of mycophenolate mofetil, b.i.d 
• If the symptoms are not relieved within 3-5 days, consider other 
immunosuppressants based on local guidelines 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose, it should be considered that the 
bioavailability of oral corticosteroids is relatively low. 
* If AST/ALT ≤ 8 × ULN and T. Bili ≤ 5 × ULN, I-O treatment can be delayed rather than discontinued. 
**For Grade 4 hepatitis, the recommended starting dose of methylprednisolone intravenous injection is 2 mg/kg/day. 

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4. Management Principles for Endocrine Adverse Events 
 
Non-inflammatory causes of disease should be excluded. If it is due to a non-inflammatory cause, a symptomatic treatment should 
be given while the I-O therapy should be continued. Visual field tests, endocrinology consultation and imaging examinations are 
considered 
Asymptomatic TSH 
elevation 
• Continue I-O treatment as per study protocol 
• If TSH < 0.5 × LLN or TSH > 2 × ULN, or TSH results are out of range in 2 consecutive subsequent measurements: 
According to clinical indications, detect the level of free T4 in subsequent cycles; consider endocrinology consultation 
Symptomatic 
endocrinopathy 
Suspected adrenal crisis 
(Such as severe 
dehydration, hypotension, 
and shock incommensurate 
with the disease severity) 
• Assess endocrine functions 
• Consider pituitary scans 
Observation of symptoms and abnormalities in laboratory test 
results/pituitary scans: 
• Delay I-O treatment as per study protocol 
• 1-2 mg/kg/day of methylprednisolone IV or equivalent PO 
• Start a corresponding hormone therapy 
No abnormalities in laboratory test results/pituitary MRI but the symptoms 
persist: 
• Repeat the laboratory test within 1-3 weeks and repeat the pituitary MRI 
scan 1 month later 
If there is improvement (with or without 
hormone replacement): 
• Reduce the steroid dose for at least 
1 month, and consider use of 
prophylactic antibiotics to prevent 
opportunistic infections 
• Resume I-O treatment as per study 
protocol 
• Patients with adrenal insufficiency may 
need to continue the use of 
mineralocorticoid-containing steroids 
• Delay or discontinue I-O treatment as per study protocol 
• Exclude sepsis 
• Intravenous injection of a stress dose of mineralocorticoid-containing 
steroids 
• Intravenous infusion 
• Consult an endocrinologist 
• If the adrenal crisis is ruled out, treat the symptomatic endocrinopathy 
using the methods described above 
If subjects receiving intravenous injection of steroids show continuous clinical improvements, it is allowed, at the start of dose tapering or earlier, to switch to oral 
administration of corticosteroids (such as prednisone) at equivalent dose. When switching to oral corticosteroids with an equivalent dose in the lungs and liver, it should be 
considered that the bioavailability of oral corticosteroids is relatively low. 

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5. Management Principles for Skin Adverse Events 
 
(Weber JS, Postow M, Lao CD, Schadendorf D. Management of Adverse Events Following Treatment With Anti-Programmed Death-1 
Agents. Oncologist. 2016 Jul 8: 2016-0055.) 
Rash Grade 
(NCI CTCAE v4) 
Handling 
Follow-Up 
Grade 1-2 
Coverage ≤ 30% of 
body surface area 
(BSA) 
Grade 3-4 
Coverage > 30% body 
surface area (BSA); or 
life-threatening results 
• Symptomatic treatment (e.g., antihistamines, 
topical steroids) 
• Continue I-O treatment as per study protocol 
• Delay or discontinue I-O treatment as per study 
protocol 
• Consider skin biopsy 
• Consultation with the Department of Dermatology 
• 1.0-2.0 mg/kg/day of methylprednisolone IV or 
equivalent IV 
If symptoms persist for > 1-2 weeks or recur: 
• Consider skin biopsy 
• Delay I-O treatment as per study protocol 
• Consider 0.5-1.0 mg/kg/day of methylprednisolone IV or 
equivalent oral dose Once improved, reduce the dose of steroids 
for at least 1 month and consider prophylactic antibiotics to 
prevent opportunistic infections, and resume I-O treatment as per 
study protocol 
If it is aggravated: 
• Provide treatment according to the method for Grade  
3-4 situations 
If it is improved to Grade 1: 
• Reduce the dose of steroids for at least 1 month and add 
prophylactic antibiotics to prevent opportunistic infections 
• Resume I-O treatment as per study protocol 
Once a patient given intravenous injections of steroids shows a sustained clinical improvement, the patient can switch to an equivalent dose of oral corticosteroids (e.g., 
prednisone) by the time or before the dose of steroid injections starts to be gradually reduced. 
When switching to oral corticosteroids with an equivalent dose in the lungs and liver, it should be considered that the bioavailability of oral corticosteroids is relatively low. 

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Appendix V Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) 
(New Response Evaluation Criteria in Solid Tumors: Revised RECIST Version 1.1) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
1 BACKGROUND 
Omitted 
2 PURPOSE 
Omitted 
3 MEASURABILITY OF TUMOR AT BASELINE 
3.1 Definition 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1 Measurable lesions 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 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 nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15 mm in short axis by CT scan (CT scan slice thickness no greater than 5 mm). 
At baseline and during follow-up, only the short axis will be measured and followed. 
3.1.2 Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10mm or pathological lymph 
nodule with ≥ 10mm to < 15mm short axis) as well as truly non-measurable lesions. 
Non-measurable lesions include: meningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses 
unable to be diagnosed or followed by imaging techniques, and cystic lesions. 

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3.1.3 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 to measure bone 
lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions; 
 
Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by tomography 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 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 
noncystic lesions are present in the same patient, 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 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
3.2 Specifications by Methods of Measurements 
3.2.1 Measurements of lesions 
All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
28 days (4 weeks) before the beginning of the treatment. 

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3.2.2 Method of Assessment 
The same method and technique should be used to assess lesions at baseline and during 
follow-up. Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) 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 cutaneous 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both imaging and clinical examination, imaging 
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, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT and MRI: CT is currently the best available and reproducible method for efficacy evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. 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 whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. 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. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be used to confirm CR when biopsies are obtained, or to 
determine relapse in studies where recurrence following CR or surgical excision is an endpoint. 
Tumor biomarkers: Tumor biomarkers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper limit of normal at baseline, they must return to 
the normal levels for evaluation of complete response. Because tumor biomarkers 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 CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line studies in ovarian cancer. 

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Cytology/Histology: These techniques can be used to differentiate between PR and CR in certain 
cases specified in the protocol (e.g., residual benign tumor tissue is often present in the lesions of 
germ cell tumors). 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 the criteria for response or stable disease in order to differentiate 
between response (or stable disease) and PD. 
4 TUMOR RESPONSE ASSESSMENT 
4.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable lesions at baseline should be included in protocols where objective response is the 
primary endpoint. Measurable lesion is defined by the presence of at least one measurable lesion. 
In trials where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if enrollment is restricted 
to those with measurable lesions or whether patients with non-measurable lesions are also 
eligible. 
4.2 Baseline Documentation of "Target" and "Non-target" Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ), representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal tissues which may be visible by 
imaging even if not involved by tumor metastasis. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes needs to be measured at baseline. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by tumor metastasis. Nodule size is normally reported as two dimensions in the plane in which 

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the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smallest of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. Nodes with short axis ≥ 10 mm but < 15 mm should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions 
shall be recorded as "present", "absent", or in rare cases "unequivocal progression". Multiple 
non-target lesions involving the same organ can be recoreded as a single item (e.g., "multiple 
enlarged pelvic lymph nodes" or "multiple liver metastases"). 
4.3 Response Criteria 
4.3.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodules 
(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 as 
compared with baseline. 
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, the sum must also demonstrate an absolute increase of at least 5 
mm (the appearance of one or more new lesions is also considered PD). 
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. 
4.3.2 Special notes on the evaluation 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 complete response criteria 

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are met, since a normal lymph node is defined as having a short axis of < 10 mm. CRFs 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 CRF. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement shall 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 can be assigned. (Note: It is less likely that this rule will be 
used for lymph nodules since they usually have a definable size when normal and are frequently 
surrounded by adipose tissues as in the retroperitoneum; however, if a lymph nodule is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm can 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 evaluation 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: When non-nodal lesions fragmented, 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. 
4.3.3 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 nodules must be non-pathological in size (< 10 mm short axis). 

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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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 PD. 
4.3.4 Special notes on assessment of progression of non-target lesions 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease, 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 the overall tumor load has increased sufficiently to the point where treatment 
must be discontinued. 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 patient has only non-measurable disease: This circumstance arises in some phase III 
studies when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment. 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 patients 
for unequivocal progression is to consider if the increase in overall disease load 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. For example, 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 treatment". 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 patient 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. 

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4.3.5 New Lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important. There are no specific criteria for the identification of radiographically 
detected lesions; however, the finding of a new lesion should be unequivocal. For example, it 
should not be attributable to differences in scanning technique, change in imaging modality, or 
findings thought to represent something other than tumor (for example, some new bone lesions 
that may be simply healing, or re-occurrence of pre-existing lesions). This is particularly 
important when the patient'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 that is not scanned at baseline will be considered a new 
lesion and will indicate PD. An example of this is the patient who has visceral disease at baseline 
and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain 
metastases are considered to be evidence of PD even if he/she did not have brain imaging at 
baseline. 
If a new lesion is equivocal, for example, because of its small size, continued treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial identification. 
While FDG-PET response assessments generally 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 imaging can be identified according to the following process: 
Negative FDG-PET at baseline, with a positive 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, PD 
is confirmed. 
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 required 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 imaging examination, this is not PD. 

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4.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement for confirmation. On occasion a response 
may not be documented until after the end of treatment, so protocols should be clear if 
post-treatment assessments are to be considered in the evaluation of best overall response. 
Protocols must specify how any new treatment introduced before progression will affect best 
response evaluation. The patient's best overall response evaluation will depend on the findings of 
both target and non-target diseases and will also take into consideration the characteristics of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to determine either one is the BOR. 
4.4.1 Time point response 
It is assumed that at each time point specified in protocol, an efficacy response occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 1. Time point response: patients with target (+/– non-target) disease. 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Inevaluable 
Non 
PR 
PR 
Non-PD or not all evaluated 
Non 
PR 
SD 
Non-PD or not all evaluated 
Non 
SD 
Not all evaluated 
Non-PD 
Non 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease,  
and NE = inevaluable 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 

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Table 2. Time point response: patients with non-target disease only. 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
Non 
CR 
Non-CR/Non-PD 
Non 
Non-CR/Non-PDa 
Not all evaluated 
Non 
Inevaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a: "Non CR/non-PD" is preferred over SD for non-target lesion. Since SD is increasingly used as an endpoint for 
efficacy evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 Missing assessments and unevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements is made at an evaluation, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) has/have no effect on the 
assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
4.4.3 Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
BOR determination in studies where confirmation of complete or partial response is not required: 
BOR in these studies is defined as the best response across all time points (for example, a patient 
who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at the last cycle has a BOR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
calculated from baseline. If the minimum time is not met when SD is otherwise the BOR, the 
patient's BOR depends on the subsequent assessments. For example, a patient who has SD at 
Cycle 1, PD at Cycle 2 and does not meet minimum duration for SD, will have a BOR of PD. 
The same patient lost to follow-up after the first SD assessment would be considered not 
evaluable. 
BOR determination in studies where confirmation of complete or partial response is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the best overall response can be interpreted as in Table 3. 

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Table 3. Best overall response when confirmation of CR and PR required. 
Overall Response at 
First Time Point 
Overall Response at 
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 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even the disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR). Best overall response will depend on whether minimum duration for SD is met. However, sometimes 
CR may be claimed when subsequent scans suggest small lesions are 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. 
4.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodules decrease to a normal 
size of < 10 mm, they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodules are normal in order not to overstate progression should it be 
based on increase in size of the nodules. As noted earlier, this means that subjects with CR may 
not have a total sum of zero on the CRF. 
In studies where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/evaluations will be addressed in determination of response and progression. For example, in 
most studies it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 

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Subjects with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as symptomatic deterioration. 
Efforts should be made to evaluate objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a description of an objective response: it is a reason for 
discontinuation of treatment. The objective response status of such patients is to be determined 
by evaluation of target and non-target disease as shown in Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study specific 
and shall be clearly described in each protocol (depending on treatment duration and treatment 
cycle). 
In some circumstances it may be difficult to distinguish residual lesions from normal tissues. 
When the evaluation of complete response depends upon this definition, it is recommended to 
perform a biopsy before evaluating the efficacy of complete remission of local lesions. FDG-PET 
may be used to confirm 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. 
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 evaluation. If at 
the next scheduled evaluation, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
4.5 Frequency of Tumor Re-Evaluation 
Frequency of tumor re-evaluation during treatment should be protocol-specific and consistent 
with the type and schedule of treatment. However, in the phase II studies where the beneficial 
effect of treatment is not known, follow-ups for every 6-8 weeks (timed to coincide with the end 
of a cycle) is reasonable. Interval adjustments can be justified in specific regimens or 
circumstances. The protocol should specify which organ sites are to be evaluated at baseline 
(usually those most likely to be involved with metastatic disease for the tumor type under study) 
and how often evaluations are repeated. Normally, all target and non-target sites are evaluated at 
each assessment. In selected circumstances, certain non-target organs may be evaluated less 
frequently. For example, bone scans may need to be repeated only when CR is identified in target 
disease or when progression in bone is suspected. 

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After the treatment, the need for tumor re-evaluations depends on whether the study has as made 
the response rate or the time to an event (progression/death) an endpoint. If time to an event 
(e.g., TTP/DFS1/PFS) is the main endpoint of the study, then routine scheduled re-evaluation of 
protocol specified sites of disease is warranted. In randomized comparative studies in particular, 
the scheduled assessments should be performed as identified on a calendar schedule (for 
example: every 6-8 weeks on treatment or every 3-4 months after treatment) and should not be 
affected by delays in therapy, drug holidays or any other events that might lead to imbalance in a 
treatment group in the timing of disease assessment. 
4.6 Confirmatory Measurement/Duration of Response 
4.6.1 Confirmation 
In non-randomized studies where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized studies (phase II or III) 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 study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies which are not blinded. 
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. 
4.6.2 Duration of overall response 
The duration of overall response will be measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). The duration of overall complete response will be measured 
from the time criteria are first met for CR until the first date that recurrent or progressive disease 
is truly documented. 
                                                        
1 Disease free survival 

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4.6.3 Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized studies, 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 patients achieving SD for a minimum period of time is an endpoint in a particular 
study, the protocol should specify the minimal time interval required between two measurements 
for determination of SD. 
Note: The duration of response and stable disease as well as the progression-free survival 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. 
4.7 PFS/TTP 
4.7.1 Phase II clinical studies 
This guideline is focused primarily on the use of objective response as study endpoints for phase 
II trials. In some circumstances, response rate may not be the optimal method to assess the 
potential anti-tumor activity of new agents/regimens. In such cases, PFS/PPF at landmark time 
points might be considered appropriate alternatives to provide an initial signal of biologic effect 
of new agents. It is clear, however, that in an uncontrolled trial, these measures are subject to 
criticism since an apparently promising observation may be related to biological factors such as 
patient selection and not the impact of the intervention. Thus, phase II screening trials utilizing 
these endpoints are best designed with a randomized control. Exceptions may exist where the 
behavior patterns of certain cancers are so consistent (and usually consistently poor), that a 
non-randomized trial is justifiable. However, in these cases it will be essential to document with 
care the basis for estimating the expected PFS or PPF in the absence of an active control.2 
                                                        
2 Proportion of progress-free 

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Appendix VI Percent Bone Marrow Content in Human Skeleton