Conditions: Lung Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 397
Healthy volunteers: no

Brief summary:
Efficacy and Safety Evaluation of IBI308 in Patients with advanced or metastatic Non-squamous NSCLC

Detailed description:
Sintilimab is expected to increase the PFS from 6 months to 9.2 months. Anti-PD-1 therapy in Chinese non-squamous NSCLC naïve patients will be investigated in this clinical trial.

Additionally the correlation between PD-L1 expression and the response to Sintilimab treatment in Chinese non-squamous NSCLC as well as the role of iRECIST in immune checkpoint inhibitor treatment evaluation will also be assessed.

Arms:
arm 1: Injection; dosage form: 10ml: 100mg; frequency: 200mgQ3W (qualer 3 weeks); duration: randomization to the date of the first documented tumor progression per RECIST v1.1 criteria Sintilimab 200mg + pemetrexed/ platinum 4 cycles then Sintilimab 200mg + pemetrexed maintains arm 2: placebo 2 vials + pemetrexed/ platinum 4 cycles then Sintilimab 200mg + pemetrexed maintains

Interventions: intervention 1: Sintilimab intervention 2: Pemetrexed intervention 3: Platinum intervention 4: Placebos
Intervention descriptions: intervention 1: 10 mL:100 mg，200mg，Q3W (qualer 3 weeks), day1, I.V. intervention 2: 500mg/m\^2; Q3W (qualer 3 weeks), day1, I.V. intervention 3: Q3W (qualer 3 weeks), day1, I.V.; first 4 cycles. intervention 4: 10 mL:100 mg，200mg，Q3W (qualer 3 weeks), day1, I.V.

Protocol document:
Prot_SAP_000.pdf: 
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Clinical Study Protocol  
Study Title:  
A Randomized, Double-blind, Phase III Study Evaluating 
the Efficacy and Safety of Sintilimab or Placebo in 
Combination 
with 
Pemetrexed 
and 
Platinum-based 
Chemotherapy in the First-line Treatment of Advanced or 
Recurrent Non-squamous Non-small Cell Lung Cancer 
(ORIENT-11)  
Protocol Number:  
CIBI308C302  
Version Date and 
Version Number:  
Aug 09, 2019/Version 3.0  
Product Name:  
Sintilimab (Recombinant Fully Human Anti-Programmed 
Death Receptor-1 Monoclonal Antibody, R&D code: 
IBI308)  
Study Phase:  
Phase III  
Sponsor:  
Innovent Biologics (Suzhou) Co., Ltd.  
No. 168 Dongping Street, Suzhou Industry Park 
Jiangsu Province, China  
Sponsor Contact:  
Hui Zhou     
Vice President, Medical Science and Strategy Oncology  
021-31652896  
hui.zhou@innoventbio.com  
 
Confidentiality Statement  
This document is the confidential information of Innovent Biologics (Suzhou) Co., 
Ltd.. 
The content of this document shall not be disclosed to any person other than the 
investigators, research consultants or related personnel, and Institutional Review 
Board/Independent Ethics Committee. 
The information contained in this document must not be used for any purpose, except 
for the evaluation or conduction of this study, without the written consent of the Sponsor. 


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Sponsor Signature Page  
 
Protocol Title: A Randomized, Double-Blind, Phase III Study Evaluating the Efficacy 
and Safety of Sintilimab or Placebo in Combination with Pemetrexed and Platinum-based 
Chemotherapy in the First-Line Treatment of Advanced or Recurrent Non-Squamous 
Non-Small Cell Lung Cancer (ORIENT-11)  
Project Number: CIBI308C302  
 
Position  
Name (Print)  
Signature  
 
Date  
 
Vice President, 
Medical Science 
and Strategy 
Oncology   
 
Hui Zhou 
 
 
 
 
 
 
 
 
 
Senior Director, 
Biostatistics  
 
Xing Sun 
 
 
 
 
 
 
 
 
 


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Protocol Synopsis  
Protocol Number  CIBI308C302  
Sponsor  
Innovent Biologics (Suzhou) Co., Ltd.  
Study drug  
Sintilimab (R&D Code: IBI308)  
Active 
Ingredients  
Recombinant Fully Human Anti-Programmed Death Receptor-1 (PD-1) 
Monoclonal Antibody  
Study Title 
  
A Randomized, Double-blind, Phase III Study Evaluating the Efficacy and 
Safety of Sintilimab or Placebo in Combination with Pemetrexed and 
Platinum-based Chemotherapy in the First-line Treatment of Advanced or 
Recurrent Non-squamous Non-small Cell Lung Cancer (ORIENT-11)  
Study Phase 
Phase III  
Estimated 
Duration of Study 
Expected to be about 23 months (from first subject enrollment to primary 
statistical analysis)  
Study Objectives 
Primary Objective:  
 To compare the progression-free survival (PFS) per RECIST v1.1 in 
the first-line treatment of advanced or recurrent non-squamous non-
small cell lung cancer (NSCLC) treated with sintilimab in 
combination with pemetrexed and platinum-based chemotherapy 
versus placebo in combination with pemetrexed and platinum-based 
chemotherapy. 
Secondary Objectives:  
 To compare the overall survival (OS) between the two treatment 
arms;  
 To compare the objective response rate (ORR) per RECIST v1.1 
between the two treatment arms;  
 To compare the disease control rate (DCR) per RECIST v1.1 
between the two treatment arms;  
 To compare the time to objective response (TTR) per RECIST v1.1 
between the two treatment arms;  
 To compare the duration of response (DOR) per RECIST v1.1 
between the two treatment arms;  
 To evaluate the safety and tolerability of sintilimab in combination 
with pemetrexed and platinum-based chemotherapy.  


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Exploratory Objectives:  
 To evaluate the efficacy of sintilimab per the immune Response 
Evaluation Criteria in Solid Tumors (iRECIST);  
 To explore the population pharmacokinetic (PK) characteristics of 
sintilimab;  
 To explore the biomarkers that can potentially predict the efficacy of 
sintilimab arm including but not limited to, PD-L1 expression, 
and RNA in tumor specimens, circulating tumor DNA (ctDNA) and 
T cell receptor (TCR) in peripheral blood;  
 To compare the quality of life of subjects treated with sintilimab 
combined with chemotherapy and placebo combined with 
chemotherapy using Lung Cancer Symptom Scale (LCSS) and 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC QLQ-C30, V3.0 Chinese 
version);  
 To compare PFS in the sintilimab arm receiving subsequent 
antineoplastic therapy after disease progression versus placebo arm 
crossing over to receive sintilimab.  
Study Design  
This study is a randomized, double-blind, multicenter, phase III study of 
sintilimab 
in 
combination 
with 
pemetrexed 
and 
platinum-based 
chemotherapy or placebo in combination with pemetrexed and platinum-
based chemotherapy in the first-line treatment of subjects with advanced or 
recurrent non-squamous NSCLC in China.  
Subjects in this study will receive 4 cycles of sintilimab or placebo in 
combination with pemetrexed and platinum (cisplatin or carboplatin) 
followed by maintenance therapy with sintilimab or placebo in combination 
with pemetrexed until disease progression, intolerable toxicity, withdrawal of 
consent, death, or other protocol-specified circumstances in which treatment 
should be discontinued, whichever occurs first. Approximately 378 subjects 
with advanced or recurrent non-squamous NSCLC who have not previously 
received systemic therapy for advanced disease will be randomized at a 2:1 
ratio to the sintilimab group (experimental group) and the placebo group 
(control group), with 252 subjects in the sintilimab group and 126 subjects in 
the placebo group. The actual number of subjects enrolled may differ from 
the planned number due to unforeseen reasons, such as faster enrollment 
speed than expected. The final screening end date will be estimated before 
the enrollment of 378 subjects and best effort will be made to ensure that the 


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total number of subjects enrolled do not exceed 110% of the planned number, 
i.e., 414 subjects, of which 276 subjects are expected in the experimental 
group and 138 subjects are expected in the control group. The primary 
efficacy endpoint of the study is PFS per RECIST v1.1 assessed by 
independent radiographic review committee (IRRC). Subjects in the control 
group whose disease progression are confirmed may crossover to receive 
sintilimab monotherapy at the discretion of the investigator and subjects. The 
sintilimab monotherapy may continue until disease progression, intolerable 
toxicity, withdrawal of consent, death or other protocol-specified 
circumstances, whichever occurs first. The maximum treatment duration of 
sintilimab is 24 months.  
Interim analysis will be conducted during the study when 70% PFS events 
occur. The results and report of the analysis will be provided to the 
independent data monitoring committee (IDMC). The IDMC will make 
recommendation on whether the study result can be submitted for application 
in advance based on whether the interim result of this study meets the pre-
specified efficacy boundary. IDMC charter will be finalized and approved 
before the interim analysis. Responsibilities of IDMC members and 
associated procedures will be defined in the IDMC charter.  
Estimation of 
Sample Size  
It is assumed that the median PFS of subjects receiving sintilimab 
treatment will be improved from 6 months to 9.2 months [with a hazard ratio 
(HR) = 0.65]. With a projected enrollment time of 15 months, follow-up time 
of 8 months and an estimated dropout rate of 0.5% per month, to provide 
approximately 90% power under a two-sided α of 0.05, a total of 378 subjects 
need to be randomized to obtain the required 263 PFS events in this study. 
The actual number of subjects enrolled may differ from the planned number 
due to unforeseen reasons, such as faster enrollment speed than expected. The 
final screening end date will be estimated before the enrollment of 378 
subjects and best effort will be made to ensure that the total number of 
subjects enrolled do not exceed 110% of the planned number, i.e., 414 
subjects, of which 276 subjects are expected in the experimental group and 
138 subjects are expected in the control group. 
An interim analysis will be conducted during the study when 70% PFS 
events (i.e. 184 events) occur, and the primary interim analysis will be based 
on PFS.  
This study is expected to be conducted in 30 ~ 40 sites in China.  


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Inclusion Criteria  1) 
Has signed written informed consent before any study-related 
procedure;  
2) 
Is ≥ 18 and ≤ 75 years old;  
3) 
Has a life expectancy of at least 3 months;  
4) 
Has at least one measurable lesion based on RECIST v1.1 assessed by 
the investigator;  
Measurable lesions in a previously irradiated or locally treated area can 
be selected as target lesions if progression has been demonstrated in such 
lesions;  
5) 
Has a histologically or cytologically confirmed diagnosis of locally 
advanced (stage IIIB/IIIC), metastatic, or recurrent (stage IV) non-
squamous NSCLC according to the 8th edition of the TNM classification 
in the International Association for the Study of Lung Cancer and the 
American Joint Committee on Cancer. Meanwhile, subjects with stage 
IIIB/IIIC non-squamous NSCLC should not be eligible for radical 
surgery or radical radiochemotherapy;  
6) 
Ineligible for EGFR or ALK target therapy (documented evidence of 
absence of sensitizing EGFR mutations and ALK gene rearrangements 
is required);  
7) 
Eastern Cooperative Oncology Group performance status (ECOG PS) of 
0 or 1;  
8) 
Has not received prior systemic antineoplastic therapy for 
advanced/recurrent non-squamous NSCLC;  
Subjects who have received prior adjuvant chemotherapy are eligible if 
the adjuvant chemotherapy is completed at least 6 months prior to the 
recurrence of disease;  
9) 
Has adequate hematopoietic function as defined by an absolute 
neutrophil count ≥1.5 × 109/L, platelet count ≥100 × 109 /L, 
hemoglobin ≥90 g/L [without transfusion in 7 days and without 
dependence on erythropoietin (EPO)];  
10) Has adequate hepatic function, defined as a total bilirubin level≤1.5 × 
upper limit of normal (ULN); aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) levels ≤2.5 × ULN in subjects 
without liver metastases, AST and ALT levels ≤5 × ULN in subjects 
with documented liver metastases;  
11) Has adequate renal function, defined as serum creatinine (Cr) ≤ 1.5 
× ULN or calculated creatinine clearance ≥ 60ml/min (Cockcroft-
Gault formula);  


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Urine protein < 2 +, or 24-hour urine protein < 1g;  
12) Has adequate coagulation function, defined as international normalized 
ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN ; if the subject is 
receiving anticoagulant therapy, as long as the PT is within the proposed 
range for the anticoagulant, the subject is eligible;  
13) Female subjects of childbearing potential should have a negative urine 
or serum pregnancy test within 3 days prior to receiving the first dose of 
study drug (Cycle 1, Day 1). If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required;  
14) If there is a risk of conception, male and female subjects must use highly 
effective contraception (i.e., a method with a failure rate of less than 1% 
per year) for at least 180 days after end of treatment.  
Exclusion 
Criteria  
1) 
Has predominantly squamous histology NSCLC;  
Mixed cell types must be primarily (≥90%) adenocarcinoma cells; if 
small cell elements are present, the subject cannot be enrolled;  
2) 
Is currently participating in an interventional clinical study or received 
other investigational drugs or device within 4 weeks prior to the first 
dose of drug treatment;  
3) 
Has previously received the following therapies: anti-PD-1, anti-PD-L1, 
or anti-PD-L2 agents or agents directed at another stimulatory or co-
inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137);  
4) 
Has received Chinese medicines with anti-lung cancer indications or 
immunomodulatory drugs (including thymosin, interferon, interleukin, 
except for local use to control pleural effusion) within 2 weeks prior to 
first dose of drug treatment, or has undergone major surgery within 3 
weeks prior to first dose of drug treatment;  
5) 
Has received radiotherapy in lung with a dose > 30 Gy within 6 months 
prior to the first dose of study treatment;  
6) 
Has completed palliative radiotherapy within 7 days prior to the first 
dose of study treatment;  
7) 
Has 
clinically 
active 
diverticulitis, 
intra-abdominal 
abscess, 
gastrointestinal obstruction;  
8) 
Has received solid organ or blood system transplantation;  
9) 
Has clinically uncontrollable pleural effusion or ascites (subjects who 
doesn’t need drainage of effusion or has no significant increase in 
effusion 3 days after stopping drainage can be enrolled);  
10) Has a known severe allergic reaction (≥grade 3) to any component of 
sintilimab, pemetrexed, cisplatin, or carboplatin or to any excipients;  


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11) Has active autoimmune disease that has required systemic therapy (e.g., 
use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs) within 2 years prior to the first dose of study treatment. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroids 
replacement 
therapy 
for 
adrenal 
or 
pituitary 
insufficiency) is not considered a form of systemic therapy;  
12) Diagnosed with immunodeficiency or receiving systemic glucocorticoid 
therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of study treatment;  
Physiological doses of glucocorticoids (≤10 mg/day of prednisone or 
equivalent glucocorticoid) is allowed;  
13) Has not adequately recovered from toxicity and/or complications caused 
by any intervention prior to starting study treatment (i.e. ≤Grade 1 or 
to baseline, excluding asthenia or alopecia);  
14) Has other malignancies diagnosed within 5 years prior to the first dose 
of study treatment, with the exception of radically treated basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, and/or 
radically resected carcinoma in situ;  
15) Has 
symptomatic 
central 
nervous 
metastases. 
Subjects 
with 
asymptomatic metastases or stable metastases after treatment may 
participate in the study as long as all of the following criteria are met: 
measurable lesion outside the central nervous system; no meningeal, 
midbrain, pontine, medullary, or spinal metastases; clinically stable for 
at least 2 weeks; and discontinuation of hormonal therapy 14 days prior 
to the first dose of study treatment;  
16) Has a known history of non-infectious pneumonitis requiring 
corticosteroid therapy within 1 year prior to the first dose of study 
treatment or has current interstitial lung disease;  
17) Has active infection requiring systemic therapy;  
18) Is unable or unwilling to take folic acid or vitamin B12 supplementation; 
19) Has psychiatric or substance abuse disorder that would interfere with 
compliance with the requirements of the study;  
20) Has a known history of Human Immunodeficiency Virus (HIV) 
infection (i.e., HIV 1/2 antibodies positive), known active syphilis 
infection, active pulmonary tuberculosis;  
21) Has known untreated active hepatitis B;  
Note: Subjects with hepatitis B who meet the following criteria are also 
eligible:  


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HBV viral load must be < 1000 copies/ml (200 IU/ml) or below the lower 
limit of detection before the first dose of study treatment. Subjects with 
active hepatitis B should receive anti-HBV therapy to avoid viral 
reactivation throughout the study treatment;  
For subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral 
load (-), prophylactic anti-HBV treatment is not required, but viral 
reactivation should be closely monitored;  
22) Has active HCV infection (HCV antibody positive and HCV-RNA level 
above the lower limit of detection);  
23) Has received a live vaccine within 30 days prior to the first dose (Cycle 
1, Day 1);  
Note: Inactivated viral vaccines for seasonal influenza within 30 days 
prior to the first dose of study treatment are allowed; live attenuated 
influenza vaccines administered intranasally are not allowed;  
24) Has uncontrolled concurrent medical conditions, such as:  
a) 
Esophageal or gastric varices requiring immediate intervention 
(e.g., band ligation or sclerotherapy) or with a high risk of bleeding 
in the opinion of the investigator or in consultation with a 
gastroenterologist or hepatologist. Subjects who have portal 
hypertension (including splenomegaly with the evidence of 
imaging evaluation) or has a history of variceal bleeding should 
receive endoscopic examination within 3 months prior to 
enrollment to evaluate whether the subjects are eligible;  
b) 
Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B 
or worse cirrhosis;  
c) 
Significant 
malnutrition 
(e.g. 
need 
intravenous 
nutrition 
supplements). Subjects with malnutrition remedied more than 4 
weeks prior to the first dose of study treatment are eligible;  
d) 
The tumor compresses the surrounding vital organs (such as 
esophagus) accompanied with relevant symptoms, or compresses 
the superior vena cava or invades the major mediastinal blood 
vessels, heart, etc.;  
e) 
Class II-IV congestive heart failure (New York Heart Association 
classification), poorly controlled and clinically significant 
arrhythmia;  
f) 
Uncontrolled arterial hypertension even after receiving standard 
treatment (systolic blood pressure≥160 mmHg or diastolic blood 
pressure≥100 mmHg);  


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g) 
Any arterial thrombosis, embolism, or ischemia such as myocardial 
infarction, unstable angina, cerebrovascular accident, or transient 
ischemic attack within 6 months prior to enrollment. With a 
history of deep vein thrombosis, pulmonary embolism, or any other 
serious thromboembolism within 3 months prior to enrollment 
(thrombosis caused by implantable venous port or catheter, or 
superficial venous thrombosis is not considered "serious" 
thromboembolism);  
25) Has a history or current evidence of any disease, treatment, or laboratory 
abnormality that may interfere with the results of the study, prevent the 
subject from fully participating in the study, or other condition that the 
subject is ineligible for enrollment, in the opinion of the investigator;  
26) Is breast-feeding. 
Study Drug and 
Mode of 
Administration  
1. 
Sintilimab: 200 mg, administer intravenous infusion on the first day of 
each cycle, Q3W.  
2. 
Placebo: 2 vials, administer intravenous infusion on the first day of each 
cycle, Q3W.  
3. 
Pemetrexed: 500 mg/m2 , administer intravenous infusion on the first 
day of each cycle, Q3W.  
4. 
Cisplatin: 75 mg/m2 , administer intravenous infusion on the first day of 
each cycle, Q3W or 
Carboplatin: AUC 5 mg* min/ml, administer intravenous infusion on the 
first day of each cycle, Q3W.  
Evaluation 
Criteria  
Efficacy Evaluation:  
 
Evaluate PFS, OS, ORR, DOR, DCR, and TTR per RECIST v1.1;  
 
Evaluate iORR, iTTR, iDCR, iPFS, and iDOR per iRECIST.  
Safety evaluation:  
 
Incidence, severity and relationship with the study drug of all 
adverse events (AEs), treatment emergent adverse events (TEAEs), 
immune related adverse events (irAEs) and serious adverse events 
(SAEs);  
 
Number of subjects who discontinued treatment due to the above 
adverse events;  
 
Positive rate of anti-drug antibody (ADA) and neutralizing 
antibody (NAb);  
 
Changes in vital signs, physical examination, and laboratory results 
before, during, and after study treatment.  


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Statistical 
Methods  
The primary analysis of this study is to confirm that sintilimab in 
combination with chemotherapy prolongs PFS compared to placebo in 
combination with chemotherapy.   
Efficacy evaluation  
Stratified log-rank test will be used to compare PFS between groups and 
stratified Cox proportional hazards model will be used to estimate HR and its 
95% confidence interval (CI) between groups. Stratification factors (gender, 
PD-L1 expression level, platinum), age (>60, ≤60), smoking status 
(former/current smoker, non-smoker), number of organs with metastatic 
lesions (> 2, ≤2), and other significant covariates will be considered in the 
model, and their HR and 95% CI will be estimated. Median PFS and its 95% 
CI will be estimated using the Kaplan-Meier method, and survival curves will 
be plotted.  
Stratified log-rank test will be used to compare OS between groups, and 
stratified Cox proportional hazards model will be used to estimate HR and its 
95% CI between groups. Stratification factors (gender, PD-L1 expression 
level, platinum), age (>60, ≤60), smoking status (former/current smoker, 
non-smoker), number of organs with metastatic lesions (> 2, ≤2), and other 
significant covariates will be considered in the model, and their HR and 95% 
CI will be estimated. Median OS and its 95% CI will be estimated using the 
Kaplan-Meier method, and survival curves will be plotted.  
The two groups’ ORR and DCR of tumor efficacy evaluation per 
imaging assessment and 95% CI will be evaluated respectively. The 
difference between the rates and 95% CI will be calculated. Quality of life 
scores will be linearly transformed using the range method, and the crude 
scores will be transformed into standardized scores with values within 0 ~ 
100. Descriptive statistics and Wilcoxon test will be performed for the results, 
and descriptive statistics and Wilcoxon test will be used for the performance 
status score (ECOG PS).  
Safety evaluation  
The exposure of subjects to the study drug will be summarized, 
including treatment cycles, dose adjustment, cumulative number of dose 
adjustments of both groups.  
The cumulative incidence of adverse events, adverse events leading to 
withdrawal from the study, adverse events leading to death and serious 
adverse events will be summarized. The incidence (the occurrence number is 
calculated as the subjects who have experienced a certain adverse event at 
least once) by systems/ organ classification and preffered term will be 


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calculated. The severity of adverse events: if the same subject has 
experienced the same adverse event many times, the most serious one will be 
counted for analysis; if the same subject has experienced different adverse 
events, the most serious adverse event will be counted for analysis. 
Laboratory parameters: descriptive summaries of laboratory values will 
be primarily for abnormal values. Laboratory abnormalities will be 
summarized according to the worst grade in NCI CTCAE Version 4.03.  
Immunogenicity data will be analyzed using descriptive statistics.  
Vital signs: use mean±standard deviation, maximum, minimum, and 
median describe measurements and changes by visit.  
Physical examination, ECG (including QTcF), blood pressure 
monitoring, etc.  
The population PK profile of sintilimab in the advanced non-squamous 
NSCLC population will be analyzed using nonlinear mixed effects modeling. 


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 Table 1. Study Flow Chart 
Phase  
Screening 
Phase  
Combination 
treatment 
period (1 cycle every 21 days)  
Maintenance therapy  
(1 treatment cycle 
every 21 days)  
End of Treatment Visit 22  Safety Follow-up22  
Survival Follow-up 23  
1  
2  
3  
4  
Scheduling Window  
- 28 ~ -1  
Day 1 (± 3 days) 
Day 1 (± 3 days)  
Within 7 days after the 
end of treatment  
30 (± 3) days after the last 
dose  
Every 90 days (± 7 days)  
General Study Procedures  
 
Written informed consent 1  
X  
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X  
 
 
 
 
 
 
 
 
Demographics/Past Medical 
History/Prior Therapies 2  
X  
 
 
 
 
 
 
 
 
Vital signs 3  
X  
X  
X  
X  
X  
X  
X  
X  
 
Weight/Height 4  
X  
X  
X  
X  
X  
X  
X  
X  
 
Physical Examination  
X  
 
 
 
 
 
X  
X  
 
ECOG PS score  
X  
X  
X  
X  
X  
X  
X  
X  
 
12-lead ECG 5  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hematology/Blood 
biochemistry/Urinalysis 6  
X  
 
X  
X  
X  
X  
X  
X  
 
Coagulation function 7  
X  
 
 
 
 
 
X  
X  
 
Pregnancy test 8  
X  
 
 
 
 
 
 
 
 
Thyroid function 9  
X  
 
X  
X  
X  
X  
X  
X  
 


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Phase  
Screening 
Phase  
Combination 
treatment 
period (1 cycle every 21 days)  
Maintenance therapy  
(1 treatment cycle 
every 21 days)  
End of Treatment Visit 22  Safety Follow-up22  
Survival Follow-up 23  
1  
2  
3  
4  
Scheduling Window  
- 28 ~ -1  
Day 1 (± 3 days) 
Day 1 (± 3 days)  
Within 7 days after the 
end of treatment  
30 (± 3) days after the last 
dose  
Every 90 days (± 7 days)  
Virological antibody tests 
(HIV, 
HBV, 
HCV 
and 
Treponema pallidum specific 
antibodies) 10  
X  
 
 
 
 
 
 
 
 
HCV-RNA if HCV antibody 
positive 11  
X  
 
X  
X  
X  
X  
X  
X  
 
HBV-DNA if positive for 
HBsAg and/or HBcAb 12  
X  
 
X  
X  
X  
X  
X  
X  
 
Blood cardiac enzymes and 
troponin 13  
X  
 
X  
X  
 
 
 
 
 
Review Adverse Events 14  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant medications  
X  
X  
X  
X  
X  
X  
X  
X  
 
Quality of Life Questionnaire 
15  
 
X  
X  
 
X  
X  
X  
 
 
Subsequent 
antineoplastic 
therapy  
 
 
 
 
 
 
X  
X  
X  
Efficacy Measurements  
 
Tumor Imaging 16  
X  
 
X  
 
X  
X  
 
 
 


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Phase  
Screening 
Phase  
Combination 
treatment 
period (1 cycle every 21 days)  
Maintenance therapy  
(1 treatment cycle 
every 21 days)  
End of Treatment Visit 22  Safety Follow-up22  
Survival Follow-up 23  
1  
2  
3  
4  
Scheduling Window  
- 28 ~ -1  
Day 1 (± 3 days) 
Day 1 (± 3 days)  
Within 7 days after the 
end of treatment  
30 (± 3) days after the last 
dose  
Every 90 days (± 7 days)  
PK and Immunogenicity  
 
Immunogenicity 17  
 
X  
X  
 
X  
X  
X  
 
 
PK 18  
 
X  
X  
 
X  
X  
 
 
 
Study Drug Administration 
19  
 
Sintilimab or placebo  
 
X  
X  
X  
X  
X  
 
 
 
Pemetrexed  
 
X  
X  
X  
X  
X  
 
 
 
Cisplatin or carboplatin  
 
X  
X  
X  
X  
 
 
 
 
Exploration of Biomarkers   
Archived or fresh tumor 
tissue sample 20  
X  
 
 
 
 
 
 
 
 
Whole blood 21  
 
X  
X  
 
X  
X  
 
 
 
Notes:  
1. 
The signing of the informed consent form (ICF) should precede any study procedures.  
2. 
Prior therapies include: therapies for the initial diagnosis, including chemotherapy, radiation therapy, and surgery, as well as therapies for prior concurrent 
conditions within the last 30 days.  
3. 
Vital signs included: temperature, pulse, respiratory rate, and blood pressure.  


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4. 
Height will be measured only at screening. Weight will be measured prior to each dose, at the end of treatment visit, and at the safety follow-up visit. If a 
subject's body weight fluctuated less than 10% from baseline (the day of the first dose of study treatment), the baseline body weight will be used to calculate the 
amount of chemotherapy administered. Otherwise, the actual dose will be calculated based on the body weight on the scheduled day of dosing or the day before it. 
The actual dose can also be calculated based on the body weight on the day of dosing or the day before it according to clinical practice regardless of the baseline 
weight.  
5. 
Time point of 12-lead ECG examination: during screening period, before administration of each cycle, at the end of treatment visit and at the safety follow-up 
visit.  
6. 
Hematology includes: red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell count (WBC), platelet count (PLT), white blood cell 
differential (lymphocytes, neutrophils, monocytes, eosinophils, basophils). Blood biochemistry includes: liver function (TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, 
TP, LDH), renal function (UREA or BUN, Cr), blood electrolytes (Na, K, Cl, Mg, Ca, P), amylase, and glucose. Urinalysis includes: PH, specific gravity, UWBC, 
UPRO, URBC, UGLU. Subjects whose urinalysis results showed urine protein ≥2+ during screening period should undergo a 24-hour urine protein quantification. 
Hematology, blood biochemistry, urinalysis are to be performed within 7 days prior to the first dose of study drug in the screening period, within 3 days prior to the 
start of each cycle of study drug starting from Cycle 2, at the end of treatment visit and at the safety follow-up visit. Tests will be conducted in each local lab. 
Subjects with hemoglobin≥90 g/L 3 days prior to the start of the second cycle can receive drug.  
7. 
Coagulation tests include: PT and INR are to be performed within 7 days prior to the first dose of study treatment in the screening period, at the end of treatment 
visit and at the safety follow-up visit. Tests will be conducted in each local lab.  
8. 
Women of childbearing potential will have a urine or serum pregnancy test performed within 3 days prior to the first dose in the screening period. If the result of 
urine pregnancy test cannot be confirmed as negative, serum pregnancy test will be performed, and the result of serum pregnancy will prevail. Tests will be 
conducted in each local lab.  


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9. 
To be performed within 28 days prior to the first dose, within 3 days prior to the start of each cycle of study medication in Cycle 2, at the end of treatment visit 
and at the safety follow-up visit. T3/FT3, FT4 and TSH will be tested at screening period. Only TSH will be tested at the beginning of Cycle 2. If there are any 
abnormalities, other thyroid function tests will be considered. Tests will be conducted in each local lab.  
10. Tests for HIV, specific antibodies to Treponema pallidum and HCV, and tests for hepatitis B (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) should be completed 
within 28 days prior to the first dose. A screening examination will be conducted in each local lab.  
11. To test for anti-HCV antibodies at the screening visit. For HCV antibody-positive subjects, HCV-RNA load are to be measured once during screening, within 3 
days prior to the start of study drug administration in each cycle starting from Cycle 2, at the end of treatment visit and at the safety follow-up visit, or sooner if 
clinically indicated. During the course of study treatment, it is not necessary to wait for the test result to be administered first with the study drug. 
12. Five items of hepatitis B are to tested at the screening visit, and for HBsAg and/or HBcAb positive subjects, HBV-DNA load are to be measured once during the 
screening period, within 3 days before the start of study drug administration in each cycle starting from Cycle 2, at the end of treatment visit and at the safety follow-
up visit, or earlier if clinically indicated. During the course of study treatment, it may be unnecessary to wait for the test results and the study drug can be used first.  
13. Cardiac biomarker testings and troponin test include at least: creatine kinase (CK), creatine kinase myocardial band (CK-MB), troponin (troponin T or troponin 
I). Subsequent examinations will be performed at the discretion of the investigator within 7 days prior to the first dose of study drug in the screening period and 
within 3 days prior to each cycle of study drug in Cycles 2 and 3.  
14. Safety assessments of AEs and laboratory tests will be performed according to CTCAE v4.03. For the definition, recording, relevance judgment, severity 
judgment, reporting time limit and handling of AEs and SAEs, refer to the description in Section 8 of the protocol.  
15. Quality of life questionnaires include EORTC QLQ-C30 assessments will be performed prior to the first dose, at each imaging evaluation, and at the end of 
treatment visit.  
16. Tumor response evaluation will be based on RECIST v1.1 and iRECIST. Tumor imaging usually includes contrast-enhanced CT or MRI. The examination parts 
must include brain, chest, abdomen and pelvis. For subjects without brain metastases at baseline, routine brain imaging is not required thereafter. The same imaging 
technique should be used for the same subject during the study. Baseline evaluations will be performed within 28 days prior to study entry, and the investigator may 


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collect imaging results for assessment within 28 days prior to study entry. Tumor imaging evaluation will be performed once respectively at Week 6 (±7 days) and 
Week 12 (±7 days) from the time of first dosing, and then every 9 weeks (± 7 days); tumor imaging evaluation will be performed every 12 weeks (± 7 days) after 
Week 48. Subjects with initial documented radiographic disease progression must undergo imaging evaluation at least 4 weeks after the date of the first tumor 
imaging indicating progressive disease and no later than 8 weeks to confirm disease progression if clinically stable. Subjects who discontinue treatment for reasons 
other than radiographic disease progression should continue to undergo imaging assessments at protocol-specified imaging intervals until any of the following events 
occur: initiation of new antineoplastic therapy, disease progression, subject withdrawal of ICF, and death, whichever occurs first. Tumor imaging evaluation should 
be performed at the end of treatment if the end of treatment is more than 4 weeks since the last imaging examination for tumor assessment. The evaluation will be 
completed after the occurrence of PD confirmed by central imaging and investigator in RECIST v1.1; the evaluation of iRECIST will start from the first PD visit in 
RECIST v1.1 until the end of efficacy assessment.  
17. Immunogenicity testing will be performed during Cycles 1/2/4/8/12/16, and every 8 cycles thereafter (Cycles 24, 32, etc.) within 1 hour prior to the start of 
sintilimab/placebo infusion and safety follow up. If an infusion-related reaction occurs during sintilimab/placebo infusion, blood samples should be taken near the 
start of the event, end of event, and around 30 days after the reaction for immunogenicity analysis. Tests should be conducted at the central lab. 
18. PK sampling will be performed at the following time points: within 1 hour before the start of sintilimab/placebo infusion in Cycle 1, immediately (+ 5 min) after 
the end of sintilimab/placebo infusion in Cycle 1, and within 1 hour before the start of sintilimab/placebo infusion in Cycle 2/4/12. Tests will be conducted at the 
cental lab. 
19. The subjects in the test group will be given sintilimab 200 mg combined with pemetrexed + cisplatin or carboplatin via intravenous infusion once every 3 weeks; 
the subjects in the control group will be given placebo combined with pemetrexed + cisplatin or carboplatin via intravenous infusion once every 3 weeks. After 
completion of 4 cycles of treatment with sintilimab or placebo in combination with pemetrexed plus cisplatin or carboplatin, proceed to the maintenance phase with 
sintilimab or placebo in combination with pemetrexed until disease progression, intolerability of toxicity, withdrawal of ICF, death, or other protocol-specified 
circumstances in which treatment should be discontinued, whichever occurs first. Subjects in the control arm who have centrally confirmed and/or confirmed 
radiographic PD may crossover to receive sintilimab monotherapy at the discretion of the investigator. Treatment should be discontinued until disease progression, 


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intolerable toxicity, withdrawal of consent, death, or other protocol-specified condition, whichever occurs first. The maximum duration of treatment with sintilimab is 
24 months. See Table 2 for details of the specific procedures for crossover treatment with sintilimab after imaging PD confirmed and/or confirmed by central 
imaging.  
20. The subjects should provide 5 ~ 10 sections of archived or fresh tumor tissue samples which meet the test requirements during the screening period.  
21. Subjects will be required to provide a 10ml whole blood specimen for tumor biomarker testing at the following time points: prior to the first dose, at each 
imaging evaluation during the treatment period, and prior to the next treatment and confirmation of disease progression. Tests will be conducted in each local lab.  
22. End of treatment visit: within 7 days after the end of treatment. Safety follow-up visit: 30±3 days after last dose, or prior to initiation of new antineoplastic 
therapy. If the end of treatment visit and safety follow-up visit are within 7 days, only the end of treatment visit will be performed. If the safety follow-up visit is prior 
to the end of treatment visit, only the end of treatment visit will be performed. Refer to Section 6.2.4 for details.  
23. Survival follow-up visit: every 90 days (±7 days) after the safety follow-up visit, phone call is acceptable. Refer to Section 6.2.5 for details.  


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 Table 2. Flow Chart of Crossover Phase to Sintilimab Monotherapy 
Phase  
Crossover Treatment Cycles with Sintilimab (Every 21 days per 1 cycle) 1  
End of Treatment Visit 13  
Safety Follow-up 13  
Survival Follow-
up 14  
1  
2  
3  
4  
5  
6  
7 
and 
above  
Scheduling Window (days)  
- 28 ~ -1  ± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
Within 7 days after the 
end of treatment  
30 (± 3) days after 
the last dose  
Every 90 days (± 
7)  
General Study Procedures  
 
Vital signs 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Weight/Height 3  
X  
 
 
 
 
 
 
 
 
 
Physical Examination  
X  
 
 
 
 
 
 
X  
X  
 
ECOG PS score  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
12-lead ECG 4  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Hematology/Blood 
Biochemistry/Urinalysis 5  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Coagulation function 6  
X  
 
 
 
 
 
 
X  
X  
 
Pregnancy test 7  
X  
 
 
 
 
 
 
 
 
 
Thyroid function 8  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Virological testing (HIV, HBV, HCV 
and Treponema pallidum specific 
antibodies) 9  
X  
 
 
 
 
 
 
 
 
 


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Phase  
Crossover Treatment Cycles with Sintilimab (Every 21 days per 1 cycle) 1  
End of Treatment Visit 13  
Safety Follow-up 13  
Survival Follow-
up 14  
1  
2  
3  
4  
5  
6  
7 
and 
above  
HCV-RNA if HCV antibody 
positive 9  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
HBV-DNA if positive for HBsAg 
and/or HBcAb 9  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Blood cardiac enzymes and troponin 
10  
X  
X  
X  
 
 
 
 
 
 
 
Review Adverse Events 11  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant medications  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Subsequent antineoplastic therapy  
 
 
 
 
 
 
 
X  
X  
X  
Efficacy Measurements  
 
Tumor Imaging 12  
X  
 
 
X  
 
 
X  
 
 
 
Study Drug Administration  
 
Sintilimab 200mg IV Q3W  
X  
X  
X  
X  
X  
X  
X  
 
 
 
Notes:  
1. 
All subjects who enter the crossover treatment phase of sintilimab must have their overall status assessed by the investigator and meet the requirements before 
continuing to receive sintilimab; Examination after the last dose may be used as a pre-crossover assessment. Subjects must be at least 21 days after completion of the 
last dose of chemotherapy to be treated with sintilimab, regardless of confirmed disease progression.  
2. 
Vital signs include: temperature, pulse, respiratory rate, and blood pressure.  


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3. 
Weight/height will only be measured prior to the first dose.  
4. 
Time point of 12-lead ECG: prior to administration of each cycle of sintilimab, at the End of Treatment visit and at the safety follow-up visit.  
5. 
Hematology includes: RBC, HGB, HCT, WBC, PLT, white blood cell differential [lymphocytes, neutrophils, monocytes, eosinophils, basophils]. Blood 
biochemistry includes: liver function [TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH], renal function [UREA or BUN, Cr], blood electrolytes (Na, K, Cl, Mg, 
Ca, P), amylase, and glucose. Urinalysis includes: PH, specific gravity, UWBC, UPRO, URBC and UGLU. Hematology, blood biochemistry, urinalysis are to be 
performed within 7 days prior to the first dose, within 3 days prior to the start of each cycle starting from Cycle 2, at the End of Treatment visit and at the safety 
follow-up visit. Tests will be conducted in each local lab. Subjects with hemoglobin≥90 g/L 3 days prior to the start of the second cycle can receive drug.  
6. 
Coagulation tests include: PT and INR are to be performed within 7 days prior to the first dose of treatment, at the End of Treatment visit and at the safety 
follow-up visit. Tests will be conducted in each local lab. 
7. 
Women of childbearing potential will have a urine or serum pregnancy test performed within 3 days prior to the first dose. If the result of urine pregnancy test 
cannot be confirmed as negative, serum pregnancy test will be performed, and the result of serum pregnancy will prevail. Tests will be conducted in each local lab. 
8. 
Thyroid function tests will be performed within 14 days before the first dose, within 3 days before the start of each cycle in Cycle 2, at the end of treatment visit 
and at the safety follow-up visit. Tests will be conducted in each local lab. 
9. 
Includes HIV, Treponema pallidum specific antibody and HCV antibody tests, and hepatitis B test should be completed within 14 days before the first dose. For 
HCV antibody-positive subjects, HCV-RNA load may be measured once within 14 days prior to the first dose, within 3 days prior to the start of study drug 
administration starting from Cycle 2, at the end of treatment visit and safety follow-up visit, or sooner if clinically indicated; it may be unnecessary to wait for the test 
result to be taken prior to study drug administration during the course of study treatment. For HBsAg and/or HBcAb positive subjects, HBV-DNA load will be 
measured once within 14 days prior to the first dose, within 3 days prior to the start of study drug administration starting from Cycle 2, at the end of treatment visit 
and safety follow-up visit, or earlier if clinically indicated; during the course of study treatment, it is not necessary to wait for the test result to be administered first 
with the study drug. Tests will be conducted in each local lab. 
10. The cardiac biomarker and troponin testing shall at least include: creatine kinase (CK), creatine kinase myocardial band (CK-MB), troponin (troponin T or 


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troponin I). Subsequent examinations will be performed at the discretion of the investigator within 7 days prior to the first dose of study medication and within 3 days 
prior to the start of each cycle of study medication for Cycles 2 and 3.  
11. AEs and laboratory safety evaluations will be assessed according to CTCAE v4.03. For the definition, recording, relevance judgment, severity judgment, 
reporting time limit and treatment of AEs and SAEs, refer to the description in Section 8 of the protocol.  
12. Tumor response evaluations will be based on RECIST v1.1 and iRECIST. Tumor imaging usually includes contrast-enhanced CT or MRI of the brain, chest, 
abdomen, and pelvis. For subjects without brain metastases prior to the first dose, routine brain imaging is not required thereafter. The same imaging technique 
should be used for the same subject during the study. The investigator may collect imaging results 28 days prior to the first dose for assessment. Tumor imaging 
evaluations will be performed every 9 weeks (±7 days) from the time of first dose. Subjects with initial documented radiographic disease progression must undergo 
imaging evaluation at least 4 weeks after the date of the first tumor imaging indicating progressive disease and no later than 8 weeks to confirm disease progression if 
clinically stable. For subjects who discontinue treatment for reasons other than radiographic disease progression, imaging evaluations should continue to be 
performed every 9 weeks (±7 days) as specified in the protocol until any of the following events occur: initiation of new antineoplastic therapy, disease progression, 
subject withdrawal of ICF, and death, whichever occurs first. Tumor evaluation should be performed at the end of treatment if the end of treatment is more than 4 
weeks since the last imaging examination for tumor assessment. The evaluation will be completed after the occurrence of investigator-confirmed PD in RECIST v1.1; 
the evaluation of iRECIST will start from the first PD visit in RECIST v1.1 until the end of efficacy assessment.  
13. End of treatment visit: within 7 days after the end of treatment. Safety follow-up visit: will be performed 30±3 days after the last dose, or before starting a new 
anti-tumor treatment. If the end of treatment visit and safety follow-up visit are within 7 days, only the end of treatment visit will be performed. If the safety follow-
up visit is prior to the end of treatment visit, only the end of treatment visit will be performed. Refer to Section 6.3.4 for details.  
14. Survival visit: every 90 days (±7 days) after the safety visit, phone call is acceptable. Refer to Section 6.3.5 for details.  


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Table of Content 
Protocol Synopsis ......................................................................................................... 3 
Table of Content ........................................................................................................ 24 
List of Abbreviations................................................................................................. 30 
1. 
Study Background ............................................................................................. 32 
1.1 
Disease Background ................................................................................... 32 
1.2 
Sintilimab ................................................................................................... 34 
1.2.1 
Mechanism of Action ................................................................................. 34 
1.2.2 
Clinical Study Results ................................................................................ 35 
1.2.3 
Phase Ib Preliminary Clinical Efficacy of Sintilimab in First-Line Treatment 
of Non-Squamous NSCLC .......................................................................................... 36 
1.3 
Risk/Benefit Assessment ............................................................................ 37 
2. 
Study Objectives ................................................................................................ 38 
2.1 
Primary Objectives ..................................................................................... 38 
2.2 
Secondary Objectives ................................................................................. 38 
2.3 
Exploratory Objectives ............................................................................... 38 
3. 
Study Design ..................................................................................................... 39 
3.1 
Overall Design ............................................................................................ 39 
3.1.1 
Trial Blinding.............................................................................................. 41 
3.1.2 
Estimation of Sample Size .......................................................................... 41 
3.1.3 
Randomization ............................................................................................ 42 
3.1.4 
Stratification ............................................................................................... 42 
3.2 
Design Rationale ........................................................................................ 43 
3.2.1 
Rationale for Selecting Randomized Double-Blind Study Design ............ 43 
3.2.2 
Rationale for Selection of Dose Regimen and Dose of Sintilimab ............ 43 
3.2.3 
Rationale for Selection of PFS as the Primary Study Endpoint ................. 43 
3.2.4 
Rationale for Crossover to Sintilimab Monotherapy After Progression in the 
Control Arm ................................................................................................................. 44 
3.2.5 
Rationale for the Use of iRECIST to Assess Exploratory Efficacy Endpoints
 
44 
3.3 
Independent Data Monitoring Committee .................................................. 44 
4. 
Study Population ............................................................................................... 45 


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4.1 
Inclusion criteria ......................................................................................... 45 
4.2 
Exclusion Criteria ....................................................................................... 46 
4.3 
Restrictions During the Study .................................................................... 49 
4.3.1 
Use in Pregnancy ........................................................................................ 49 
4.3.2 
Contraception ............................................................................................. 49 
4.3.3 
Use in Nursing Women ............................................................................... 50 
4.4 
Criteria forDiscontinuation/Withdrawal and Withdrawal of Informed 
Consent 50 
4.4.1 
Discontinuation/Withdrawal ....................................................................... 50 
4.4.2 
Withdrawal of Informed Consent ............................................................... 51 
4.4.3 
Clinical Criteria for Early Study Termination ............................................ 51 
5. 
Study Treatment ................................................................................................. 52 
5.1 
Use of Study Drug ...................................................................................... 53 
5.1.1 
Use of Sintilimab ........................................................................................ 53 
5.1.2 
Use of Chemotherapy ................................................................................. 54 
5.2 
Dose Modification ...................................................................................... 55 
5.2.1 
General Principles....................................................................................... 55 
5.2.2 
Dose Modifications for Sintilimab ............................................................. 55 
5.2.3 
Management of Infusion Reactions Related to Sintilimab ......................... 58 
5.2.4 
Dose Modification of Chemotherapy ......................................................... 59 
5.3 
Principles for Managing Immune Checkpoint Inhibitor Toxicities ............ 61 
5.4 
Concomitant Therapy ................................................................................. 62 
5.4.1 
Acceptable Concomitant Medications ........................................................ 62 
5.4.2 
Prohibited Concomitant Medications ......................................................... 62 
5.4.3 
Drug Interactions ........................................................................................ 64 
5.5 
Drug Management ...................................................................................... 64 
5.5.1 
Drug Management ...................................................................................... 64 
5.5.2 
Drug Dispensation ...................................................................................... 65 
5.5.3 
Drug Return and Destruction ...................................................................... 65 
5.6 
Study Drug Records ................................................................................... 66 
5.7 
Complaint Handling ................................................................................... 66 
6. 
Study Procedures ............................................................................................... 66 
6.1 
Enrollment and Randomization .................................................................. 66 
6.1.1 
Enrollment and Randomization .................................................................. 66 


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6.1.2 
Enrollment Error Handeling ....................................................................... 67 
6.2 
Study Plan and Schedule ............................................................................ 67 
6.2.1 
Screening Period ......................................................................................... 67 
6.2.1.1 
Past Medical History .................................................................................. 68 
6.2.1.2 
Prior Medications ....................................................................................... 68 
6.2.1.3 
Concomitant Medications ........................................................................... 69 
6.2.2 
Baseline (prior to Cycle 1 Day 1) ............................................................... 69 
6.2.3 
Treatment Period Visits .............................................................................. 69 
6.2.4 
End of Treatment Visit/Safety Follow-Up Visit ......................................... 70 
6.2.5 
Survival Follow-up ..................................................................................... 71 
6.2.6 
Subsequent Anti-tumor Therapy ................................................................. 71 
6.3 
Crossover for Subjects of Control Arm after Documented Disease 
Progression .................................................................................................................. 71 
6.3.1 
Assessment before the first dose (Crossover Phase) .................................. 72 
6.3.2 
Concomitant medications (Crossover Phase) ............................................. 73 
6.3.3 
Treatment Period Visits (Crossover Phase) ................................................ 73 
6.3.4 
End of Treatment Visit/Safety Visit (Crossover Phase) .............................. 74 
6.3.5 
Survival Follow-up Visit (Crossover Phase) .............................................. 74 
6.3.6 
Subsequent Anti-tumor Treatment (Crossover Phase) ............................... 75 
6.4 
Other Procedures ........................................................................................ 75 
6.4.1 
Treatment Discontinuation/Withdrawal ..................................................... 75 
6.4.2 
Lost to Follow-up ....................................................................................... 75 
6.4.3 
Unblinding .................................................................................................. 76 
7. 
Study Evaluation ............................................................................................... 77 
7.1 
Efficacy Evaluation .................................................................................... 77 
7.1.1 
Tumor Imaging and Assessment of Disease ............................................... 77 
7.1.2 
Initial Tumor Imaging ................................................................................. 78 
7.1.3 
Tumor Imaging During the Study............................................................... 78 
7.1.4 
End of Treatment and Follow-up of Tumor Imaging ................................. 79 
7.1.5 
iRECIST Assessment of Disease ................................................................ 79 
7.2 
Safety Assessment ...................................................................................... 80 
7.2.1 
Physical Exam ............................................................................................ 80 
7.2.1.1 
Full Physical Exam ..................................................................................... 80 
7.2.1.2 
Directed Physical Exam.............................................................................. 80 


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7.2.1.3 
Height, Weight, and Vital signs .................................................................. 80 
7.2.1.4 
12-Lead Electrocardiogram (ECG) ............................................................ 81 
7.2.1.5 
ECOG Performance Status ......................................................................... 81 
7.2.2 
Laboratory Procedures/Assessments .......................................................... 81 
7.2.2.1 
Laboratory Safety Evaluations (Hematology, blood coagulation, urinalysis, 
Chemistry, etc.) ............................................................................................................ 81 
7.2.2.2 
Pregnancy Test ............................................................................................ 83 
7.2.2.3 
Central Laboratory Evaluations .................................................................. 83 
7.3 
Pharmacokinetics ........................................................................................ 83 
7.4 
Immunogenicity .......................................................................................... 83 
7.5 
Quality of Life Assessment ........................................................................ 84 
7.6 
Biomarker analysis ..................................................................................... 84 
7.6.1 
Tissue Biomarkers ...................................................................................... 84 
7.6.2 
Blood Biomarkers ....................................................................................... 85 
7.7 
Storage and Destruction of Biological Samples ......................................... 85 
8. 
Safety Reporting and Adverse Event Management ........................................... 85 
8.1 
Definition of Adverse Events ..................................................................... 85 
8.2 
Definition of Serious Adverse Event .......................................................... 86 
8.3 
Evaluating Adverse Events ......................................................................... 87 
8.4 
Recording Adverse Events ......................................................................... 91 
8.4.1 
Adverse Event Collection and Times ......................................................... 91 
8.4.2 
Follow-up of Adverse Events ..................................................................... 91 
8.4.3 
Contents of AE records ............................................................................... 91 
8.5 
Expedited Reporting of SAEs and Pregnancy ............................................ 94 
8.6 
Events of Abnormal Hepatic Function ....................................................... 95 
8.7 
Management of Drug-Related Toxicity ...................................................... 96 
8.8 
Immune-related Adverse Events ................................................................. 96 
8.9 
Emergency Unblinding ............................................................................... 96 
9. 
Statistical Considerations .................................................................................. 97 
9.1 
Statistical Analysis Plan ............................................................................. 97 
9.2 
Statistical Assumptions and Sample Size ................................................... 97 
9.3 
Definition of Analysis Set .......................................................................... 97 
9.4 
Statistical Analysis Methods ....................................................................... 98 
9.4.1 
Statistical Analysis General Method .......................................................... 99 


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9.4.1.1 
Analysis of primary endpoint indicators .................................................... 99 
9.4.1.2 
Analysis of secondary endpoint indicators: .............................................. 100 
9.4.2 
Safety Analysis ......................................................................................... 101 
9.4.2.1 
Drug Exposure .......................................................................................... 101 
9.4.2.2 
Adverse Events ......................................................................................... 102 
9.4.2.3 
Laboratory Tests ....................................................................................... 102 
9.4.2.4 
Immunogenicity Indicators ....................................................................... 102 
9.4.2.5 
ECG Examination ..................................................................................... 102 
9.4.2.6 
Vital 
signs, 
Physical 
examination, 
and 
Other 
safety 
related 
examinations .............................................................................................................. 103 
9.4.3 
Compliance Analysis ................................................................................ 103 
9.4.4 
Baseline Characteristics of Subjects ......................................................... 103 
9.4.5 
Interim Analysis ........................................................................................ 103 
9.4.6 
Subgroup Analysis .................................................................................... 104 
9.4.7 
Adjustment for Multiple Comparisons and Multiplicity .......................... 104 
9.4.8 
Data Lists of Responsive Subjects ........................................................... 104 
9.4.9 
Exploratory Analysis ................................................................................ 104 
10. 
Quality Assurance and Quality Control ........................................................... 104 
10.1 
Clinical Monitoring .................................................................................. 105 
10.2 
Data Management/Coding ........................................................................ 105 
10.3 
Quality Assurance Audits ......................................................................... 107 
11. 
Ethics ............................................................................................................... 107 
11.1 
Ethics Committee ..................................................................................... 107 
11.2 
Ethics of this Study ................................................................................... 108 
11.3 
Subject Information and Informed Consent ............................................. 108 
11.4 
Data Protection for Subjects ..................................................................... 109 
12. 
Study Management .......................................................................................... 109 
12.1 
Data Processing and Record Keeping ...................................................... 109 
12.2 
Access to Raw Data/Documents .............................................................. 109 
12.3 
Protocol Amendment ................................................................................ 109 
12.4 
Responsibilities of Investigators ............................................................... 110 
12.5 
Publication Policy ..................................................................................... 110 
12.6 
Finance and Insurance .............................................................................. 111 
13. 
References ....................................................................................................... 112 


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14. 
Appendix ......................................................................................................... 113 
Appendix 1: ECOG PS ............................................................................................. 113 
Appendix 2: Calculation of creatinine clearance and body surface area .................. 114 
Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) .......... 115 
Appendix 4: Response Evaluation Criteria in Immune Solid Tumors (iRECIST) ... 126 
 
 
List of Tables  
 
Table 1. Study Flow Chart ...................................................................................... 13 
Table 2. Flow Chart of Crossover Phase to Sintilimab Monotherapy .................... 20 
Table 3. Effective method of contraception (must use at least 1 method) .............. 50 
Table 4. Study Treatment ........................................................................................ 52 
Table 5. Dosage Modification Guidelines for Sintilimab ....................................... 55 
Table 6. Guidelines For The Management of Sintilimab-related Infusion Reactions
 ........................................................................................................................ 58 
Table 7. Dose Modifications for Chemotherapy agents ......................................... 60 
Table 8. Dose Modifications for Chemotherapy based on Hematologic Nadir from 
Previous Cycle ................................................................................................ 60 
Table 9. Dose Modifications for Chemotherapy based on AE grade ..................... 60 
Table 10. Laboratory Tests ..................................................................................... 81 
Table 11. Detailed Rules for the Evaluating Adverse Events ................................. 88 
Table 12. Hepatic impairment requiring reporting as an SAE ............................... 95 
 
List of Figures 
Figure 1. Overall flow chart ................................................................................... 41 


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List of Abbreviations  
Abbreviations 
Full Name 
ADA  
Anti drug antibody  
ADR  
Adverse drug reaction  
AE  
Adverse event  
ALT  
Alanine transaminase  
ALK  
Anaplastic lymphoma kinase  
AST  
Aspartate aminotransferase  
BOR  
Best overall response  
CI  
Confidence interval  
CR  
Complete Response             
Cr  
Creatinine  
CRF  
Case Report Form  
CTLA-4  
Cytotoxic T Lymphocyte Antigen 4  
ct-DNA  
Circulating tumor DNA  
DCR  
Disease control rate  
DOR  
Duration of response  
DLT  
Dose-limited toxicity  
EC  
Ethics Committee  
ECG  
Electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
EGFR  
Epidermal growth factor receptor  
EMA  
European medicines agency  
EORTC QLQ  
European organization for research and treatment of cancer quality of life 
questionnaire  
FAS  
Full Analysis Set  
FDA  
Food and drug administration  
GCP  
Good Clinical Practice  
HBV  
Hepatitis B virus  
HCV  
Hepatitis C virus  
HIV  
Human Immunodeficiency Virus  
HR  
Hazard ratio  
ICF  
Informed consent form  
ir-AE  
Immune-related Adverse Event  
IRRC  
Independent Radiographic Review Committee  
iRECIST  
Immune Response Evaluation Criteria In Solid Tumors  
irRECIST  
Immune-related Response Evaluation Criteria In Solid Tumors  


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Abbreviations 
Full Name 
ITT  
Intention to treat  
LCSS  
The Lung Cancer Symptom Scale  
NAb  
Neutralizing antibody  
NSAIDS  
Nonsteroidal Anti-inflammatory Drugs  
NSCLC  
Non Small Cell Lung Cancer  
ORR  
Objective Response Rate  
OS  
Overall Survival  
PD  
Progressive Disease  
PD-1  
Programmed Cell Death 1  
PD-L1  
Programmed Death-Ligand 1  
PFS  
Progression-Free Survival  
PK  
Pharmacokinetic  
PPS  
Per-Protocol Set  
PR     
Partial Response  
RECIST  
Response Evaluation Criteria In Solid Tumors  
SAE  
Serious Adverse Event  
SD  
Stable Disease  
SS  
Safety Analysis Set  
TBIL  
Total Bilirubin  
TEAE  
Treatment Emergent Adverse Event  
TSH  
Thyroid Stimulating Hormone  
TTR  
Time to Response  
ULN  
Upper Limit of Normal  


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1. Study Background 
1.1 Disease Background  
Cancer has been one of the leading causes of death in the world and has become a 
major disease that seriously endangers human life and health and restricts social and 
economic development. Nowadays, the incidence of cancer and the number of deaths 
are still rising rapidly. In 2012, it was estimated that 14.1 million new cancer cases and 
8.2 million new cancer deaths occurred worldwide[1]. China also faces an increasingly 
serious challenge from cancer. According to the data released by the National Cancer 
Center in February 2017, there are 4.29 million new cancer cases and 2.81 million 
cancer deaths in China every year, equivalent to 12,000 cancer cases and 7,500 cancer 
deaths every day. However, with the further development of the aging population in 
China, cancer incidence and mortality will continue to rise[2]. Among all cancer deaths, 
lung cancer (25.2%) is ranked number one, followed by liver cancer (14.4%), gastric 
cancer (14.3%), and esophageal cancer (9.3%). These four types of cancer have poor 
prognosis, accounting for 63.2% of all cancer deaths[2]. 
Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of 
all lung cancer cases, and approximately 70% of NSCLC subjects are diagnosed with 
locally advanced or metastatic disease that is ineligible for surgical resection. Moreover, 
a significant proportion of subjects with early-stage NSCLC who undergo surgery still 
have a chance of recurrence or distant metastasis, and will progress to death eventually. 
Approximately 60% of NSCLC in China are non-squamous NSCLC. The treatment 
modality for subjects with advanced non-squamous NSCLC is based on chemotherapy, 
and target therapy can be used in a subset of subjects. Epidermal growth factor receptor 
(EGFR) mutation rate is approximately 40% in Chinese non-squamous NSCLC. EGFR 
inhibitors (gefitinib, erlotinib or icotinib) are recommended for first-line treatment of 
advanced NSCLC subjects with sensitizing EGFR mutation. The ALK rearrangement 
rate in China is about 3%, and the ALK inhibitor crizotinib is recommended as the first-
line treatment for advanced NSCLC subjects with ALK rearrangement. The first-line 
standard treatment for advanced non-squamous NSCLC without sensitive EGFR 
mutation and ALK rearrangement is platinum-based doublet chemotherapy, with a 
survival of only 6-9 months after failure of first-line chemotherapy [3] . New drug 
development for advanced non-squamous NSCLC is an important task that is still a long 
way off. In recent years, there has been rapid research progress in activating the body's 


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own immune system by inhibiting immune checkpoints and attacking tumor cells. The 
use of immune checkpoint inhibitors (such as anti-PD-1/PD-L1 antibody) provides a 
new clinical approach for the first-line treatment of NSCLC, especially recurrent or 
metastatic NSCLC.  
KEYNOTE-021G was a randomized, open-label, multicenter cohort study of subjects 
with advanced non-squamous NSCLC who had not received prior chemotherapy and had 
no EGFR sensitivity mutations/ALK rearrangement. Subjects were randomized to receive 
pembrolizumab in combination with pemetrexed plus carboplatin or pemetrexed plus 
carboplatin alone. Subjects in the chemotherapy arm may crossover to receive 
pembrolizumab monotherapy at the discretion of the investigator after documented 
disease progression. The primary endpoint of the study was objective response rate 
assessed by RECIST v1.1 criteria. One hundred and twenty-three subjects participated in 
the study, in which 60 subjects received pembrolizumab in combination with 
chemotherapy and 63 subjects received standard first-line chemotherapy with a median 
follow-up of 10.6 months. The objective response rate of the experimental group was 
significantly better than that of the control group (55% vs 29%, p = 0.016). The PFS rate 
of the experimental group was also significantly better than that of the control group (HR 
= 0.53, p = 0.01). There were 20 subjects in the control group who crossed over to receive 
pembrolizumab. The incidence of adverse events was similar between the two groups, 
and subjects were tolerable [4]. KEYNOTE-189, an efficacy validation study for 
KEYNOTE-021G, enrolled subjects with metastatic non-squamous NSCLC who had not 
received prior antineoplastic therapy and had no EGFR sensitivity mutation/ALK 
rearrangement. The study was blinded and the subjects enrolled were randomized at a 2:1 
ratio to receive either pembrolizumab plus platinum-based standard chemotherapy (n = 
410) or placebo plus platinum-based standard chemotherapy (n = 206). Subjects in the 
chemotherapy group could crossover to receive pembrolizumab monotherapy after 
confirmation of disease progression at the discretion of the investigator. The primary 
endpoint of the study was PFS assessed by IRRC according to RECIST v1.1 and OS. The 
median follow-up of the study was 10.5 months, and the overall survival rate at 12 months 
was significantly better in the experimental group than in the control group (69.2% vs 
49.4%, HR = 0.49, P<0.001), median PFS was also significantly better in the 
experimental group than in the control group (8.8 months vs 4.9 months, HR = 0.52, p < 
0.001) and safety data was similar between two groups [5] .  


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Based on the results of the above two clinical studies, anti-PD-1 monoclonal antibody 
in first-line treatment of advanced non-squamous NSCLC subjects has a positive efficacy 
and tolerable toxicity. It is worthy to actively conduct relevant studies in advanced non-
squamous NSCLC subjects in China as soon as possible to fill the gap in first-line 
treatment of immune anti-tumor therapy in Chinese subjects.  
1.2 Sintilimab 
1.2.1 Mechanism of Action  
Immune checkpoint therapy is a research and development hotspot in recent years, 
and continues to make great breakthroughs. Unlike cytotoxic drugs, monoclonal 
antibodies or small molecule tyrosine kinase inhibitors that target tumor driver genes, 
immune checkpoint therapy does not act directly on tumor cells, but improves the 
function of T cells by blocking the inhibitory signals of T cell proliferation and 
activation, relieves the tolerance of the immune system to tumor cells, and improves the 
effective recognition and killing of tumor cells by T cells. Immune checkpoint targets 
that have shown significant clinical efficacy include cytotoxic T lymphocyte-associated 
antigen-4 (CTLA-4) and programmed cell death receptor 1/ligand 1 (PD-1/PD-L1) [6].  
Currently, FDA has approved 5 anti-PD-1/PD-L1 monoclonal antibody, including 
anti-PD-1 monoclonal antibody nivolumab (trade name: Opdivo) from Bristol-Myers 
Squibb Company (BMS), anti-PD-1 monoclonal antibody pembrolizumab (trade name: 
Keytruda) from Merck & Co Inc, and anti-PD-L1 monoclonal antibody atezolizumab 
(trade name: Tecentriq) from Roche, anti-PD-L1 monoclonal antibody avelumab (trade 
name: Bavravio) from Pfizer/ Merck KGaA, and anti-PD-L1 monoclonal antibody 
durvalizumab (trade name: Imfinzi) from AstraZeneca. The approved indications include 
advanced melanoma, advanced NSCLC, advanced classic Hodgkin's lymphoma, 
advanced tumour of head and neck, advanced renal cell carcinoma and others [6]. In 
addition, many promising indications are currently in phase III clinical studies or in the 
application phase. The approval of the above drugs has confirmed the important position 
of anti-PD-1/PD-L1 antibody drugs in cancer immunotherapy. At present, there is no anti-
PD-1/PD-L1 antibody drug approved in China. It is of great significance to actively 
develop such inhibitors to provide better treatment options for Chinese subjects with 
advanced cancer.  


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Sintilimab (R&D Code: IBI308) is a recombinant fully human IgG4 anti-PD-1 
monoclonal antibody. Many preclinical trials in vitro have demonstrated the ability of 
sintilimab to block the PD-1 pathway. The results of various completed preclinical 
pharmacodynamics, animal pharmacokinetics and toxicology studies show that 
sintilimab has the characteristics of a definite target, reliable cell strain source and good 
drug stability, and sintilimab has showed good activity in various completed preclinical 
studies. For the detailed study results, please refer to the Investigator's Brochure.  
1.2.2 Clinical Study Results  
    In September 2016, a phase Ia dose escalation study of sintilimab (study code 
CIBI308A101-1a) was initiated. Phase 1a study enrolled subjects with advanced solid 
tumors who had failed standard therapies. Dose escalation followed the classical “3+3” 
design and four dose levels (1 mg/kg, 3 mg/kg, 200 mg and 10 mg/kg) were evaluated. 
After completion of the 1 mg/kg dose group, subjects were randomized 1:1 to undergo 
evaluation independently at two dose groups, 3 mg/kg and 200 mg dose levels. The dose-
limiting toxicity (DLT) observation period was 28 days after the first dose in each dose 
group, and subjects who completed the DLT observation period were allowed to enter 
subsequent treatment with sintilimab every two weeks (1 mg/kg, 3 mg/kg and 10 mg/kg) 
or every three weeks (200 mg) until disease progression, intolerable toxicity, withdrawal 
of consent or occurrence of other reasons for discontinuation of study treatment, 
whichever occurred first.  
Pharmacokinetic study in subjects with stage Ia advanced solid tumors showed that 
the plasma concentration of sintilimab injection increased gradually from the start of 
infusion, reached Cmax after discontinuation, and then decreased slowly. In vivo exposure 
to sintilimab increased proportionally with increasing dose within the dose range of 1 to 
10 mg/kg, suggesting linear kinetics. Elimination half-life of sintilimab in subjects with 
solid tumors following a single dose (Geo. Mean [CV%]) was 14.4 [28.9%] days, 
clearance was 11.5 [42.5%] mL/h, volume of distribution at steady state was 5.43 [34.4%] 
L, and apparent volume of distribution was 5.77 [33.2%] L. PK profiles were similar to 
those of similar approved anti-PD-1 antibodies (nivolumab, pembrolizumab).  
In a pharmacodynamic study in subjects with stage Ia advanced solid tumors, a 
single 1 mg/kg (N = 3) dose of sintilimab resulted in rapid (24-hour) occupancy (mean ≥ 
95%) of PD-1 on the surface of CD3+ cells in peripheral blood of subjects. The occupancy 


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maintained when the drug concentration decreased in the study (28 days) and in the 
following consecutive dose. The PD-1 occupancy results in the 3 mg/kg (N = 3), 200 mg 
(N = 3) and 10 mg/kg (N = 3) dose groups were similar to those in the 1 mg/kg group, 
suggesting that the PD-1 receptor occupancy level was not dose- or concentration-
dependent within the dose range of 1-10 mg/kg. It has also demonstrated promising 
antitumor activity in subjects with a variety of advanced solid tumors whose standard 
therapies have failed. The best overall response was PR in 2 subjects and SD in 2 subjects 
per RECISTv1.1. Two subjects had irPR and three subjects had irSD per irRECIST. One 
additional subject of hepatocellular carcinoma who had failed sorafenib before enrollment 
was assessed PD in this study and still continued with sintilimab monotherapy. The 
subject’s tumor burden decreased from PD and was assessed irSD per irRECIST after 3 
cycles of post-PD treatment. As of October 30, 2017, this subject was still receiving 
treatment with sintilimab. Subjects who receive immunotherapy may experience tumor 
pseudoprogression, which is significantly different from the efficacy profile of 
conventional chemotherapy. An increase in tumor burden followed by a decrease was 
observed in 1 of 12 subjects treated with sintilimab. Response criteria for immune solid 
tumors have been cited in the following sintilimab clinical studies to explore trends in 
tumor pseudoprogression. As of October 30, 2017, a total of 3 subjects died (due to 
disease progression) in this phase 1a study.  
1.2.3 Phase Ib Preliminary Clinical Efficacy of Sintilimab in First-Line Treatment 
of Non-Squamous NSCLC  
The phase 1b study was a multicenter clinical study in Chinese subjects with 
advanced solid tumors, in which Cohort D enrolled subjects with advanced, recurrent or 
metastatic non-squamous NSCLC who had not previously received systemic anti-tumor 
therapy. Subjects were treated with sintilimab combined with pemetrexed and cisplatin. 
This cohort was to evaluate safety, tolerability and preliminary efficacy of sintilimab 
combined with chemotherapy. As of March 30, 2018, 21 subjects were enrolled and 
treated with the study drug (the maximum cycles of treatment was 13), and 19 of them 
had at least 1 imaging evaluation. Best overall response (BOR) results, assessed per 
RECIST v1.1, were 1 complete response (CR), 9 partial response (PR), 6 stable disease 
(SD), and 3 progressive disease (PD). The objective response rate was 52.6%.  


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1.3 Risk/Benefit Assessment  
Based on the mechanism of drug action and the clinical safety information available 
for sintilimab, the expected possible adverse events during the clinical study of sintilimab  
are mainly various immune inflammations caused by the activation of immune system, 
such as pneumonia, thyroiditis, hepatitis, dermatitis/skin lesions, etc. According to the 
available clinical data of anti-PD-1 monoclonal antibody drugs, although the incidence 
of adverse events is high, it can be well tolerated. Only a small proportion of subjects will 
discontinue the drug due to adverse events, and most adverse events can be solved after 
related treatment. Due to the variability of early symptoms in immune-related adverse 
events, investigators should pay special attention to the early symptoms and signs of 
various immune-related reactions during clinical studies. They should make timely and 
correct judgment, make dose adjustment and give corresponding effective treatment 
according to Section 5.2.2 of the protocol, so as to reduce the risk of drug use for subjects. 
In addition, attention should be paid to exclude subjects with autoimmune diseases in 
clinical studies to avoid aggravation of the original diseases caused by immune system 
activation.  
Pemetrexed combined with platinum is the current standard chemotherapy regimen 
for the first-line treatment of advanced non-squamous NSCLC subjects. This study is to 
evaluate the efficacy and safety of the chemotherapy combined with or without sintilimab 
in the first-line treatment of advanced non-squamous NSCLC subjects. This study will 
therefore provide subjects with standard effective first-line chemotherapy to ensure 
clinical benefit for subjects. The phase I clinical data of sintilimab showed that sintilimab 
has definite pharmacological activity and good tolerability in subjects with advanced 
tumors, and demonstrated preliminary anti-tumor activity in treatment-naïve subjects 
with advanced non-squamous NSCLC. We intend to conduct a large-scale multicenter, 
randomized, phase III controlled study in subjects with advanced, recurrent or metastatic 
non-squamous NSCLC who have not previously received systemic anti-tumor therapy. 
The purpose of this clinical study is to evaluate the efficacy and safety of sintilimab 
combined with standard chemotherapy regimen in this population and provide data basis 
for approving in relevant indication.  


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2. Study Objectives  
2.1 Primary Objectives  
Progression-free survival (PFS) per RECIST v1.1 in the first-line treatment of 
advanced or recurrent non-squamous NSCLC treated with sintilimab in combination with 
pemetrexed and platinum-based chemotherapy versus placebo in combination with 
pemetrexed and platinum-based chemotherapy.  
2.2 Secondary Objectives  
 
To compare the overall survival (OS) between the two treatment arms;  
 
To compare the objective response rate (ORR) per RECIST v1.1 between the 
two treatment arms;  
 
To compare the disease control rate (DCR) per RECIST v1.1 between the two 
treatment arms;  
 
To compare the time to objective response (TTR) per RECIST v1.1 between the 
two treatment arms;  
 
To compare the duration of response (DOR) per RECIST v1.1 between the two 
treatment arms;  
 
To evaluate the safety and tolerability of sintilimab in combination with 
pemetrexed and platinum-based chemotherapy.  
2.3 Exploratory Objectives  
 
To evaluate the efficacy of sintilimab in subjects per the immune Response 
Evaluation Criteria in Solid Tumors (iRECIST);  
 
To explore the population pharmacokinetic characteristics of sintilimab;  
 
To explore the biomarkers that can potentially predict the efficacy of 
sintilimab arm including, but not limited to, PD-L1 expression, and RNA in 
tumor specimens, circulating tumor DNA (ctDNA) and T cell receptor (TCR) 
in peripheral blood;  
 
To compare the quality of life of subjects treated with sintilimab combined 
with chemotherapy and placebo combined with chemotherapy using Lung 
Cancer Symptom Scale (LCSS) and European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, V3.0 
Chinese version);  
 
To compare PFS in the sintilimab arm receiving subsequent antineoplastic 


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therapy after disease progression versus placebo arm crossing over to receive 
sintilimab. 
3. Study Design  
3.1 Overall Design  
This study is a randomized, double-blind, multicenter, phase III study of sintilimab 
in combination with pemetrexed and platinum chemotherapy or placebo in combination 
with pemetrexed and platinum chemotherapy in the first-line treatment of subjects with 
advanced or recurrent non-squamous NSCLC in China.  
In this study, subjects will receive 4 cycles of sintilimab or placebo in combination 
with pemetrexed, cisplatin or carboplatin, followed by maintenance therapy with 
sintilimab or placebo in combination with pemetrexed. The maximum treatment 
duration of sintilimab is 24 months. In the study, approximately 378 subjects with 
advanced or recurrent non-squamous NSCLC who have not previously received 
systemic therapy will be randomized at a 2:1 ratio to the experimental sintilimab group 
and the control placebo group, with 252 subjects in the sintilimab group and 126 
subjects in the placebo group. The actual number of subjects enrolled may differ from 
the planned number due to unforeseen reasons, such as faster enrollment speed than 
expected. The final screening end date will be estimated before the enrollment of 378 
subjects and best effort will be made to ensure that the total number of subjects enrolled 
do not exceed 110% of the planned number, i.e., 414 subjects, of which 276 subjects 
are expected in the experimental group and 138 subjects are expected in the control 
group.   
The primary efficacy endpoint of the study is PFS per RECIST v1.1 assessed by 
independent radiographic review committee (IRRC) of sintilimab in combination with 
pemetrexed and platinum chemotherapy versus placebo in combination with 
pemetrexed and platinum chemotherapy as the first-line treatment of advanced or 
recurrent non-squamous NSCLC. Tumor imaging evaluation will be performed at Week 
6 (±7 days) and Week 12 (±7 days), and then every 9 weeks (±7 days); after Week 
48, tumor imaging evaluation will be performed every 12 weeks (±7 days). Treatment 
decisions will be made by the investigators based on tumor imaging evalution until the 
first objective imaging evidence of progressive disease (PD).  


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After the first evidence of radiographic PD per RECIST v1.1, the investigator 
should repeat imaging at least 4 weeks later if subject is clinically stable, and if PD is 
still confirmed, the subject may be unblinded after communicating with the Sponsor. 
After unblinding, subjects in the experimental group will discontinue study drug 
treatment, while subjects in the control group can crossover to receive sintilimab 
monotherapy at the discretion of the investigator until disease progression, intolerable 
toxicity, withdrawal of consent, death, or other protocol-specified circumstances, 
whichever occurred first. If clinical instability (refer to Section 7.1.3) coexists at the 
time of the first PD, radiographic confirmation after 4 weeks is not required. The subject 
may be unblinded and all study treatment will be discontinued after communicating 
with the Sponsor.  
Subjects should continue to receive treatment during the study until confirmed PD 
per RECIST v1.1, occurrence of unacceptable adverse events (AEs), presence of 
concurrent medical conditions that prevent continuation of treatment, decision by the 
investigator to discontinue treatment, withdrawal of consent by the subject, pregnancy 
of the subject, non-compliance with study treatment or procedure requirements, 
administrative reasons, or up to 24 months of treatment with sintilimab. Subjects who 
discontinue study treatment for reasons other than PD will still need to undergo imaging 
assessments at protocol-specified imaging time points to monitor disease status until 
any of the following occur: initiation of new antineoplastic therapy, disease progression, 
death, or end of study.  
Investigators will monitor possible adverse events throughout the study and grade 
the severity of adverse events according to the guidelines of the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03.  
This study will be conducted in compliance with Good Clinical Practice (GCP).  
 
 
 
 
 
 
 
 
 


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The overall flow chart is as follows:  
 
Figure 1. Overall flow chart  
Note: The actual number of subjects enrolled may differ from the planned number due to unforeseen 
reasons, such as faster enrollment speed than expected. The final screening end date will be estimated 
before the enrollment of 378 subjects and best effort will be made to ensure that the total number of 
subjects enrolled will not exceed 110% of the planned number, i.e., 414 subjects, of which 276 subjects 
are expected in the experimental group and 138 subjects are expected in the control group. 
3.1.1 Trial Blinding  
The same packaging will be used for both sintilimab and placebo in order to maintain 
blinding. The assignment will be unknown to the subjects, the investigators, Sponsor's 
staff and Sponsor’s designees who are involved in the subject's treatment or clinical 
evaluation.  
Refer to Section 6.4.3 for instructions on how to unblind subjects during the study, 
if required.  
3.1.2 Estimation of Sample Size  
It is assumed that the median progression free survival time of subjects receiving 
sintilimab treatment will be improved from 6 months to 9.2 months (with a hazard ratio 
= 0.65). With an enrollment time projection of 15 months, a projected follow-up time 
of 8 months and an estimated dropout rate of 0.5% per month, to provide approximate 
90% power under a two-sided α = 0.05, a total of 378 subjects need to be randomized 
to obtain the required 263 PFS events in this study. The actual number of subjects 
enrolled may differ from the planned number due to unforeseen reasons, such as faster 
enrollment speed than expected. The final screening end date will be estimated before 


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the enrollment of 378 subjects and best effort will be made to ensure that the total 
number of subjects enrolled will not exceed 110% of the planned number, i.e., 414 
subjects, of which 276 subjects are expected in the experimental group and 138 subjects 
are expected in the control group.  
There is one interim analysis planned in this study when 70% of total PFS events 
(184 events) occur, and the primary interim analysis will be based on PFS. 
3.1.3 Randomization  
Subjects will be randomized at a 2:1 ratio to receive either sintilimab plus 
chemotherapy or placebo plus chemotherapy. 
Centralized stratified block 
randomization will be used regardless of research center effect. Subjects who complete 
all screening assessments and satisfies the enrollment criteria will be assigned a 
randomization number generated by IWRS sequentially according to each subject’s 
randomization time. The randomization number will correspond the subject to the 
associated treatment group assigned (sintilimab or placebo). The corresponding 
investigational drug will then be dispensed. If a randomized subject withdraw from the 
study after randomization for any reasons, that randomization number will not be used 
again. The personnel in charge of the IWRS will only prepare the randomization list 
and will not involve in any direct study operation. 
In this study, central randomization system will set the limit on the percentage of 
subjects with PD-L1 expression <1% to no more than 33% of the total randomized 
subjects, i.e. not less than 67% subjects with PD-L1 expression ≥1% of the total 
randomized subjects .  
3.1.4 Stratification  
Subjects in this study will be randomized according to the following stratification 
factors: 
•   Gender (male vs female)  
•   Platinum chemotherapy (carboplatin vs cisplatin)  
•   PD-L1 expression level (< 1% or unevaluable vs ≥1%)  


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3.2 Design Rationale  
3.2.1 Rationale for Selecting Randomized Double-Blind Study Design  
This study plans to use a randomized double-blind design. On one hand, bias can be 
reduced by blinding to make the study results more reliable; on the other hand, the 2:1 
randomized distribution of the experimental group and the control group can improve the 
compliance of the subjects.  
3.2.2 Rationale for Selection of Dose Regimen and Dose of Sintilimab  
According to current Chinese and international guidelines, platinum-based doublet 
chemotherapy remains the standard first-line treatment for advanced non-squamous 
NSCLC without sensitive EGFR mutation/ALK rearrangement [7]. Based on KEYNOTE-
021G study results, FDA acceleratedly approved pembrolizumab in combination with 
pemetrexed and carboplatin for first-line treatment of metastatic non-squamous NSCLC 
in May 2017. Sintilimab is an anti-PD-1 monoclonal antibody and has demonstrated 
antitumor activity as a single agent in several immune-competent mouse models (see 
Investigator's Brochure). In the phase I clinical study of sintilimab (CIBI308A101), 
pharmacodynamic results showed that sintilimab had a definite PD-1 receptor blocking 
effect in vivo. The efficacy of sintilimab in combination with pemetrexed and cisplatin 
was satisfactory in the first-line population with previously untreated advanced non-
squamous NSCLC in phase 1b cohort D study. Therefore, this study will evaluate the 
efficacy and safety of sintilimab in combination with first-line chemotherapy in subjects 
with locally advanced, metastatic or recurrent non-squamous NSCLC.  
In this study, sintilimab 200 mg Q3W will be used. The choice of dosing regimen is 
primarily based on the safety data and exposure (concentration) -response (PD-1 receptor 
occupancy) relationship data from previous studies, along with preclinical in vitro/in vivo 
efficacy data and comparable data from similar drugs.  
3.2.3 Rationale for Selection of PFS as the Primary Study Endpoint  
PFS is a widely accepted measurement of clinical superiority for a completely new 
antineoplastic therapy in randomized phase III clinical studies and is able to demonstrate 
a satisfactory risk-benefit profile for the new therapy. It has also been identified by the 
FDA and EMA as one of the most important registration endpoints in NSCLC clinical 
studies in recent years. PFS may be evaluated by an independent central image review 
according to RECIST v 1.1 to minimize bias. Therefore, PFS is proposed as the primary 


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study endpoint in this study.  
3.2.4 Rationale for Crossover to Sintilimab Monotherapy After Progression in the 
Control Arm  
Anti-PD-1 mAb has been shown to be effective in NSCLC subjects who have failed 
first-line platinum-based chemotherapy in several studies. It has also been demonstrated 
in CIBI308A101-1b Cohort C that the continuation of sintilimab monotherapy in subjects 
with non-squamous NSCLC after failure of first-line platinum-based chemotherapy is 
beneficial and well tolerated (results not formally published). Therefore, subjects in the 
control arm of the study are allowed to crossover to continue treatment with sintilimab 
monotherapy at the discretion of the investigator and subjects after PD is confirmed.  
3.2.5 Rationale for the Use of iRECIST to Assess Exploratory Efficacy Endpoints  
Available clinical data suggests that a proportion of subjects receiving PD-1 
inhibitors may experience "disease progression" (as assessed by RECIST v1.1) before 
experiencing an objective response and/or stable disease. In this special situation, 
continued treatment still has the potential for clinical benefit. The mechanism of this 
phenomenon may be due to the increased severity of inflammation in the tumor, which 
leads to the increase of tumor mass and even the appearance of new lesions. In addition, 
anti-tumor immune response may take some time to occur. The so-called 
"pseudoprogression" rate is found to be slightly less than 10% in melanoma subjects by 
irRECIST or iRECIST criteria, while a pseudoprogression rate of around 5% has been 
reported in non-small cell lung cancer [8-9]. Therefore, iRECIST will also be used to assess 
exploratory efficacy endpoints in this study, allowing subjects to continue treatment with 
study drug if the subjects are clinically stable after initial disease progression as defined 
by RECIST v1.1. What’s more, these subjects can receive confirmed image assessment 
after 4 weeks (see Section 7.1.5 for details).  
3.3 Independent Data Monitoring Committee  
An independent data monitoring committee (IDMC) will be set up in this study to 
conduct an interim analysis of the efficacy endpoints and safety of the study. The 
composition, responsibilities and procedures of the IDMC are described in the IDMC 
charter.  


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4. Study Population  
4.1 Inclusion criteria  
Subjects must meet the following criteria for participation in this study:  
1) Has signed written informed consent before any study-related procedure;  
2) Is ≥ 18 and ≤ 75 years old;  
3) Has a life expectancy of at least 3 months;  
4) Has at least one measurable lesion based on RECIST v1.1 assessed by the 
investigator;  
Measurable lesions situated in a previously irradiated area or locally treated area can 
be selected as target lesions if progression has been demonstrated in such lesions;  
5) Has a histologically or cytologically confirmed diagnosis of locally advanced (stage 
III B/III C), metastatic, or recurrent (stage IV) non-squamous NSCLC according to 
the 8th edition of the TNM classification in the International Association for the Study 
of Lung Cancer and the American Joint Committee on Cancer. Meanwhile, subjects 
with stage IIIB/IIIC non-squamous NSCLC should not be eligible for radical surgery 
or radical radiochemotherapy; 
6) Ineligible for EGFR or ALK-target therapy (documented evidence of absence of 
sensitizing EGFR mutations and ALK gene rearrangements is required);  
7) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1;  
8) Has not received prior systemic antineoplastic therapy for advanced/recurrent non-
squamous NSCLC;  
Subjects who have received prior adjuvant chemotherapy are eligible if the adjuvant 
chemotherapy is completed at least 6 months prior to the recurrence of disease;  
9) Has adequate hematopoietic function as defined by an absolute neutrophil count≥
1.5×109 /L, platelet count≥100×109 /L, hemoglobin≥90 g/L [without transfusion in 7 
days and without dependence on erythropoietin (EPO)];  
10) Has adequate hepatic function, defined as a total bilirubin level≤1.5 × upper limit 
of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels ≤2.5 × ULN in subjects without liver metastases, AST and ALT levels 
≤5 × ULN in subjects with documented liver metastases;  
11) Has adequate renal function, defined as serum creatinine (Cr) ≤ 1.5 × ULN or 
calculated creatinine clearance ≥ 60ml/min (Cockcroft-Gault formula);  
Urine protein < 2 +, or 24-hour urine protein < 1g;  


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12) Has adequate coagulation function, defined as international normalized ratio (INR) 
or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant 
therapy, as long as the PT is within the proposed range for the anticoagulant, the 
subject is eligible;  
13) Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 3 days prior to receiving the first dose of study drug (Cycle 1, 
Day 1). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required;  
14) If there is a risk of conception, male and female subjects must use highly effective 
contraception (i.e., a method with a failure rate of less than 1% per year) for at least 
180 days after end of treatment. 
4.2 Exclusion Criteria  
 
Subjects should be excluded from participating in the study if the subject:  
1) Has predominantly squamous cell histology NSCLC; 
Mixed cell types must be primarily (≥90%) adenocarcinoma cells; if small cell 
elements are present, the subject cannot be enrolled; 
2) Is currently participating in an interventional clinical study or received other 
investigational drugs or used an investigational device within 4 weeks prior to the 
first dose of drug treatment;  
3) Has previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-
L2 agents or agents directed at another stimulatory or co-inhibitory T-cell receptor 
(e.g., CTLA-4, OX-40, CD137);  
4) Has received Chinese medicines with anti-lung cancer indications or 
immunomodulatory drugs (including thymosin, interferon, interleukin, except for 
local use to control pleural effusion) within 2 weeks prior to first dose of drug 
treatment, or has undergone major surgery within 3 weeks prior to first dose of drug 
treatment;  
5) Has received radiotherapy in lung with a dose > 30 Gy within 6 months prior to the 
first dose of study treatment;  
6) Has completed palliative radiotherapy within 7 days prior to the first dose of study 
treatment;  


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7) Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal 
obstruction;  
8) Has received solid organ or blood system transplantation;  
9) Has clinically uncontrollable pleural effusion or ascites (subjects who doesn’t need 
drainage of effusion or has no significant increase in effusion within 3 days after 
stopping drainage can be enrolled);  
10) Has a known severe allergic reaction (≥grade 3) to any component of sintilimab, 
pemetrexed, cisplatin, or carboplatin or to any excipients;  
11) Has active autoimmune disease that has required systemic therapy (e.g., use of 
disease modifying agents, corticosteroids, or immunosuppressive drugs) within 2 
years prior to the first dose of study treatment. Replacement therapy (e.g., thyroxine, 
insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic therapy;  
12) Diagnosed with immunodeficiency or receiving systemic glucocorticoid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose of 
study treatment;  
Physiological doses of glucocorticoids (≤10 mg/day of prednisone or equivalent 
glucocorticoid) is allowed;  
13) Has not adequately recovered from toxicity and/or complications caused by any 
intervention prior to starting study treatment (i.e. ≤Grade 1 or to baseline, excluding 
asthenia or alopecia);  
14) Has other malignancies diagnosed within 5 years prior to the first dose of study 
treatment, with the exception of radically treated basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ;  
15) Has symptomatic central nervous metastases. Subjects with asymptomatic 
metastases or stable metastases after treatment may participate in the study as long 
as all of the following criteria are met: measurable lesion outside the central nervous 
system; no meningeal, midbrain, pontine, medullary, or spinal metastases; clinically 
stable for at least 2 weeks; and discontinuation of hormonal therapy 14 days prior to 
the first dose of study treatment;  
16) Has a known history of non-infectious pneumonitis requiring corticosteroid therapy 
within 1 year prior to the first dose of study treatment or has current interstitial lung 
disease;  
17) Has active infection requiring systemic therapy;  


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18) Is unable or unwilling to take folic acid or vitamin B12 supplementation;  
19) Has psychiatric or substance abuse disorder that would interfere with compliance 
with the requirements of the study;  
20) Has a known history of Human Immunodeficiency Virus (HIV) infection (i.e., HIV 
1/2 antibodies positive), known active syphilis infection, active pulmonary 
tuberculosis;  
21) Has known untreated active hepatitis B;  
Note: Subjects with hepatitis B who meet the following criteria are also eligible:  
HBV viral load must be < 1000 copies/ml (200 IU/ml) or below the lower limit of 
detection before the first dose of study treatment. Subjects with active hepatitis B 
should receive anti-HBV therapy to avoid viral reactivation throughout the study 
treatment;  
For subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-), 
prophylactic anti-HBV treatment is not required, but viral reactivation should be 
closely monitored;  
22) Has active HCV infection (HCV antibody positive and HCV-RNA level above the 
lower limit of detection);  
23) Has received a live vaccine within 30 days prior to the first dose (Cycle 1, Day 1);  
Note: Inactivated viral vaccines for seasonal influenza within 30 days prior to the 
first dose of study treatment are allowed; live attenuated influenza vaccines 
administered intranasally are not allowed;  
24) Has uncontrolled concurrent medical conditions, such as:  
a) Esophageal or gastric varices requiring immediate intervention (e.g., band 
ligation or sclerotherapy) or with a high risk of bleeding, in the opinion of the 
investigator or in consultation with a gastroenterologist or hepatologist. Subjects 
who have portal hypertension (including splenomegaly with the evidence of 
imaging evaluations) or has a history of variceal bleeding should receive 
endoscopic examination within 3 months prior to enrollment to evaluate whether 
the subjects are eligible;  
b) Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B or worse 
cirrhosis;  
c) Significant malnutrition (e.g. need intravenous nutrition supplements). Subjects 
with malnutrition remedied more than 4 weeks prior to the first dose of study 
treatment are eligible;  


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d) The tumor compresses the surrounding vital organs (such as esophagus) 
accompanied with relevant symptoms, or compresses the superior vena cava or 
invades the major mediastinal blood vessels, heart, etc.;  
e) Class II-IV congestive heart failure (New York Heart Association classification), 
poorly controlled and clinically significant arrhythmia;  
f) 
Uncontrolled arterial hypertension even after receiving standard treatment 
(systolic blood pressure≥160 mmHg or diastolic blood pressure≥100 mmHg);  
g) Any arterial thrombosis, embolism, or ischemia such as myocardial infarction, 
unstable angina, cerebrovascular accident, or transient ischemic attack within 6 
months prior to enrollment. With a history of deep vein thrombosis, pulmonary 
embolism, or any other serious thromboembolism within 3 months prior to 
enrollment (thrombosis caused by implantable venous port or catheter, or 
superficial venous thrombosis is not considered "serious" thromboembolism);  
25) Has a history or current evidence of any disease, treatment, or laboratory abnormality 
that may interfere with the results of the study, prevent the subject from fully 
participating in the study, or other condition that the subject is ineligible for 
enrollment, in the opinion of the investigator;  
26) Is breast-feeding. 
4.3 Restrictions During the Study  
4.3.1 Use in Pregnancy  
Human IgG1 and IgG4 are known to be able to cross the placental barrier, so the study 
drug is not recommended during pregnancy. Women who are pregnant cannot be enrolled 
in this study.  
4.3.2 Contraception 
A female subject of childbearing potential who is sexually active with a non-
sterilized male partner, and a non-sterilized male subject who is sexually active with a 
female partner of childbearing potential must use at least one of the acceptable methods 
of effective contraception listed in Table 3. Effective method of contraception (must use 
at least 1 method) from the start of the screening period to 180 days after receiving the 
last dose. Subject should discuss with a responsible physician regarding the 
discontinuation of contraception after the above time point. Periodic abstinence, safe 
period contraception, and withdrawal are not acceptable methods of contraception. 


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Women of childbearing potential are defined as those who have experienced menarche, 
have not undergone sterilization (bilateral tubal ligation, bilateral salpingectomy, or total 
hysterectomy), and are not postmenopausal.  
Table 3. Effective method of contraception (must use at least 1 method)  
Barrier method  
Intrauterine device method  
Hormonal method  
Male condom with spermicide  T-ring with copper  
Implant  
Diaphragm with spermicide  
Progesterone containing T-ring a  Contraceptive injections or 
injections  
Diaphragm with spermicide  
Levonorgestrel-releasing 
intrauterine device system (e.g. 
Mirena ®) a 
Combined contraceptive pill  
Low dose oral contraceptive 
pill  
Contraceptive patch  
a This is also seen as a hormonal approach  
Menopause is defined as no menses without an alternative medical cause for at least 
12 months. Requirements based on age are as follows:  
 
Female ≥50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy and whose luteinizing hormone and follicle 
stimulating hormone levels are within the postmenopausal range are considered 
menopausal; 
 
Female <50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, had radiation-induced oophorectomy with last 
menses > 1 year ago, had chemotherapy-induced amenorrhea with last menses > 
1 year ago, or had undergone surgical sterilization (bilateral oophorectomy or 
hysterectomy) are considered menopausal.  
4.3.3 Use in Nursing Women 
It is unknown whether sintilimab is excreted in breast milk. Since many drugs are 
excreted in breast milk, sintilimab may potentially be toxic in infants. Breastfeeding 
lactating women cannot be enrolled in this study. 
4.4 Criteria forDiscontinuation/Withdrawal and Withdrawal of Informed Consent 
4.4.1 Discontinuation/Withdrawal  
Since some clinical data may be important for the study after treatment 


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discontinuation/withdrawal, these data and information should be collected until the 
subject's last scheduled visit, even if the subject has discontinued/withdrawn from 
treatment. 
Subjects may discontinue treatment at any time for any reason at the discretion of 
subjects’ personal or discontinue treatment at the discretion of the investigator should any 
adverse event occur. In addition, the investigator or Sponsor may discontinue treatment 
of a subject if the subject is unsuitable for treatment, violates the protocol, or for 
administrative and/or other safety reasons.  
Subjects should discontinue treatment but continue to be followed for any of the 
following reasons:  
o The subject or the subject's legally authorized representative requests treatment 
discontinuation.  
o Occurrence of protocol-specified adverse events requiring discontinuation of 
treatment (refer to Section 5.2).  
o Development of another malignancy that requires active treatment.  
o Concurrent illness that precludes further study treatment.  
o The investigator decide to withdraw the subject from the treatment.  
o Positive serum pregnancy test.  
o Poor subject compliance.  
o The clinical status or personal circumstances of the subject that, in the opinion of the 
investigator and/or Sponsor, would put the subject at unnecessary risk if the study 
drug is to be continued.  
o Completed 24 months of treatment with sintilimab.  
For subjects who discontinue treatment but continue to be followed in the study, all 
visits and procedures listed in the Study Flow Chart (Table 1, Table 2Table 2. Flow Chart 
of Crossover Phase to Sintilimab) should be completed.  
4.4.2 Withdrawal of Informed Consent  
If a subject or the subject's legally authorized representative withdraws consent of 
participating in the study, the subject will no longer be treated or followed at the scheduled 
protocol visit.  
4.4.3 Clinical Criteria for Early Study Termination  
The study may be terminated early if the following criteria are met:  


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 Inaccurate or incomplete quality and quantity of data records  
 Poor compliance with the protocol and regulatory requirements  
 The incidence or severity of adverse drug events in this or other studies suggests a 
possible hazard to the subject's health  
 A change or discontinuation of study drug development is planned.  
If the Sponsor decides that the study drug is no longer provided, sufficient notice 
will be given to appropriately adjust the subject's treatment.  
5. Study Treatment  
The investigational drugs of this study are defined as sintilimab or placebo and 
chemotherapy (pemetrexed, carboplatin/cisplatin).  
The first dose of study treatment should be started on the day of randomization 
(Cycle 1, Day 1), and no later than 48 hours after randomization. The Sponsor should be 
notified if the first dose is not administered within 48 hours. Every effort should be made 
to conduct the study treatment on the day of randomization. For the rest of the treatment 
cycles, at the discretion of the investigator, the study treatment can be administered 3 days 
before or after the scheduled day of administration for administrative reasons.  
After completion of all pre-dose procedures and evaluations detailedly listed in the 
study flow chart, study treatment will be started on Day 1 of each cycle.  
Table 4. Study Treatment 
Drug 
Dose/Potency  
Dose 
Frequency  
Route of 
Administration 
Regimen/Treatme
nt Period 
Use 
Sintilimab 1  
200 mg  
Q3W  
Intravenous 
infusion  
Cycle 
every 
21 
days, dosing on 
Day 1  
Experimental 
group  
Placebo 1  
2 vials  
Q3W  
Intravenous 
infusion  
Cycle 
every 
21 
days, dosing on 
Day 1  
Control group  
Pemetrexed2  
500 mg/m2  
Q3W  
Intravenous 
infusion  
Cycle 
every 
21 
days, dosing on 
Day 1  
Experimental/
Control group 
Cisplatin  
75 mg/m2  
Q3W  
Intravenous 
infusion  
Cycle 
every 
21 
days, dosing on 
Experimental/
Control group 


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Day 1, 4 cycles of 
continuous use  
Carboplatin  
AUC5  
Q3W  
Intravenous 
infusion  
Cycle 
every 
21 
days, dosing on 
Day 1, 4 cycles of 
continuous use  
Experimental/
Control group 
1. 
Sintilimab/placebo should be infused prior to the administration of chemotherapy.  
2. 
If a subject's body weight fluctuated less than 10% from baseline (the day of the first dose of study 
treatment), the baseline body weight will be used to calculate the amount of chemotherapy 
administered. Otherwise, the actual dose will be calculated based on the body weight on the 
scheduled day of dosing or the day before it. The actual dose can also be calculated based on the 
body weight on the day of dosing or the day before it according to clinical practice regardless of 
the baseline weight. The protocol allows a ±5% deviation from the calculated total infusion dose 
for dosing convenience.  
All the drugs in Table 4 will be supplied by the Sponsor in a unified manner, and all 
the commercially purchased drugs should be provided with the product/batch number. 
The local sites are responsible for recording the batch number, manufacturer and 
expiration date.  
5.1 Use of Study Drug  
5.1.1 Use of Sintilimab  
The main active ingredient of sintilimab is a recombinant fully human anti-
programmed death receptor-1 (PD-1) monoclonal antibody at a concentration of 10 
mg/mL. This product is a clear, colorless liquid, free from foreign matter, floccules and 
precipitates. The excipients include 5.88 mg/ml sodium citrate (dihydrate), 30.06 mg/ml 
mannitol, 3.73 mg/ml histidine, 2.92 mg/ml sodium chloride, 0.0075 mg/ml edetate 
disodium, 0.2 mg/ml polysorbate 80, and citric acid (monohydrate) to adjust pH to 6.0.  
The smallest packaging unit of sintilimab is one box, with each box containing 2 
vials of sintilimab injection. The package is printed with the drug name, dosage form, 
strength, drug code, batch number, shelf life, storage condition and information of the 
Sponsor. The same information is printed on the label of the vial and the box, but there is 
no information on dosage form, precautions, dosage and administration on the label of 
the vial. All boxes and vials are labeled with "For Clinical Study Use Only". Sintilimab 
should be stored at 2-8℃, protected from light, with a shelf life of 24 months. If any 


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quality problems such as turbidity and precipitation occur in the injection, it should be 
sealed up immediately and the Sponsor should be informed immediately.  
The preparation and administration of sintilimab is as follows:  
1. Fully extract 2 vials of sintilimab injection and transfer it into a 100mL 
intravenous bag containing 0.9% (weight/volume) sodium chloride solution. Record the 
time when the preparation process starts.  
2. Gently invert the infusion bag to mix the solution, ensuring uniformity of the 
contents. Do not shake vigorously so as to avoid bubbles. If a large amount of bubbles 
appear, allow the IV bag to stand until the bubbles disappear.  
3. Administer the drug with a 0.2 ~ 1.2 μm in-line filter (the infusion time is 
recommended to be controlled within 30 ~ 60 min). Record the start and stop time of 
infusion.  
Note: Prior to preparation, make sure that sintilimab injection is clear without any 
quality issues such as turbidity or precipitation. Ensure that the time from sintilimab 
drawing to the end of infusion does not exceed 24 hours (the storage condition of prepared 
drug is at 2-8℃ in refrigerator); avoid mixing with other drugs; avoid administering as 
an intravenous push.  
5.1.2 Use of Chemotherapy 
Other concomitant standard chemotherapy will be prepared as described in their 
approved package inserts, and the doses selected are as follows:  
 
Pemetrexed: 500 mg/m2  
 
Cisplatin: 75 mg/m2  
 
Carboplatin: AUC 5 (using Calvert formula). Carboplatin dose should not exceed 
750 mg.  
Calvert formula  
Total Dose (mg) = (target AUC) × (CrCl + 25)  
The estimated CrCl used in the Calvert formula should not exceed 125 ml/min  
Maximum carboplatin dose (mg) = target AUC 5 (mg×min/ml) × (125 + 25) 


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= 5 × 150ml/min = 750 mg  
5.2 Dose Modification  
5.2.1 General Principles  
Dose modifications must be based on the maximum toxicity experienced during a 
cycle. Subject's hematological, hepatic and renal functions must meet the dosing 
requirements, and the toxicity needs to resolve to CTCAE grade 0 ~ 1 or baseline (except 
for alopecia, asthenia or other conditions that do not affect the safety of the subject in the 
judgment of the investigator; HGB≥90 g/L is eligible for treatment) prior to resuming 
subsequent cycle. Refer to 5.2.2 -5.2.4 for specific toxicity adjustment. Treatment for 
each new cycle may be delayed if the subject did not recover to the level of dose 
resumption within the planned dosing interval due to drug toxicity. For one or more drug 
administrations that delayed due to toxicity, every effort should be made to keep the same 
cycle of administration as other study drugs after recovery.  
All medication modifications should be documented, including reasons and methods 
used.  
5.2.2 Dose Modifications for Sintilimab  
Sintilimab dose reduction is not permitted throughout the study, and the principles 
for the suspension and permanent discontinuation of sintilimab are shown in Table 5. If a 
dose delay occurs during a 3-week cycle of treatment with sintilimab, all future dosing 
days will be delayed to ensure that the dosing interval between treatment cycles with 
sintilimab is 21±3 days. AEs associated with sintilimab are generally immune-related 
AEs. For suspension due to immune-related AEs, based on the type and severity of the 
AE, dosing may be resumed after recovery.  
Table 5. Dosage Modification Guidelines for Sintilimab 
Adverse Events 
Associated with 
Sintilimab  
Severity  
Dose 
Modification  
Pneumonia  
Grade 2 pneumonitis  
Dose Hold a 
Recurrent grade 2 pneumonitis, grade 3 or 4 
pneumonitis  
Permanent 
Discontinuation 
Diarrhea/enterocolitis Grade 2 or 3 diarrhea or enterocolitis  
Dose Hold a 


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Adverse Events 
Associated with 
Sintilimab  
Severity  
Dose 
Modification  
Grade 4 diarrhea or enterocolitis  
Permanent 
Discontinuation 
Dermatitis  
Grade 3 dermatitis 
Dose Hold a  
Grade 4 dermatitis 
Permanent 
Discontinuation 
Hepatitis  
Grade 2 elevations in AST, ALT, or TBIL for 
subjects with normal ALT, AST, or TBIL at 
baseline; elevations in AST, ALT, or TBIL ≥ 50% 
(Grade 2 requirement met) and lasting < 7 days for 
subjects with AST, ALT, or TBIL > ULN at baseline 
Dose Hold a  
Grade 3 or 4 elevations in AST, ALT, or TBIL for 
subjects with normal ALT, AST, or TBIL at 
baseline; elevations in AST, ALT, or TBIL ≥50% 
(Grade 3 or 4 requirement met) and lasting ≥7 
days for subjects with AST, ALT, or TBIL > ULN at 
baseline  
Permanent 
Discontinuation 
Hypophysitis  
Grade 2 or 3 hypophysitis  
Dose Hold b 
Grade 4 hypophysitis  
Permanent 
Discontinuation 
Adrenal insufficiency  Grade 2 adrenal insufficiency  
Dose Holdb  
Grade 3 or 4 adrenal insufficiency  
Permanent 
Discontinuation 
Hyperthyroidism  
Grade 3 or 4 hyperthyroidism  
Permanent 
Discontinuation 
Hypothyroidism  
Grade 2-4 hypothyroidism  
Continued b 
Type 1 diabetes  
Grade 3 hyperglycemia  
Dose Holdb 
Grade 4 hyperglycemia  
Permanent 
Discontinuation 
Renal insufficiency  
Grade 2 or 3 Cr increase  
Dose Holda 
Grade 4 Cr increase  
Permanent 
Discontinuation 
Neurotoxicity  
Grade 2 neurotoxicity  
Dose Holda 
Grade 3 or 4 neurotoxicity  
Permanent 
Discontinuation 


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Adverse Events 
Associated with 
Sintilimab  
Severity  
Dose 
Modification  
Other AEs  
First occurrence of other grade 3 AE  
Dose Holda  
Grade 2 myocarditis  
Dose Holda 
Grade 3 AE that cannot be reduced to Grade 0-
2/baseline within 7 days or recovered to Grade 0-
1/baseline within 14 days  
Permanent 
Discontinuation 
Recurrent grade 3 or 4 (except endocrine disorders) Permanent 
Discontinuation 
c 
a: Resume dosing after improvement to Grade 0-1 or baseline.  
b: Hypophysitis, adrenal insufficiency, thyroid insufficiency/hypothyroidism, and type 1 diabetes may 
be reintroduced if adequately controlled or only physiologic hormone replacement therapy required.  
c: For recurrent Grade 3 or 4 laboratory abnormalities, discontinuation should be based on concomitant 
clinical symptoms/signs and clinical judgment of the investigator.  
The maximum length allowed for drug suspension is 12 weeks. If after 12 weeks, 
the subject cannot recover to the state that he/she can be re-administered with sintilimab, 
the subject must permanently discontinue sintilimab and enter the follow-up phase of the 
study, except for the following two cases:  
 Corticosteroids are used for the treatment of immune-related adverse events and the 
course of corticosteroid taper leads to the delay of sintilimab administration for more 
than 12 weeks. In this case, the decision on whether to continue treatment with 
sintilimab should be discussed with the Sponsor’s medical manager. Tumor imaging 
evaluation should not be affected by treatment interruption and will be performed as 
scheduled.  
 Treatment of an AE unrelated to sintilimab leads to treatment interruption for more 
than 12 weeks. In this case, the decision on whether to continue treatment with 
sintilimab should be made through discussion with the Sponsor’s medical manager. 
Tumor imaging evaluation should not be affected by treatment interruption and will 
be performed as scheduled.  
The related AE should be recovered to grade 0 ~ 1 or baseline or the level that investigator 
consider be eligible for treatment, with ECOG PS score of 0 ~ 1.  


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5.2.3 Management of Infusion Reactions Related to Sintilimab  
Sintilimab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylactic reactions, with signs and symptoms usually appearing 
during or shortly after the drug infusion and usually resolving completely within 24 hours 
of completing the infusion. See Table 6 for guidance on the management of sintilimab-
related infusion reactions.  
Table 6. Guidelines For The Management of Sintilimab-related Infusion Reactions  
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but respond 
promptly to symptomatic 
treatment (e.g. 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h 
Stop the infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 h of 
stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (e.g. from 100 
mL/h to 50 mL/h). Otherwise dosing 
will be held until symptoms resolve 
and the subject should be 
premedicated for the next scheduled 
dose. 
 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
Subject may be 
premedicated 1.5 h (± 30 
min) prior to sintilimab 
infusion: 
 
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500–1000 
mg PO (or equivalent dose 
of antipyretic). 
 
 


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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
permanently discontinued from 
further study treatment 
administration.  
Grade 3 or 4 
Grade 3: 
Prolonged (i.e. not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g. 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life threatening; pressors or 
ventilatory support indicated 
Stop infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
**Epinephrine should be used 
immediately for allergic reactions. 
 
Subjects is permanently 
discontinued from further study 
drug administration. 
No subsequent dosing 
Appropriate first-aid equipment should be provided in the ward and physicians should be available 
at all times during the administration. 
For more information, refer to CTCAE v4.03 (http://ctep.cancer.gov). 
Other Allowed Circumstances for Dose Modifications of Sintilimab  
Circumstances other than treatment-related AEs, such as medical/surgical events not 
related to study treatment, or administrative reasons, may result in interruption of 
treatment with sintilimab. Subjects should resume study treatment within 3 weeks of the 
interruption unless there are other results made from discussions with the Sponsor. 
Reasons for interruption should be documented in the subject's study records.  
5.2.4 Dose Modification of Chemotherapy 
If, in the opinion of the investigator, the toxicity is mainly caused by a certain 


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chemotherapy agent, dose reduction of one chemotherapy agent is acceptable; if it is 
thought that the toxicity is caused by two or more drugs, dose of relevant drugs can be 
simultaneously reduced. According to the toxicity of the drug, subjects may have 
chemotherapy discontinued and continue sintilimab (or placebo) alone or subjects may 
have sintilimab discontinued and continue chemotherapy alone. Chemotherapy may be 
interrupted for a maximum of 6 weeks after the last administration. Hematologic toxicity 
due to chemotherapy may be treated with colony-stimulating factor support (e.g., GM-
CSF, etc.) prior to the initiation of any chemotherapy, but prophylaxis prior to the first 
dose of chemotherapy is contraindicated. Different dose modifications for chemotherapy 
agents are detailed in the below table.  
Table 7. Dose Modifications for Chemotherapy agents 
 
Original dose  
Dose Level -1 
Dose Level -2 
Pemetrexed  
500 mg/m2  
375 mg/m2  
250 mg/m2  
Cisplatin  
75 mg/m2  
56 mg/m2  
38 mg/m2  
Carboplatin  
AUC 5 
Maximum dose 750 mg  
AUC 3.75 
Maximum dose 562.5 mg  
AUC 2.5 
Maximum dose 375 mg  
Recommended Dose Modifications for Chemotherapy Hematological Toxicity  
Table 8. Dose Modifications for Chemotherapy based on Hematologic Nadir from 
Previous Cycle 
 
 
Pemetrexed  
Cisplatin/Carboplatin  
Platelets  
Neutrophils  
Dose modification according to Table 7  
≥50×109 /L and  
≥0.5×109 /L  
Original dose  
Original dose  
≥50×109 /L and  
< 0.5×109 /L  
75% of the original dose  
75% of the original dose  
< 50×109 /L, no 
bleeding and  
Any circumstances  75% of the original dose  
75% of the original dose  
< 50 × 109 /L, 
and ≥Grade 2 
bleeding and  
Any circumstances  50% of the original dose  
50% of the original dose  
Any circumstances  
< 1×10 9 /L 
combined with 
fever ≥38.5℃  
75% of the original dose  
75% of the original dose  
Recommended Dose Modifications for Chemotherapy Non-Hematological Toxicity  
Table 9. Dose Modifications for Chemotherapy based on AE grade 


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Adverse Events  
CTCAE grade  Pemetrexed  
Cisplatin  
Carboplatin  
Nausea or vomiting  
Grade 3 or 4  
Original dose  
Original dose  
Original dose  
Diarrhea  
Grade 3 or 4  
75% 
of 
the 
original dose  
75% 
of 
the 
original dose  
Original dose  
Mucositis  
Grade 3 or 4  
50% 
of 
the 
original dose  
Original dose  
Original dose  
Neurotoxicity  
Grade 2  
Original dose  
50% 
of 
the 
original dose  
Original dose  
Grade 3 or 4  
75% 
of 
the 
original dose  
Drug 
discontinuation  
75% 
of 
the 
original dose  
Transaminase increased  
Grade 3  
75% 
of 
the 
original dose  
75% 
of 
the 
original dose  
75% 
of 
the 
original dose  
Grade 4  
Drug 
discontinuation  
Drug 
discontinuation  
Drug 
discontinuation  
Other  
Grade 3 or 4  
75% 
of 
the 
original dose  
75% 
of 
the 
original dose  
75% of original 
dose  
Creatinine Clearance (CrCl):  
CrCl will be calculated based on the original weight-based Cockcroft-Gault formula 
(Appendix 2). CrCl must be ≥45ml/min prior to administration of chemotherapy. 
Pemetrexed and/or platinum may be delayed for up to 6 weeks to allow the subject time 
to recover from the toxicity. If a subject’s CrCl has not recovered to ≥45 ml/min within 
6 weeks after the previous dose, platinum and/or pemetrexed must be discontinued.  
5.3 Principles for Managing Immune Checkpoint Inhibitor Toxicities 
The AE associated with the exposure to sintilimab may be of immunological etiology. 
These irAEs may occur shortly after the first dose or several months after the last dose 
and may affect more than one system at the same time. Therefore, early detection and 
initiation of therapy is essential to mitigate complications. Based on the available clinical 
study data, the majority of irAEs are reversible and manageable with dose interruption, 
corticosteroid administration, and/or other supportive care. For suspected irAEs, ensure 
appropriate assessment is performed to confirm etiology or rule out alternative causes. 
Other procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may be 
included as part of this assessment. Based on the severity of the irAE, suspend or 
permanently discontinue treatment with sintilimab and administer corticosteroids. 


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Guidelines for dose modification and toxicity management of potential irAEs are 
provided in the “Manual for the Management of Immune-related Adverse Events” 
provided by the Sponsor.  
5.4 Concomitant Therapy  
5.4.1 Acceptable Concomitant Medications  
 Medications that are in compliance with the protocol, as determined by the 
investigator (e.g., concomitant therapies used for disease-related symptoms and various 
treatment-related AEs).  
 Subjects with underlying diseases such as hypertension and diabetes requiring 
long-term medication can continue medication.  
 Local surgery or radiotherapy used for isolated lesions (excluding target lesions) 
during study treatment period (radiation fields excluding lungs).  
 Supportive care for relieving tumor-related symptoms, such as bisphosphonate 
treatment for bone metastases. 
 Topical glucocorticoids, such as topical application to the skin, eye drops, nasal 
spray, and inhalation, are allowed.  
 Subjects taking NSAIDS or salicylates will not take the NSAIDS or salicylate 
(other than an aspirin dose ≤1.3g per day) for 2 days before and 2 days after receiving 
pemetrexed. Subjects taking NSAIDS or salicylates with a long half-life (such as 
naproxen, piroxicam, diflunisal, or nabumetone) will not take the NSAIDS or salicylates 
for 5 days before and 2 days after pemetrexed.  
5.4.2 Prohibited Concomitant Medications  
Subjects are prohibited from receiving the following treatments during the treatment 
period of this study (including crossover to receive sintilimab monotherapy after 
confirmation of PD in the control group):  
 Systemic chemotherapy or biotherapy with anti-tumor effect (except for 
cytokine drugs used to treat chemotherapy-induced adverse events), as well as Chinese 
medicines with anti-tumor effects;  
 Drugs with immunomodulatory effects, including but not limited to non-specific 
immunomodulators (such as thymosin, interferon, interleukin, immunoglobulin, gamma 
globulin) and proprietary Chinese medicines with immunomodulatory effects;  
o 
Note: Interleukin-11 is allowed for the treatment of AEs.  


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 Chemotherapy not specified in this protocol;  
 Investigational agents other than sintilimab;  
 Radiation therapy for tumor control ;  
o 
Note: Radiation therapy to symptomatic discrete lesions, such as 
radiation therapy to relieve pain of bone metastases may be approved 
and allowed by the Sponsor as long as a target lesion is not included.  
 Live vaccinations within 30 days prior to the first dose of study treatment and 
while participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG, typhoid 
(oral) vaccine. Receipt of inactivated viral vaccines administered as an injection against 
seasonal influenza is permitted; live attenuated influenza vaccines administered 
intranasally are not permitted;  
 Corticosteroids. Inhaled steroids for asthma or chronic obstructive pulmonary 
disease (COPD) as part of fixed therapy are allowed. Corticosteroids for the management 
of adverse events with an underlying immune etiology are allowed. The use of 
physiological doses of corticosteroids may be approved after consultation with the 
Sponsor;  
     Note: Prophylactic corticosteroids are allowed to avoid allergic reactions (e.g., 
premedication before administration of intravenous contrast or chemotherapy).  
Based on the assessment of the investigator, subjects requiring any one of the 
treatment methods above must be excluded from the study. Subjects may be treated with 
other medications deemed medically necessary by the investigator.  
It is important that the investigator review each medication (prescription and 
nonprescription) that the subject receives prior to the start of the study and at each study 
visit.  
 At each visit, subjects must be asked about any new medications received.  
 To minimize the risk of drug-drug interactions, all measures must be taken to 
limit concomitant medications that are truly necessary.  
 During administration, hepatotoxic drugs should be avoided (i.e., hepatotoxic 
drugs with warnings in the package insert). The investigators are encouraged to search 
through www.livertox.nih.gov website to review each potentially hepatotoxic drug.  
Restrictions specific to concomitant medications during the study are listed below.  
The following medications/therapies must be avoided during the dosing and for 14 days 
after dosing:  


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Known hepatotoxic drugs, including but not limited to:  
 Etifoxine  
 Isoniazid  
 Nitrofurantoin  
 Ketoconazole  
 Amiodarone  
 Phenytoin  
Prohibited medications as described in the exclusion criteria are not allowed to be 
used.  
There are no prohibited medications during the post-treatment follow-up period.  
5.4.3 Drug Interactions  
 
Sintilimab: No drug interaction information is currently available. 
 
Pemetrexed: In subjects with mild to moderate renal insufficiency, the use of 
NSAIDS with a short half-life is not recommended for at least 2 days before, 
the day of, and at least 2 days after receiving pemetrexed. The use of NSAIDS 
with a long half-life is not recommended for at least 5 days before, the day of, 
and at least 2 days after receiving pemetrexed.  
 
Cisplatin: Aminoglycoside antibiotics, amphotericin B or cephalothin, etc. used 
in combination with cisplatin, have additive nephrotoxic effect. When 
probenecid is used in combination with cisplatin, it may cause hyperuricemia; 
chloramphenicol or its furosemide acid or sodium diuretic may increase the 
ototoxicity of cisplatin; antihistamines may mask the symptoms of tinnitus and 
vertigo caused by cisplatin.  
 
Carboplatin: May alter renal function, although increased nephrotoxicity with 
aminoglycosides and other nephrotoxic agents has not been confirmed, it is 
recommended to avoid using these drugs together. 
5.5 Drug Management  
5.5.1 Drug Management  
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frozen. All study drugs are to be transported to each local site by cold chain transportation, 
and should be kept and dispensed by a designated personnel.  
The study drug should be stored in the refrigerator that only the authorized personnel 
can open. After receiving the drug, the investigator should ensure that the temperature 
during the transport is maintained within the specified range. After verification, the study 
drug should be signed for receipt and stored at the specified temperature. If abnormalities 
of the storage temperature during transportation or storage at the local site arise, the drug 
should be transferred to the specified temperature as soon as possible to relieve the 
temperature and not be used for the time being. This matter should be reported to the 
Sponsor in a timely manner, and the drug should be handled according to the Sponsor's 
advice.  
All the study drugs provided by the Sponsor should only be used for this clinical 
study and should not be used for any purposes other than those specified in this protocol. 
The investigator must commit to not provide the study drug to any person unrelated to 
this study.  
Sintilimab that is discontinued for special reasons should be stored under the same 
storage conditions until the inspector has checked it and arranged it to be recycled. 
5.5.2 Drug Dispensation  
Stratified randomization will be used in this study, and the randomization list will be 
provided and generated by statisticians using SAS statistical software. After confirming 
that the subject meets all of the inclusion and exclusion criteria, the local site will log into 
the IWRS, which will assign a random number to the subject and provide the subject with 
a medication number.  
5.5.3 Drug Return and Destruction  
In this study, used sintilimab containers need to be recycled, and chemotherapy 
containers will be destroyed on site according to applicable guidelines and procedures 
established at the local site and local facilities.  
All unused study drugs should be returned to the Sponsor for destruction after the 
study is completed/terminated or beyond the shelf life. The return of study drug will be 
arranged by the CRA designated by the Sponsor.  


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5.6  Study Drug Records  
The designated personnel of the local site should timely record the receipt, 
distribution, use, inventory, destruction, recovery and destruction of the study drugs 
according to the requirements of relevant laws and regulations and guidelines.  
5.7 Complaint Handling   
In order to ensure the safety, monitor the quality of study participants and assist in 
process and drug improvement, the Sponsor will collect product complaints related to the 
investigational product used in the clinical study.  
Complaints related to concomitant medications will be reported directly to the 
manufacturer according to the product instructions.  
The investigator or his/her designee is responsible for completing the following 
product complaint process in accordance with the relevant provisions of this study:  
A study-specific complaint form is to be used to document the reported product 
complaint and the associated full description.  
Fax the completed Product Complaint Form to the Sponsor or its designee within 24 
hours.  
If the investigator is asked to return the product for investigation, the investigator 
should return a copy of the product complaint form with the product.  
6. Study Procedures  
6.1 Enrollment and Randomization  
6.1.1 Enrollment and Randomization  
Investigators will enroll subjects as follows:  
1. Obtain signed informed consent from the subject prior to any study-related 
procedures.  
2. Confirm the subject's eligibility for inclusion by the principal investigator or 
appropriately trained designee after reviewing the inclusion/exclusion criteria.  


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3. Randomize the subjects, stratified by gender (male or female), platinum 
chemotherapy (cisplatin or carboplatin), and PD-L1 expression level (< 1% or 
≥1%).  
Subjects who do not meet the relevant criteria for this study (screen failure) may be 
re-screened. If re-screening is considered, the investigator must contact the Sponsor. Each 
subject can be re-screened only once. The subject must re-sign the informed consent form 
(ICF) and will be reassigned with a new identification number when re-screened.  
6.1.2 Enrollment Error Handeling 
Inclusion criteria must be strictly adhered to. If subjects who do not meet the 
inclusion and exclusion criteria are found to be enrolled, the Sponsor's medical manager 
and the investigator will discuss whether to continue the subject's participation in the 
study with study drug. If the investigator determines that it is appropriate for the subject 
to continue the study from a medical perspective, and the Sponsor's medical manager 
agrees with the investigator's decision, the subject may continue the study and receive 
treatment with the study drug. If, in the opinion of the investigator, it is medically 
appropriate for the subject to continue in the study, but the Sponsor's medical manager 
disagrees with the investigator's decision, the subject must not continue the study. 
Subjects accidentally enrolled in the study will be allowed to continue in the study only 
after the investigator has received written approval from the Sponsor.  
6.2 Study Plan and Schedule  
6.2.1 Screening Period  
The following study procedures must be completed at screening (Day -28 ~ -1) to 
ensure subject eligibility:  
 
Signing informed consent form  
 
Checking inclusion/exclusion criteria  
 
Recording the demographics, past medical history and past medications  
 
Recording the vital signs, height and weight  
 
Physical examination  
 
ECOG PS score  


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 
12-lead ECG  
 
Hematology/blood biochemistry/urinalysis/blood cardiac biomarker and 
troponin testing (within 7 days before the first administration)  
 
Coagulation function test (within 7 days before the first administration)  
 
Pregnancy test (within 3 days prior to the first dose)  
 
Thyroid function test (within 28 days prior to the first dose)  
 
HIV antibody, Treponema pallidum specific antibody, hepatitis B tests (HBsAg, 
HBsAb, HBcAb, HBeAg, HBeAb) and HBV-DNA, HCV antibody and HCV-
RNA (within 28 days before the first administration)  
 
Adverse events evaluation 
 
Concomitant medications  
 
Tumor imaging evaluation  
 
Archived or fresh tumor tissue samples  
Detailed instructions for tumor imaging evaluations and safety evaluations are provided 
in Sections 7.1 and 7.2.  
6.2.1.1 Past Medical History  
Past medical history will be collected by the investigator or qualified designee. 
Medical history will include all active conditions, as well as any condition diagnosed 
within the last 10 years and considered clinically significant by the investigator. The 
detailed disease information of NSCLC will be recorded separately, including history of 
smoking, surgery and drug allergy, but will not be listed as a medical history. Any 
autoimmune disease, regardless of the date of onset, should be documented.  
6.2.1.2 Prior Medications  
The investigator or qualified designee will review the subject's prior medications, 
including any washout requirements specified in the protocol, and document medications, 
including alternative/supplemental medications, taken by the subject within 30 days prior 
to the first dose of study drug.  


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6.2.1.3 Concomitant Medications  
The investigator or qualified designee will document all the medications the subject 
used throughout the study (from signing of ICF through the safety follow-up visit).  
All medications associated with the reporting of SAEs should be recorded as defined 
in Section 8.4.  
6.2.2 Baseline (prior to Cycle 1 Day 1)  
 Recording the vital signs  
 Weight  
 ECOG PS score  
 12-lead ECG  
 Adverse events evaluation 
 Concomitant medications  
 EORTC QLQ-C30 V3.0 Chinese version  
 PK and immunogenicity  
 Whole Blood Biomarker Specimen Collection  
6.2.3 Treatment Period Visits  
 
Recording vital signs and body weight, and baseline body weight will be used 
to calculate the amount of chemotherapy administered if a subject's body weight 
fluctuated less than 10% from baseline (the day of the first dose of study 
treatment), the baseline body weight was used to calculate the amount of 
chemotherapy administered. Otherwise, the dose will be calculated based on the 
body weight on the scheduled day of dosing or the day before it. The actual dose 
can also be calculated based on the body weight on the day of dosing or the day 
before it according to clinical practice regardless of the baseline weight. The 
protocol allows a ±5% deviation from the calculated total infusion dose for 
dosing convenience. 
 
ECOG PS score  
 
12-lead ECG  


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 
Hematology/blood biochemistry/urinalysis/cardiac enzymes and troponin  
 
Thyroid function  
 
HBV-DNA and/or HCV-RNA (if applicable)  
 
PK and immunogenicity  
 
Adverse events evaluation 
 
Concomitant medications  
 
Tumor imaging evaluation  
 
Study drug administration  
 
EORTC QLQ-C30 V3.0 Chinese version  
 
Whole blood sample collection for biomarkers  
See Table 1 for a flow chart of study treatment period visits. Details of the physical 
examination are provided in Section 7.2.1 and details of tumor imaging evaluation, 
safety evaluation, and PK/immunogenicity blood sampling are provided in Sections 
7.1-7.4.  
6.2.4 End of Treatment Visit/Safety Follow-Up Visit  
There will be an end of treatment visit and a safety follow-up visit. The end of 
treatment visit will occur within 7 days of the end of treatment; the safety follow-up 
visit will occur 30 ± 3 days  after the last dose, or before the start of a new 
antineoplastic therapy. If the end of treatment visit and safety follow-up visit are 
within 7 days, only the end of treatment visit will be performed. If the safety follow-
up visit is prior to the end of treatment visit, only the end of treatment visit will be 
performed. The following contents are included: (See Study Flow Chart Table 1, 
Table 2 for details)  
 
Recording the vital signs  
 
Weight  
 
Physical examination  
 
ECOG PS score  


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 
12-lead ECG  
 
Hematology/blood biochemistry/urinalysis 
 
Coagulation test  
 
Thyroid function  
 
HBV-DNA and/or HCV-RNA (if applicable)  
 
Immunogenicity  
 
Adverse events evaluation  
 
Concomitant medications  
 
Document subsequent antineoplastic therapy (if applicable)  
 
EORTC QLQ-C30 V3.0 Chinese version  
6.2.5 Survival Follow-up   
Subjects who experience disease progression (as assessed by the IRRC) or who 
initiate new antineoplastic therapy or discontinue treatment for other reasons will enter 
the survival follow-up phase. Date of first survival follow-up contact should be 90 days 
(±7 days) after safety follow-up visit. 
Note: If a subject does not have a 30-day safety follow-up visit, then this date should 
be calculated from the end of treatment.  
6.2.6 Subsequent Anti-tumor Therapy 
The investigator or qualified designee will collect all the information about new anti-
tumor therapies initiated after the last dose of the study drugs and the corresponding 
efficacy. If a subject starts a new antineoplastic therapy within 30 days after the last dose 
of study treatment, a safety visit must be performed prior to the first dose of new therapy.  
Subjects will enter the survival follow-up visit after starting a new antineoplastic 
therapy. Refer to Section 6.2.5 survival follow-up visits for detailed instructions regarding 
survival status follow-up.  
6.3  Crossover for Subjects of Control Arm after Documented Disease Progression 
Subjects of control arm will have the opportunity to be unblinded and crossover to 
receive sintilimab monotherapy once they experience disease progression (confirmed by 


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IRRC). Subjects who permanently discontinue chemotherapy due to an adverse event, 
withdrawal of consent, or for any reasons other than progressive disease, will not be 
eligible for crossover to sintilimab monotherapy. Crossover subjects must not initiate 
treatment with sintilimab earlier than 21 days after their last dose of chemotherapy 
regardless of the time of progression.  
Subjects in the control arm whose disease progression per RECIST v1.1 is confirmed 
by IRRC may crossover to receive sintilimab monotherapy at the discretion of the 
investigator (with the Sponsor’s agreement) and subject’s will. Subjects who meet the 
following conditions are eligible for crossover:  
 
The evidence of disease progression per RECIST v1.1 (confirmed by IRRC);  
 
Treatment-related AEs (except for asthenia or alopecia) must be have recovered 
to ≤Grade 1 or baseline (HGB ≥90 g/L);  
 
If a subject is unstable as a result of a new or progressing brain metastasis, the 
subject can not receive crossover treatment;  
 
ECOG PS score 0 ~ 1;  
 
Subject has not received any systemic chemotherapies other than the 
chemotherapy administered during the treatment phase; 
 
If the subject received radiotherapy, palliative radiotherapy (less than or equal 
to 30 Gy) needs to be completed at least 7 days prior to the first dose of crossover 
treatment. 
The study procedure for crossover phase is as follows.  
6.3.1 Assessment before the first dose (Crossover Phase)  
The following study procedures must be completed prior to the first dose to ensure 
the subject is eligible for this study, and the examination at the end of the last 
chemotherapy may be used as a pre-crossover assessment:  
 
Verify whether the subject meets the requirements in Section 6.3  
 
Record vital signs, height and weight  
 
Physical examination  
 
ECOG PS score  


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 
12-lead ECG  
 
Hematology/blood biochemistry/urinalysis/cardiac biomarkers and troponin test 
(within 7 days prior to the first dose)  
 
Coagulation test (within 7 days before the first administration)  
 
Pregnancy test (within 3 days prior to the first dose)  
 
Thyroid function (within 14 days before the first dose)  
 
HIV antibody, specific antibody to Treponema pallidum, hepatitis B tests 
(HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) and HBV-DNA, HCV antibody and 
HCV-RNA (within 14 days before the first dose)  
 
Adverse events evaluation  
 
Concomitant medications  
 
Tumor imaging evaluation  
6.3.2 Concomitant medications (Crossover Phase)  
The investigator or qualified designee will document the subject's medication use 
throughout the duration of the study (from the time of the first dose of sintilimab until the 
safety follow-up visit).  
All medications associated with the reporting of SAEs should be recorded as defined 
in Section 8.4.  
6.3.3 Treatment Period Visits (Crossover Phase)  
 
Recording vital signs  
 
ECOG PS score  
 
12-lead ECG  
 
Hematology/blood biochemistry/urine routine/blood cardiac biomarker and 
troponin test 
 
Thyroid function  
 
HBV-DNA and/or HCV-RNA (if applicable)  
 
Adverse events evaluation 


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 
Concomitant medications  
 
Tumor imaging evaluation 
 
Study drug administration  
See Table 2 for a study flow chart of study treatment period visits. Details of the 
physical examination are provided in Section 7.2.1 and details of the tumor imaging 
evaluation and safety evaluation are provided in Sections 7.1-7.2.  
6.3.4 End of Treatment Visit/Safety Visit (Crossover Phase)  
There will be an end of treatment visit and safety follow-up visit. The end of 
treatment visit should occur within 7 days of the end of treatment; the safety follow-up 
visit should occur 30 ± 3 days after the last dose of study treatment or before the 
initiation of a new antineoplastic therapy. If the end of treatment visit and safety follow-
up visit are within 7 days, only the end of treatment visit will be performed. If the safety 
follow-up visit is prior to the end of treatment visit, only the end of treatment visit will be 
performed. Include the following:  
 
Record vital signs  
 
Physical examination  
 
ECOG PS score  
 
12-lead ECG  
 
Hematology/blood biochemistry/urinalysis 
 
Coagulation test  
 
Thyroid function  
 
HBV-DNA and/or HCV-RNA (if applicable)  
 
Adverse events evaluation 
 
Concomitant medication  
 
Document subsequent antineoplastic therapy (if applicable)  
6.3.5 Survival Follow-up Visit (Crossover Phase)  
Once a subject experiences disease progression (based on the evaluation of the 
local site) or starts a new anti-cancer therapy or discontinue treatment for other reasons , 


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the subject moves into the survival follow-up phase. The date of first survival follow-up 
should be 90 days (±7) after the safety follow-up visit.  
Note: If the subject does not have a 30-day safety follow-up visit, then this date 
should be counted from the end of treatment.  
6.3.6 Subsequent Anti-tumor Treatment (Crossover Phase)  
The investigator or qualified designee will collect all new anti-tumor treatment and 
corresponding efficacy information after the last dose. If a subject starts a new 
antineoplastic therapy within 30 days after the last dose of study treatment, a safety 
follow-up visit must be performed prior to the first dose of new therapy.  
Subjects will enter the survival follow-up phase after initiation of new antineoplastic 
therapy. Refer to Section 6.3.5 Survival Follow-up Visit for detailed instructions 
regarding survival status follow-up.  
6.4 Other Procedures  
6.4.1 Treatment Discontinuation/Withdrawal  
Subjects who discontinue treatment/withdraw from treatment prior to complection 
of the treatment regimen should be encouraged to continue to be followed for all 
remaining study visits.  
When a subject discontinues/withdraws from the treatment, all applicable activities 
scheduled for the end of treatment visit should be performed. Any adverse events which 
are present at the time of discontinuation/withdrawal should be followed up in accordance 
with the safety requirements outlined in Section 8.4 (Recording Adverse Events). 
Subjects who have completed 24 months of treatment with sintilimab may be 
discontinued. Subjects who discontinue treatment after completing 24 months of 
sintilimab treatment should return to the local site for a end of treatment visit and then 
enter the follow-up phase of this study. 
6.4.2 Lost to Follow-up  
If the subject fails to return to the local site for the required study visits and/or the 
local site can not contact the subject, then the following procedures will be performed:  
 
The local site must attempt to contact the subject and reschedule the missed visit. 
If the subject is contacted, the subject should be informed of the importance of 


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adhering to the protocol-specified visit schedule.  
 
At each missed visit, the investigator or designee must make every effort to 
resume contact with the subject (e.g., by calling and/or mailing to the subject’s 
last known address). These contact attempts should be documented in the 
subject's medical record.  
 
Note: A subject is not considered lost to follow-up until the last scheduled visit 
for an individual subject has been reached. The amount of missing data for a 
subject should be managed according to pre-specified guidelines for data 
handling and analysis.  
6.4.3 Unblinding  
In general, after initial imaging of disease progression is assessed by the investigator 
based on RECIST v1.1, if the subject is clinically stable, the current treatment can be 
continued followed by imaging assessment confirmation 4-8 weeks later (based on 
RECIST v1.1). If progression is confirmed and the investigator assesses that the subject 
can not benefit from current treatment, unblinding may be performed with permission 
from the Sponsor. Subjects in the experimental group will end the study treatment and 
subjects in the control group can conditionally cross over to sintilimab monotherapy 
based on the investigator's assessment and the subject's will, until disease progression, 
intolerable toxicity, new anti-tumor treatment, withdrawal of ICF, lost to follow-up,  
death and occurrence of other reasons for discontinuation of study treatment, whichever 
occurs first. If progression is not confirmed, the study treatment can be continued until 
imaging PD is confirmed and the investigator assesses that there is no benefit to continue 
treatment, unblinding will be handled as before. If the subject is clinically unstable after 
the initial imaging of disease progression, confirmation after 4-8 weeks is not required. 
Unblinding will be performed directly after obtaining permission from the Sponsor, and 
unblinding will be handled as before. When the principle investigator or sub-investigator 
needs to identify the blinded therapy used by a subject and the dosage administered to the 
subject in an emergency (e.g., in the event of a serious adverse event), he/she will contact 
the Sponsor and CRO by telephone and make a request for emergency unblinding. The 
severity/toxicity grade of AE, AE’s relation to study drug, and reason for the observed 
AE must be documented by the principle investigator or sub-investigator in the medical 
charts prior to unblinding. Before emergency unblinding, the investigator should 


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complete the unblinding request form.  
In addition, the investigator must log into the IWRS system and perform the 
unblinding in the IWRS system to update drug disposition. The IWRS must be used for 
emergency unblinding in the event that unblinding is required for subject safety.  
After unblinding, the information of unblinding (e.g., date, reason, and person 
responsible for unblinding) must be documented promptly and the Sponsor's medical 
manager should be notified as soon as possible. Only the principal investigator or 
designee should unblind the corresponding subject's code. The unblinding result should 
not be informed to Sponsor personnel involved in this study. If, after unblinding, the 
investigator assesses that the subject can benefit from continuation of the original on-
protocol treatment, the medication can be continued until any of the following events 
occurred: disease progression, intolerable toxicity, new antineoplastic therapy, 
withdrawal of ICF, lost to follow-up or death, or other reasons for treatment 
discontinuation, whichever occurs first.  
7. Study Evaluation  
7.1 Efficacy Evaluation  
7.1.1 Tumor Imaging and Assessment of Disease 
Tumor imaging usually includes contrast-enhanced computed tomography (CT) or 
magnetic resonance imaging (MRI). The examination sites must include brain, chest, 
abdomen and pelvic cavity. For subjects without brain metastases at baseline, routine 
cranial imaging is not required thereafter. The same imaging technique should be used for 
the same subject during the study.  
The investigator at the local site will confirm the presence of measurable lesions 
based on RECIST v1.1 at screening to determine subject eligibility. Per RECIST v1.1, a 
maximum of 5 target lesions in total and 2 target lesions per organ. The time windows for 
RECIST v1.1 assessment and iRECIST assessment are to be consistent.  
All scheduled imaging for all subjects at the local site will be submitted to the IRRC 
facilitator. Furthermore, additional imaging (including other modalities) that are obtained 
at unscheduled time points to evaluate disease progression, as well as imaging obtained 
for other reasons but captures radiographic progression, should also be submitted to the 
IRRC facilitator.  


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7.1.2 Initial Tumor Imaging  
Initial tumor imaging at screening must be performed within 28 days prior to the 
date of randomization. Prior to randomization, the site investigator must confirm that the 
subject has measurable disease per RECIST v1.1.  
Scans performed as part of routine clinical management may be evaluated by the 
investigator as a screening tumor imaging assessment if its quality meets diagnostic 
quality and the imaging is performed within 28 days prior to the date of randomization.  
The method used for tumor burden assessment at baseline must be consistent with 
that used for each subsequent follow-up assessment (CT/MRI). Additional parts of 
involvement will be examined as indicated by each subject's symptoms and signs.  
7.1.3 Tumor Imaging During the Study 
Tumor imaging evaluation will be performed once at Week 6 (±7 days) and Week 
12 (±7 days), respectively, and then once every 9 weeks (±7 days). After 48 weeks, 
tumor imaging evaluation will be performed every 12 weeks (±7 days). Subjects with 
initial investigator assessed radiographic PD should undergo imaging evaluation at least 
4 weeks after the date of the first tumor imaging indicating PD and no later than 8 weeks 
to confirm PD if clinically stable. Subjects in the control group may start the crossover 
phase after confirmation and/or verification of PD by IRRC vendor. In the crossover 
phase, tumor imaging evaluation will be performed every 9 weeks (±7 days) from the 
start of treatment with sintilimab until radiographic PD is initially documented. Imaging 
evaluation should be performed at least 4 weeks after the date of the first tumor imaging 
indicating PD and no later than 8 weeks to confirm PD if clinically stable.  
Subjects assessed to be clinically unstable should be discontinued from the study 
treatment with the agreement of the Sponsor after initial evaluation of radiographic PD. 
For the clinically unstable subjects, repeating imaging confirmation of PD is not needed.  
Clinical stability is defined as follows:  
 
Absence of clinically significant symptoms and signs indicating disease 
progression (including worsening of laboratory values)  
 
No reduction in ECOG PS  
 
Absence of rapid disease progression  
 
Absence of progressive tumors at important anatomical sites requiring other 
urgent medical intervention (e.g. spinal cord compression) 


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For subjects who discontinue treatment for reasons other than radiographic disease 
progression, imaging evaluations should continue at protocol-specified imaging intervals 
until any of the following events occur: initiation of new antineoplastic therapy, disease 
progression, subject’s withdrawal of ICF, and death.  
CT/MRI of the brain should be performed for all subjects prior to initiation of study 
treatment. Brain metastases will be assessed as non-target lesions. For subjects without 
brain metastases prior to the first dose, routine cranial imaging is not required thereafter.  
If the investigator is unable to assess disease progression, particularly for non-target 
and new lesions, the subject may continue treatment until the evaluation time point that 
clinical disease status indicate an unscheduled evaluation or it is the following next 
scheduled evaluation. If progression is confirmed by repeat imaging evaluation, the date 
of progression should be the date of initial new lesion appeared.  
The primary analysis of this study will be based on tumor evaluation by IRRC per 
RECIST v1.1. See Appendix 3 for the evaluation method.  
7.1.4 End of Treatment and Follow-up of Tumor Imaging 
In subjects who discontinue study treatment without documented PD by IRRC, 
efforts should be made to continue monitoring their disease status by using the same 
imaging schedule used if on treatment (every 6 weeks or every 9 weeks or every 12 weeks) 
until disease progression, intolerable toxicity, withdrawal of ICF, death, or other protocol-
specified circumstances that treatment should be discontinued, whichever occurs first.  
Imaging at the end of treatment visit is not mandatory if the timing of the previous 
scan was obtained within 4 weeks prior to the date of end of treatment. 
7.1.5 iRECIST Assessment of Disease 
As described below, iRECIST is a modified version of RECIST v1.1 for the 
pharmacological treatment of immune checkpoint inhibitors in order to account for the 
unique tumor response to immunotherapeutic agents. Tumor response and progression 
will be assessed using iRECIST by the site investigator/local imaging evaluation. This 
data will be collected in the clinical database.  
     See Appendix 4 for the main contents of iRECIST.  


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7.2 Safety Assessment  
Each subject will be assessed by the investigator or qualified designee to evaluate 
possible new or worsening adverse events as specified in the study flow chart, in which 
evaluations may be more frequently done if clinical status indicates. Adverse events will 
be graded and recorded according to NCI CTCAE (Version 4.03) during the study and 
follow-up. The toxicity profile will be based on the following aspects: severity, causality, 
toxicity grade, and action taken for the study treatment.  
All AEs of unknown etiology associated with study treatment exposure should be 
evaluated whether they are events of potential immunological etiology.  
Refer to Sections 8.3 and 8.4 for detailed instructions on the assessment and 
recording of AEs.  
7.2.1 Physical Exam  
7.2.1.1 Full Physical Exam  
The investigator or clinical designee will perform a complete physical exam during 
the screening period. Clinically significant abnormal findings should be recorded as 
medical history. In addition, a complete physical examination will be performed as 
described in the test flow chart. After the first dose of study treatment, new clinically 
significant abnormal findings should be recorded as AEs. 
7.2.1.2 Directed Physical Exam  
For cycles that do not require a full physical exam per the study flow chart, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing on Day 1 of each treatment cycle. New clinically significant 
abnormal findings should be recorded as AEs.  
7.2.1.3 Height, Weight, and Vital signs  
Vital signs will be recorded by the investigator or qualified designee during the 
screening period, prior to each dose of study treatment and at discontinuation of treatment 
as indicated in the study flow chart. Body weight are to be measured prior to each 
scheduled dose, at the end of treatment visit, at the safety visit, and prior to the first dose 
(crossover phase) during the course of the study. Baseline body weight will be used to 
calculate the amount of chemotherapy administered if the subject's body weight 
fluctuated less than 10% from baseline (day of first dose of study treatment). Otherwise, 
the actual dose will be calculated based on the body weight on the scheduled day of dosing 
or the day before it. The actual dose can also be calculated based on the body weight on 
the day of dosing or the day before it according to clinical practice regardless of the 
baseline weight. 


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Height will only be measured at the first visit. Vital signs will include body 
temperature, pulse, respiratory rate, blood pressure.  
7.2.1.4 12-Lead Electrocardiogram (ECG)  
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional ECGs may be performed at other time points as clinically necessary.  
7.2.1.5 ECOG Performance Status  
The investigator or qualified designee will assess ECOG status at screening, prior to 
the administration of each dose of study treatment, and at discontinuation of study 
treatment as indicated in the study flow chart.  
7.2.2 Laboratory Procedures/Assessments  
Details regarding specific laboratory procedures/assessments are provided below. 
The total amount of blood/tissue to be drawn/collected throughout the study (from pre-
study to post-study visits), including approximate blood/tissue volumes drawn/collected 
by visit and by sample type, is provided in the Study Procedures Manual. Refer to the 
laboratory assessment section of the study flow chart.  
7.2.2.1 Laboratory Safety Evaluations (Hematology, blood coagulation, urinalysis, 
Chemistry, etc.)  
See Table 10 for laboratory tests for analysis of hematology, coagulation, urinalysis 
and chemistry.  
Table 10. Laboratory Tests 
Hematology 
Chemistry  
Urinalysis  
Other  
Hemoglobin  
Albumin  
PH  
Pregnancy test (blood or 
urine)a  
Platelet count  
Alkaline phosphatase  Glucose  
Total 
triiodothyronine 
(T3) or FT3, FT4 and 
TSH b   
WBC (total and 
differential) c 
Alanine 
aminotransferase  
Proteind  
Anti-HCV antibody  
RBC  
Aspartate 
aminotransferase  
Specific gravity  
HCV-RNA  
Hematocrit  
Calcium  
Urine leukocyte  
HBsAg  
INR  
Chloride  
Urine red blood cells  HBV-DNA  


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Hematology 
Chemistry  
Urinalysis  
Other  
PT  
Creatinine  
 
Anti-HBc  
 
Blood glucose  
 
HBeAg  
 
Phosphorus  
 
HBsAb  
 
Magnesium  
 
HBeAb  
 
Potassium  
 
HIV antibody  
 
Sodium  
 
Treponema 
pallidum 
specific antibody  
 
Total bilirubin  
 
Creatine phosphokinase 
CK  
 
Direct bilirubin  
 
Creatine phosphokinase 
isoenzyme CK-MB  
 
Total protein  
 
Troponin T or Troponin 
I  
 
Blood urea or urea 
nitrogen  
 
 
 
Amylase  
 
  
 
Lactate dehydrogenase  
 
 
Γ-GT  
 
 
FT4 = free thyroxine; anti-HBc = hepatitis B core antibody; HBeAg = hepatitis B e antigen; HBeAb 
= hepatitis B e antibody; HBV = hepatitis B virus; HBsAb = hepatitis B surface antibody; HbsAg = 
hepatitis B surface antigen; HCV = hepatitis C virus; INR = international normalized ratio; PT = 
prothrombin time; RBC = red blood cell; T3 = total triiodothyronine; TSH = thyroid stimulating 
hormone; WBC = white blood cell.  
a. Perform on women of childbearing potential only, within 72 hours prior to Cycle 1 Day 1.  
b. Total T3 is preferred; if not available, free T3 may be tested.  
c. Leukocyte differential included lymphocytes, neutrophils, monocytes, basophils, and eosinophils.  
d. If urine protein is ≥ 2 +, 24h urine protein quantitative examination should be performed.  
Laboratory tests for screening should be performed within 7 days prior to the first 
dose of study treatment. Exceptions include hepatitis and thyroid serology, which may be 
performed within 28 days prior to the first dose (blinded phase) or within 14 days prior 
to the first dose (crossover phase). After Cycle 1, pre-dose laboratory safety tests can be 
conducted up to 3 days prior to dosing, unless otherwise specified in the flow chart.  
Laboratory test results must be reviewed by the investigator or qualified designee 
prior to each study treatment administration and assessed to be acceptable, unless 
otherwise specified in the flow chart. Unresolved abnormal labs that are drug-related AEs 
should be followed until resolution. Labs do not need to be repeated after the end of 
treatment if labs are within normal range. 


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7.2.2.2 Pregnancy Test  
All women who are considering to participate in the study and are not surgically 
sterile or postmenopausal must undergo a pregnancy test within 3 days prior to the first 
dose of study drug. If urine tests are not negative, a serum test is required. Subjects must 
be excluded/terminated in the event of a positive or borderline positive test result.  
7.2.2.3 Central Laboratory Evaluations 
Refer to the Procedures Manual for sample collection, storage, and shipment 
instructions for central laboratory evaluations.  
7.3 Pharmacokinetics  
Pharmacokinetic test will only be performed during combination phase. PK 
sampling will be performed within 1 hour before the infusion of sintilimab in Cycle 1, 
immediately (+ 5 min) after the infusion of sintilimab in Cycle 1 and within 1 hour before 
the infusion of sintilimab in Cycle 2/4/12.  
Every time point, 3.5 mL of whole blood will be collected in clotting vacuum tubes, 
then serum is separated and frozen in aliquots for PK analysis. Sample collection, storage, 
shipment and analysis are described in the Laboratory Manual provided by the Sponsor's 
designated central laboratory.  
7.4 Immunogenicity  
Immunogenicity tests will be performed during Cycles 1/2/4/8/12/16, and every 8 
cycles thereafter (Cycles 24, 32, etc.) within 1 hour prior to the start of sintilimab/placebo 
infusion and safety follow up. If an infusion-related reaction occurs during 
sintilimab/placebo infusion, blood samples should be taken near the start of the event, end 
of event, and around 30 days after the reaction for immunogenicity analysis. Tests should 
be conducted at the central lab. 
Each subject will be tested for anti-drug antibody (ADA) titers, and ADA positive 
serum specimens will be further tested for neutralizing antibodies (NAbs).  
Every time point, 5 mL of whole blood will be collected in a coagulation promoting 
vacutainer, and serum will be separated and frozen in aliquots for ADA and NAb analysis.  
See the Laboratory Manual provided by the central laboratory designated by the 
Sponsor for details of the sample collection, storage, transportation and analysis.  


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7.5 Quality of Life Assessment  
Quality of life will be assessed using the LCSS and EORTC QLQ-C30 (V3.0 
Chinese version) scales before the first dose, at each imaging evaluation, and at the first 
end of treatment visit.  
The LCSS consists of nine graphical subscales that measure a subject's quality of 
life over the past 24 hours. The scale is divided into subject-completed and physician-
completed sections, with the subject section consisting of nine items, each of which has 
its responses drawn on a line segment. The physician mainly evaluates the number and 
severity of the subject's symptoms and uses the hierarchical method to answer. The nine 
sub-scales of the LCSS include the six main symptoms of lung cancer: loss of appetite, 
fatigue, cough, dyspnea, hemoptysis, and pain. The remaining three sub-scales include 
the subject's self-rating of lung cancer symptoms, and how the disease affects daily 
activities.  
The EORTC's QLQ-C30 is a core questionnaire for all cancer subjects, with a total 
of 30 items which are divided into 15 dimensions: five functional dimensions (physical, 
role, cognitive, emotional, and social), three symptom items (fatigue, pain, and 
nausea/vomiting), global health and quality of life , and six single items.  
7.6 Biomarker analysis  
7.6.1 Tissue Biomarkers  
With the permission from ethics committee (EC), all subjects who meet the inclusion 
criteria are required to provide acceptable tumor tissues (blocks or unstained slides) at 
baseline for analysis of PD-L1 expression levels and RNA detection. The following two 
tissues are acceptable:  
1. Archival tumor tissue: Surgery should be be within one year, and biopsy should 
be within 6 months;  
2. The fresh tumor tissues in the screening period; 5 ~ 10 unstained specimen with a 
section thickness of 4 ~ 5 μm.  
See the Laboratory Manual provided by the central laboratory designated by the 
Sponsor for detailed requirements for section sample collection, sample storage, 
transportation and analysis.  


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The test results of PD-L1 expression level will be used for randomization 
stratification. To ensure the compliance to the study, the test results will be provided to 
the randomization system directly without being provided to the investigator and subject.  
7.6.2 Blood Biomarkers  
Subjects need to provide 10 mL of whole blood sample at the following time points: 
prior to the first dose, at each efficacy evaluation during the treatment period and before 
the initiation of the next treatment, and at the time of confirmation of disease progression 
for biomarker studies, including ctDNA and TCR detection.  
The sample collection, sample storage, transportation and analysis are described in 
the Laboratory Manual provided by the Sponsor's designated central laboratory.  
7.7 Storage and Destruction of Biological Samples  
Samples will be be desensitized (including anonymized and pooled) and then 
disposed or destroyed. Additional analyses of anonymized, pooled samples may be 
performed to further assess and validate the analytical methods. Any results obtained 
from these analyses may be reported separately from the CSR.  
Sample reproducibility analysis (if performed) will be assessed simultaneously with 
the biological samples. The results of these evaluations will not be reported in the CSR 
but will be presented separately in a biological analysis report.  
8. Safety Reporting and Adverse Event Management  
8.1 Definition of Adverse Events  
An adverse event is defined as any untoward medical occurrence, whether or not 
there is a causal relationship with the study drug, in a clinical study subject from the time 
informed consent form is signed through 90 days after the last dose of study drug, and 
includes, but is not limited to, the following:  
 Exacerbation of pre-existing (prior to clinical study) medical conditions/diseases 
(including worsening of symptoms, signs, laboratory abnormalities);  
 Any newly developed adverse medical conditions (including symptoms, signs 
and newly diagnosed diseases);  
 Clinically significant abnormal laboratory values or results.  


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8.2 Definition of Serious Adverse Event 
A serious adverse event is an adverse event that meets at least one of the following 
criteria:  
 Results in death, excluding death due to disease progression in the study 
indication.  
 Is life threatening (life threatening is defined as an AE that places the subject at 
risk of death, and does not include an AE that, had it occurred in a more severe form, 
might cause death).  
 Requires hospitalization or prolongation of hospitalization, excluding the 
following:  
 Rehabilitation institutions  
 Nursing homes 
 Routine emergency room admissions  
 Same-day surgery (e.g., outpatient/same-day/ambulatory surgery)  
 Hospitalization or prolonged hospitalization is unrelated to AE itself. For 
example, hospitalization due to original disease and there are no new 
adverse events and aggravation of the original diseases (e.g. to check for 
laboratory abnormalities that persist even before the study); hospitalization 
for management reasons (e.g. annual routine physical examination); 
hospitalization during the clinical trial as specified in the study protocol (e.g. 
procedures required according to the study protocol); and hospitalization 
that is unrelated to adverse events (e.g. elective surgery); scheduled 
treatment or surgery; admission only to use blood products. 
 Results in a persistent or significant disability/incapacity.  
 Congenital anomaly/birth defect.  
 Other important medical events: defined as events that jeopardize the subject or 
require medical intervention to prevent one of outcomes listed above.  


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8.3 Evaluating Adverse Events  
The investigator will assess all adverse events per NCI CTCAE Version 4.03. Any 
adverse event which changes CTCAE grade will be recorded on the adverse event case 
report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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Table 11. Detailed Rules for the Evaluating Adverse Events  
CTCAE  
Grading  
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated  
Grade 2  
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate daily activities  
Grade 3  
Severe or medically significant event requiring medication but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL  
 
Grade 4  
Life-threatening consequences; urgent intervention indicated  
 
Grade 5  
Death related to AE  
Seriousness  
A serious adverse event is any adverse event occurring at any dose or during any use of study drug that:  
 
† Results in death;  
 
† Is life-threatening; or places the subject, in the view of the investigator, at immediate risk of death (Note: This does not include an adverse event 
that, had it occurred in a more severe form, might cause death);  
 
† Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions);  
 
† Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. Note: Hospitalization for an existing condition that did not worsen during 
the study [including hospitalization for elective procedure] does not constitute a serious adverse event. A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of the study drug and is recorded in the subject's medical history);  
 
† Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);  
 
Other important medical events Although not fatal, life-threatening, or requiring hospitalization, such an event may also be considered a serious 
adverse event if, based on appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed previously (designated above by a †).  
Duration  
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units.  
Action taken  
Did the adverse event cause the study drug to be discontinued?  


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Relationship 
to 
Sponsor’s 
Product  
Did the Sponsor’s product cause the adverse event? A medically qualified investigator will be required to provide assessment of causality of the 
relationship between the study drug and the AE. The investigator’s signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was done. This signed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the study drug and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the study drug caused the adverse event;  
 
Exposure 
Is there evidence that the subject was actually exposed to study drug, such as: reliable history, acceptable compliance assessments 
(pill count, diary, etc.), expected pharmacological effect, or measurements of drug/metabolite in bodily specimen?  
Time course  
Did the AE follow in a reasonable temporal sequence from administration of the study drug? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to studies with investigational medicinal product)? 
Likely cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drugs/vaccines, or other host or 
environmental factors？ 
Dechallenge  
Was study drug discontinued or dose/exposure/frequency reduced?  
If yes, did the AE resolve or improve?  
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of study drug; (3) the study is a single-dose drug study; (4) the study drug is only used one time  
 
Rechallenge  
Was the subjet re-exposed to the study drug in this study？ 
If yes, did the AE recur or worsen?  
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.  
Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose 
study, or (3) the study drug is only used one time 


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Note: If a rechallenge is planned for an adverse event which was serious and which may have been caused by the Sponsor’s product, 
or if reexposure to the Sponsor’s product poses additional potential significant risk to the subject, then the rechallenge must be 
approved in advance by the Sponsor clinical director as per dose modification guidelines in the protocol. 
Consistency 
with study 
treatment 
profile  
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms/worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements. 
Document causality  
Use of the following scale of criteria as guidance (not all criteria must be present to be indicative of a study drug relationship). 
Related  
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the AE onset relative to the administration of the 
study drug is reasonable. The AE is more likely explained by the Sponsor’s product than by another cause. 
Unrelated  
Subject did not receive the study drug or temporal sequence of the AE onset relative to administration of the study drug is not 
reaosonable or the AE is more likely explained by another cause than the study drug. (Also be applicable for a subject with overdose 
without an associated AE). 
 
 


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8.4 Recording Adverse Events  
Investigators should use medical terminology/concepts to record AEs or SAEs. 
Spoken languages and abbreviations should be avoided. All AEs (including SAEs) should 
be recorded on the adverse event form in the electronic case report form (eCRF).  
8.4.1 Adverse Event Collection and Times 
The investigator should ask subjects non-inductive questions to be informed of the 
adverse events.  
All adverse events, including serious adverse events, whether observed by the 
investigator or spontaneously reported by the subject, will be collected from the time of 
signing the informed consent through 90 days after the last dose. During this period, if a 
subject starts a new antineoplastic therapy, only SAEs considered related to study drug 
will be recorded and reported.  
After 90 days of the last dose, the investigator should report SAEs considered related 
to the study drug or procedure.  
8.4.2 Follow-up of Adverse Events  
The subjects should be followed up until they recover to baseline or grade 0 ~ 1 or 
the investigator considers that follow-up is not necessary for reasonable reasons (such as 
can not be recovered or improved). If the AE cannot be recovered, a reasonable 
explanation should be recorded in the eCRF. The subject's recovery from AEs or SAEs, 
whether related to study drug or not, and their dates should be recorded in the eCRF and 
medical records.  
8.4.3 Contents of AE records  
The investigator is to fully document any adverse event, including diagnosis (if not, 
symptoms, signs including laboratory abnormalities), start and stop date and time (if 
applicable), CTCAE severity grade and change (Grade 3 or higher), whether a SAE, the 
action taken with the study drug, the treatment given for the AE, the outcome of the event, 
and the relationship of the AE to the study drug.  
For SAEs, the investigator should also provide the date when the AE meets the 
criteria for an SAE, the date the investigator becomes aware of the SAE, the basis for the 
SAE, the date of hospitalization, the date of discharge, the probable cause of death, the 


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date of death, whether an autopsy is performed, the causality assessment with the study 
procedures, the causality assessment with other drugs, and other possible causes of the 
SAE. The investigator shall also provide the judgment basis of relevance as well as the 
description of SAE. In the description of SAE, it is also required to include the subject's 
identification number, age, gender, height and weight; the indication of study drug, 
disease stage and the subject's relevant general conditions; the occurrence, development, 
outcome and results of the SAE and other clinical course; the laboratory test results 
related to the SAE (the examination time, unit and normal range must be provided); the 
SAE-related past history, concomitant diseases and their occurrence and duration; the 
SAE-related medication history, the initiation, duration and dosage of the concomitant 
drugs and their treatment; the initiation, duration, dosage and administration of the study 
drug treatment and other detailed information.  
The matters concerning the recording of AEs are described below:  
Diagnosis, symptoms and signs  
If a diagnosis has been made, the diagnosis should be recorded in the eCRF instead 
of the individual symptoms, signs and laboratory tests (e.g. recording of hepatic failure 
instead of jaundice, transaminase elevation and asterixis). If symptoms and signs cannot 
be assessed to be caused by this diagnosis at the time of reporting, they will be recorded 
as separate AEs/SAEs. If it is assessed that the symptoms and signs are due to the 
diagnosis, the diagnosis will be reported only and the symptoms and signs are included 
in the diagnosis. For AEs, the recording of signs and symptoms should be deleted, and 
for SAEs, a follow-up update report should be sent.  
Adverse events secondary to other events  
In general, adverse events secondary to other events (e.g. caused by other events or 
clinical sequelae) should have their primary event recorded unless the secondary event is 
serious or is a serious adverse event. Secondary events of significant clinical significance, 
if different from the primary event, should be recorded as independent adverse events in 
the eCRF. If the relationship between events is unclear, it should be recorded separately 
in the eCRF.  
Persistent or recurrent adverse events  
Persistent adverse events are those that persist without resolution between two 


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evaluation time points. 
Recurrent adverse events are those that resolved between the two evaluation time 
points but recurs later on. The occurrence of the event should be recorded separately in 
the eCRF.  
Laboratory Abnormalities  
Clinically significant laboratory abnormalities should be reported as AEs. It is the 
responsibility of the investigator to review all laboratory abnormalities and make medical 
judgment as to whether each laboratory abnormality should be reported as an AE.  
Death  
All deaths occurring during the entire study period, including the 90-day follow-up 
period after the last dose, whether or not related to study drug, should be recorded on the 
Death Report Form in the eCRF and reported to the Sponsor in a timely manner.  
When recording the death event, if the cause of death is confirmed, the cause of 
death shall be recorded as adverse event, the result of event is death, and the event shall 
be reported as SAE; if the cause of death is unknown at the time of reporting, it shall be 
recorded as unexplained death on the adverse event form of eCRF, and unexplained death 
shall be reported as SAE first, and then the exact cause of death shall be further 
investigated.  
Pre-existing medical status  
The existing symptoms/signs of subjects in the screening period of the study shall 
be recorded and reported as adverse events only when there is aggravation of severity, 
frequency and nature (except for the deterioration of the disease condition under study) 
after enrolled in the study. Changes from previous states, such as increased headache 
frequency, should be reflected in the recording.  
Disease progression  
Disease progression is defined as a worsening of the subject's condition caused by 
the primary tumor targeted by the study drug, appearance of new lesions relative to the 
primary tumor, or progression of the original lesion. Expected disease progression is not 
reported as an AE; death due to expected symptoms and signs of disease progression, life-
threatening, requires hospitalization or prolongation of existing hospitalization, results in 


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persistent or significant disability/incapacity, results in congenital anomaly/birth defect, 
or other important medical events are not to be reported in an expedited manner as SAEs.  
New antineoplastic therapies  
Only SAEs considered related to study drug should be recorded and reported within 
90 days of the subject's last dose if the subject starts a new antineoplastic therapy.  
8.5 Expedited Reporting of SAEs and Pregnancy 
SAE reporting  
The reporting period of SAEs is from the signing of informed consent to 90 days 
(inclusive) after the last dose. In case of an SAE, whether it is an initial report or a follow-
up report, the investigator must complete the Serious Adverse Event Report Form 
immediately and report to the Sponsor (drugsafety@innoventbio.com) within 24 hours 
after awareness. It shall be reported to the national regulatory authority and the ethics 
committee according to Chinese regulatory requirements.  
SAEs occurring outside of the above reporting period should also be reported if they 
are considered related to study drug.  
The investigator must complete the SAE Report Form and report to the Sponsor as 
soon as possible within 24 hours of awareness. For deaths and life-threatening SAEs, the 
investigator should urgently follow up the missing information and provide a complete 
SAE report. The investigator should also report to the ethics committee of the national 
regulatory authority according to the regulatory requirements.  
Pregnancy  
The risk of embryotoxicity exists for drugs of the same class. All subjects of 
childbearing potential participating in the clinical study must take effective contraceptive 
measures.  
If a female subject exposed to the study drug becomes pregnant during the study, the 
subject should be excluded from the study. The investigator should report the pregnancy 
to the Sponsor within 24 hours after being informed of the pregnancy, and complete the 
Clinical Study Pregnancy Report/Follow-up Form.  
If the partner of a male subject exposed to the study drug becomes pregnant during 
the study, the subject should continue the clinical study. The investigator should report 


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the pregnancy to the Sponsor within 24 hours after being informed of the pregnancy, and 
complete the Clinical Study Pregnancy Report/Follow-up Form.  
The investigator must continuously monitor the subject or the subject's partner who 
becomes pregnant and follow up with the outcome of the pregnancy until 8 weeks after 
delivery of the baby and report the results to the Sponsor.  
If the outcome of pregnancy is stillbirth, spontaneous abortion, fetal malformation 
(any congenital anomaly/birth defect), or medically-induced abortion, it should be 
considered as an SAE and be reported according to the SAE procedures and time limits.  
If a subject experiences a concurrent SAE during pregnancy, the event should be 
reported according to SAE procedures. 
8.6 Events of Abnormal Hepatic Function  
Drug-induced liver injury will be considered if abnormal AST and/or ALT levels are 
combined with abnormally elevated total bilirubin levels, and the following conditions 
are met without other causes of liver injury. Such situations should always be considered 
as important medical events.  
Table 12. Hepatic impairment requiring reporting as an SAE 
Baseline  
Normal (AST/ALT and TBIL)  
Abnormal (AST/ALT and TBIL)  
Treatment Period  
ALT or AST ≥ 3 × ULN  
with TBIL ≥ 2 × ULN  
and ALP ≤ 2 × ULN  
and no hemolysis  
AST or ALT ≥ 8 ×  ULN and 
increased TBIL ≥ 1 ×  ULN or 
TBIL ≥ 3 × ULN  
Subjects should return to the local site for evaluation as soon as possible (ideally 
within 48 hours) after being notified with the abnormalities. The evaluation should 
include laboratory tests, a detailed history and physical assessment, and should consider 
the possibility of hepatic tumor (primary or secondary).  
In addition to repeated AST and ALT tests, laboratory tests to be performed should 
also include albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase, prothrombin time/international normalized ratio, and alkaline 
phosphatase. Detailed medical history collection should include: history of alcohol 
consumption, acetaminophen, soft drugs, various types of supplements, traditional 


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Chinese medicine, chemical drug exposure history, family history, occupational exposure, 
sexual history, travel history, contact with jaundiced subjects, surgery, blood transfusion, 
history of liver disease or allergic disease, history of heart disease, and history of immune 
disease. Further examinations may also include the detection of acute hepatitis A, B, C 
and E, liver imaging (such as biliary tract), autoantibodies and cardiac ultrasound. If 
repeat testing still confirms compliance with the laboratory criteria defined in Table 12, 
the possibility of potential drug-induced liver injury should be considered in the absence 
of other causes of abnormal liver function tests, without waiting for all etiologic liver 
function test results. Cases of such potential drug-induced liver injury should be reported 
as SAEs.  
8.7 Management of Drug-Related Toxicity  
The Sponsor will conduct study-level safety reviews periodically during the study. 
Details including frequency of review, type of data reviewed will be documented in a 
separate study-level safety review plan.  
8.8 Immune-related Adverse Events  
Since the mechanism of sintilimab involves T-cell activation and proliferation, 
irAEs are likely to be observed during this study. Signs and symptoms of irAEs should 
be monitored. If there are no alternative causes (e.g. infections), signs and symptoms of 
the subjects during the study may be related to the immune system. 
Refer to Section 5.2 for dose adjustments of sintilimab and principles of AE 
management.  
8.9 Emergency Unblinding  
During the study, if there are cases that need unblind, such as the occurrence of an 
SAE, the investigator in charge of the site should make a request for unblinding, and the 
Sponsor and the principal investigator should jointly decide whether to unblind or not. If 
emergency unblinding is required, the investigator may discuss with the Sponsor and 
make a request for unblinding. After gaining authority of unblinding, the investigator can 
know the subject’s treatment allocation through the IWRS system and which treatment 
group the subject is randomized to. If emergency unblinding is conducted, it must be 
recorded in the eCRF and immediately reported to the IWRS system supplier and the 
Sponsor. After unblinding, whether it is appropriate to continue the original on-protocol 


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treatment subsequently will be decided by the investigator after communicating with the 
Sponsor.  
9. Statistical Considerations  
9.1 Statistical Analysis Plan  
A detailed statistical analysis plan (SAP) will be written after the first subject is 
enrolled and will be finalized before database lock and unblinding. The SAP will provide 
details of the analysis.  
9.2 Statistical Assumptions and Sample Size  
The primary analysis of this study is to confirm that sintilimab in combination with 
chemotherapy prolongs PFS compared to placebo in combination with chemotherapy.   
The following statistical hypotheses will be tested for the primary study endpoint in this 
study:  
Null hypothesis H 0 : PFS (t) (Placebo) = PFS (t) (Sintilimab)  
Alternative hypothesis H a : PFS (t) (Placebo) ≠ PFS (t) (Sintilimab)  
Here PFS (t) denotes the survival function of time.  
It is assumed that the median PFS of subjects receiving sintilimab treatment will be 
improved from 6 months to 9.2 months (with a hazard ratio = 0.65). With an enrollment 
time projection of 15 months, a projected follow-up time of 8 months and an estimated 
dropout rate of 0.5% per month, to provide approximately 90% power under a two-sided 
α of 0.05, a total of 378 subjects need to be randomized to obtain the required 263 PFS 
events in this study. The actual number of subjects enrolled may differ from the planned 
number due to unforeseen reasons, such as faster enrollment speed than expected. The 
final screening end date will be estimated before the enrollment of 378 subject and best 
effort will be made to ensure that the total number of subjects enrolled will not exceed 
110% of the planned number, i.e., 414 subjects, of which 276 subjects are expected in the 
experimental group and 138 subjects are expected in the control group. 
9.3 Definition of Analysis Set  
Full Analysis Set (FAS): According to the principle of intention to treat, efficacy 
evaluation will be performed on all randomized subjects who receive at least one dose of 
the study drug. Treatment groups will be analyzed based on randomization. FAS is the 


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primary analysis set and will be used for all efficacy and baseline characteristic analysis.  
Safety Set Analysis (SS): All enrolled subjects who receive at least one dose of study 
drug will be analyzed based on the actual treatment received during the study. The SS 
data will be used for all the safety analysis. Treatment groups will be analyzed based on 
the actual allocations. 
Per Protocol Set (PPS): a subset of FAS, i.e., subjects who do not have major 
protocol deviation that affect efficacy assessment (use of other antineoplastic drugs 
during the study, dose, method or course of treatment for serious protocol deviations), 
complete at least 1 cycle of medication, and have imaging evaluation results (or disease 
progression with imaging evidence). The PPS will be used for sensitivity analyses of 
primary and key secondary efficacy endpoints.  
9.4 Statistical Analysis Methods  
Analysis Endpoints  
Primary endpoint:  
 Progression Free Survival (PFS) per RECIST v1.1 by Independent Central 
Image Review 
Secondary endpoints:  
  
 Overall survival (OS) in both groups;  
  
 Objective response rate (ORR) in both groups;  
  
 Disease control rate (DCR) in both groups;  
    Time to objective response (TTR) in both groups;  
  
 Duration of response (DOR) in both groups;  
  
 Safety and tolerability of sintilimab in combination with pemetrexed plus 
platinum chemotherapy.  
Exploratory endpoints:  
 Efficacy of sintilimab in subjects per the immune Response Evaluation Criteria 
in Immune Solid Tumors (iRECIST);  


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 Population pharmacokinetic characteristics of sintilimab;  
 
Biomarkers that can potentially predict the efficacy of sintilimab arm including, 
but not limited to, PD-L1 expression, and RNA in tumor specimens, circulating 
tumor DNA (ctDNA) and T cell receptor (TCR) in peripheral blood ; 
 Quality of life of subjects between sintilimab plus chemotherapy and placebo 
plus chemotherapy by LCSS and EORTC QLQ-C30 (V3.0 Chinese version) 
scale;  
 PFS in the sintilimab arm receiving subsequent antineoplastic therapy after 
disease progression versus placebo arm crossing over to receive sintilimab. 
9.4.1 Statistical Analysis General Method  
All statistical analysis will be generated using SAS version 9.2 or higher. All 
statistical tests will be performed using two-sided α of 0.05, and 95% confidence interval 
will be used.  
In this study, drug administration will be statistically analyzed to calculate the drug 
exposure throughout the study. Baseline data will be analyzed according to full analysis 
set. All efficacy endpoints will be analyzed according to full analysis set and per protocol 
set (based on the randomized treatment). Safety analysis set will be used for safety 
analysis (based on the actual treatment). If a subject receives incorrect medication in one 
cycle but receives the correct medication in all other cycles, the subject will be assigned 
to the correct treatment group for safety analysis.  
Measurement data of each visit will be statistically described using mean ± 
standard deviation or median (minimum, maximum). The enumeration data of each visit 
in the groups will be statistically described using frequency (composition ratio).  
All statistical analyses, unless otherwise specified, will include treatment group and 
randomization stratification factors in the analysis model.  
9.4.1.1 Analysis of primary endpoint indicators  
 PFS  
PFS: the time from the date of randomization to the date of the first radiographic 
disease progression or the date of death due to any cause, whichever comes first. In the 
absence of disease progression or death before the study cut-off date, PFS will be 


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censored at the date of the last valid assessment performed before the cut-off date. In the 
absence of post baseline valid assessment, PFS will be censored at randomization date. 
A p-value by stratified log-rank test will also be provided for PFS. The HR and its 
95% CI will be estimated using the stratified Cox proportional hazards regression model. 
Stratification factors (gender, PD-L1 expression level, platinum), age ( > 60, ≤60), 
smoking (former/current smoker, non-smoker), number of organs with metastatic lesions 
(>2, ≤2), and other significant covariates will be considered in the model, and their HR 
and 95% CI will be estimated. Median PFS and its 95% CI will be estimated using the 
Kaplan-Meier method, and survival curves will be plotted. 
9.4.1.2 Analysis of secondary endpoint indicators:  
 ORR  
%
100
*
Subjects
cts
TotalSubje
PR
CR
ORR


 Binomial distribution will be used to calculate 
95% CI.  
 DCR  
%
100
*
cts
TotalSubje
SDSubjects
PR
CR
DCR



 Binomial distribution will be used to 
calculate 95% CI.  
The calculation of objective response rate and disease control rate is based on the 
optimal efficacy assessment of the second confirmed tumor during the study.  
 OS  
OS: time from the date of randomization to the date of death due to any cause. In the 
absence of the confirmation of death before the analysis cut-off date, OS will be censored 
at the last date the subject is known to be alive or at the study cut-off date, whichever is 
earlier. 
A p-value by stratified log-rank test will be provided for OS. The HR and its 95% 
CI will be estimated using the stratified Cox proportional hazards regression model. 
Stratification factors (gender, PD-L1 expression level, platinum), age ( > 60, ≤60), 
smoking (former/current smoker, non-smoker), number of organs with metastasis (> 2, 
≤2), and other significant covariates will be considered in the model, and their HR and 
95% CI will be estimated. Median OS and its 95% CI will be estimated using the Kaplan-


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Meier method, and survival curves will be plotted. 
Given that subjects in the placebo plus chemotherapy group can cross over to receive 
sintilimab monotherapy after disease progression, the effect of crossover on OS will be 
adjusted using accepted statistical methods. For example, subjects undergoing crossover 
will be censored at the time of crossover using a 2-step approach or the Rank Preservation 
Structure Failure Time (RPSFT) method proposed by Robin and Tsiatis[8] after checking 
for methodological assumptions/applicability based on the data obtained.  
 Quality of life scores of subjects in both groups  
According to the scores of LCSS and EORTC QLQ-C30 (V3.0, Chinese version), the 
quality of life of the two groups will be analyzed.  
9.4.2 Safety Analysis  
Safety analysis will be based on the SS population. Analysis of safety will include 
adverse events, clinical laboratory variables, vital signs, ECG, immunogenicity and other 
safety variables. Data will be summarized by treatment groups, and all adverse events 
from both treatment groups will be summarized. For subjects in the placebo plus 
chemotherapy group who cross over to receive sintilimab, the primary safety analysis will 
only be performed until the time of the cross over (e.g., for the placebo plus chemotherapy 
group, AEs during the period with sintilimab will not be involved in the analysis). 
Exploratory analysis will be performed on safety data from the first administration of 
sintilimab in subjects who crossover to the sintilimab monotherapy group.  
Safety analysis: The exposure of subjects to the study drug will be summarized. The 
subject number of completing X cycles, the dose adjustment during treatment, and the 
cumulative number of dose adjustments during treatment will be summarized.  
The cumulative incidence of adverse events, adverse events leading to withdrawal 
from the study, adverse events leading to death and serious adverse events will be 
summarized. The severity of adverse events: if the same subject has experienced the same 
adverse event many times, the most serious one will be counted for analysis; if the same 
subject has experienced different adverse events, the most serious adverse event will be 
counted for analysis. 
9.4.2.1 Drug Exposure  
Summarize the study drug exposure and administration time (number of cycles) of 


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subjects during the study.  
9.4.2.2 Adverse Events  
All adverse events will be coded using MedDRA.  
The incidence (frequency) and severity (according to NCI CTCAE Version 4.03) of 
adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse drug 
reactions (ADRs), serious adverse events (SAEs), AEs leading to discontinuation, etc. 
will be summarized by system organ class and preferred term in the MedDRA code.  
Subjects who discontinue treatment due to an AE, subjects who experience an SAE, 
and subjects who die due to an AE will be tabulated (including at least the AE start date 
and end date, severity, relationship with drug, action taken, and outcome).  
9.4.2.3 Laboratory Tests  
Hematology, blood biochemistry and other indicators, mean ± standard deviation, 
maximum, minimum and median will be used to describe measured values and changes 
before and after treatment. Cross classification table will be used to describe normal and 
abnormal changes before and after treatment.  
Urinalysis: Cross classification table will be used to describe normal and abnormal 
changes before and after treatment.  
The proportion of subjects with changes that are abnormal and clinically significant 
will be described, in which the investigator will judge whether the abnormality is 
clinically significant or not.  
A list of subjects with laboratory abnormalities (with or without clinical significance) 
after treatment will be provided.  
9.4.2.4 Immunogenicity Indicators  
The positive rates of anti-drug antibody (ADA) and neutralizing antibody (NAb) 
will be calculated and summarized using descriptive statistical analysis. Antibody levels 
of positive subjects will be described. 
9.4.2.5 ECG Examination  
The changes of ECG indicators from baseline will be descriptively analyzed. Cross 
classification table will be used to describe the normal and abnormal ECG changes before 


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and after treatment, and data lists will be provided.  
9.4.2.6 Vital signs, Physical examination, and Other safety related examinations  
Vital signs and changes from baseline will be descriptively analyzed. 
Subjects with abnormal changes from baseline in physical examination will be listed.  
9.4.3 Compliance Analysis  
The proportion and frequency of subjects who violate the treatment regimen will be 
summarized.  
The proportion of subjects whose study drug dose is 80% ~ 120% of the dose 
specified in the protocol will be calculated.  
The proportion of subjects completing the study and proportion of subjects 
completing different treatment cycles will be summarized. 
9.4.4 Baseline Characteristics of Subjects  
Demographic characteristics (gender, age) of subjects, diagnosis and treatment 
information of diseases with indications (tumor type, pathological diagnosis, clinical 
stage, previous treatment), tumor baseline detection (number of target lesions, non-target 
lesions, site, total diameter, etc.), other baseline information: height and weight (body 
mass index, body surface area), vital signs, ECOG PS score, laboratory tests, 
previous/new concomitant medication and etc will be descriptively analyzed.  
9.4.5 Interim Analysis  
An interim analysis will be conducted during the study when 70% PFS events occur. 
The objective of the interim analysis is to establish the superiority of sinitilimab in 
combination with chemotherapy over placebo in combination with chemotherapy in PFS. 
The interim analysis report will be reviewed by IDMC. The IDMC will make 
recommendation on whether the study result can be submitted in advance for application 
based on whether the interim results of this study meet the pre-specified efficacy boundary. 
IDMC charter will be finalized and approved before the interim analysis. If the study 
continues, the IDMC will periodically review and evaluate the safety data of the study 
until the final analysis of this study. 


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9.4.6 Subgroup Analysis  
Subgroup analysis of antitumor activity (objective response rate) will be based on 
factors that are clinically considered to potentially affect prognosis such as gender, age,  
ECOG PS score and ect.  
9.4.7 Adjustment for Multiple Comparisons and Multiplicity  
The study includes a primary study endpoint of PFS (assessed by IRRC). An interim 
analysis is planned in this study when 70% of total PFS events (184 events) occur, and 
the primary interim analysis will be based on PFS. The O’Brien-Fleming spending 
function will be used to adjust alpha value for the interim analysis. The two-sided p-value 
for the interim analysis will be 0.015 (corresponding to a HR of 0.683) and the p-value 
for the final analysis will be 0.046. The overall false positive rate will be controlled at a 
level of 0.05.  
All other analyses, unless otherwise specified, will be evaluated at a level of 0.05 
(two-sided). 
9.4.8 Data Lists of Responsive Subjects  
In addition to the data list of subjects, tumor evaluations (date of evaluation, lesion 
status and evaluation results) and efficacy endpoints of subjects with CR and PR will be 
listed separately.  
9.4.9 Exploratory Analysis  
Parameters such as iORR, iDOR, iPFS and iDCR are included in the clinical benefit 
evaluation based on iRECIST (see Section 9.4.1 for analytical methods). 
The overall baseline PD-L1 expression (<1%，≥1%), the proportion of subjects 
with different expression levels, and the corresponding ORR and DOR will be 
descriptively analyzed.  
Population PK profile of sintilimab in advanced non-squamous NSCLC population 
will be analyzed using nonlinear mixed effects model.  
10. Quality Assurance and Quality Control  
According to the GCP guidelines, the Sponsor is responsible for implementing and 
maintaining the quality assurance and quality control system per corresponding standard 
operating procedures, to ensure that the study is implemented and the authentic data is 


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collected, documented, and reported in accordance with the requirements of the protocol, 
GCP, and applicable regulations. 
10.1 
Clinical Monitoring  
The Sponsor or CRO authorized by the Sponsor will conduct clinical monitoring of 
the study. The CRA should conduct monitoring according to the standard operating 
procedures of the Sponsor or CRO, and have the same rights and responsibilities as the 
Sponsor's inspector. The inspector should maintain regular communication with the 
investigator and the Sponsor.  
Prior to the start of the study, the inspector will assess the competence of each local 
site and report problems with facilities, technical equipment, or medical personnel to the 
Sponsor. During the study, the inspector will be responsible for monitoring whether the 
investigator has obtained written informed consent from all subjects and whether the data 
records are correct and complete. The inspector will also compare the data entered into 
the eCRF with the raw data and inform the investigator of any errors or omissions. The 
inspector will also control protocol compliance at the local site, arrange for the supply of 
study drugs, and ensure that the drugs are kept in appropriate conditions.  
Monitoring visits will be conducted in accordance with applicable laws and 
regulations. Each site will receive periodic monitoring visits from the time of subject 
enrollment. The inspector should submit a written report to the Sponsor after each visit 
to the investigator.  
10.2 
Data Management/Coding  
An electronic data capture (EDC) system will be used for this study and study data 
will be entered into the eCRF by the investigator or its authorized study personnel. Prior 
to the initiation of the study or data entry, the investigator and its authorized study 
personnel should be properly trained and appropriate safety measures should be taken for 
the computer and other equiments.  
Data entry into the eCRFs should be completed as soon as possible during or after 
visiting. The eCRFs should be updated at any time to ensure that they reflect the latest 
conditions of the subjects. To avoid variations in outcome evaluations by different 
evaluators, it is recommended that the baseline and all subsequent efficacy and safety 
evaluations of a given subject should be performed by the same individual. The 


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investigators are required to review the data to ensure the accuracy and correctness of all 
the data entered into the eCRFs. If no evaluations are conducted during the study, or some 
information obtained are not evaluable, not applicable, or unknown, the investigators 
should record the above information in the eCRFs. The investigator should sign the 
verified data electronically. 
The CRA will review the eCRFs and evaluate the completeness and consistency by 
comparing them with the original document, ensuring consistency of key data. Data entry, 
corrections, and modifications should be performed by the investigator or designee. The 
data in the eCRFs is submitted to the data server and any modifications in the data should 
be recorded in the audit trail, including reasons, operator names, time, and dates of 
modifications. The roles and permission levels of the personnel responsible for data entry 
in the study site will be determined in advance. The CRA or data management personnel 
may raise a query in the EDC for suspicious data. The study site personnel are responsible 
for dealing with such query. The EDC system will record the audit trail of the query, 
including the investigator name, time, and date. 
Unless otherwise stated, the eCRFs should only be used as forms to collect data 
instead of source. The source documents are records that used by the investigators or 
hospital, including all those related to the subjects, which are able to demonstrate the 
presence, inclusion/exclusion criteria, and participation of subjects (laboratory records, 
ECGs, pharmaceutical records, and subject folders etc.).  
The investigator is responsible for the maintenance of all source documents and 
should offer the documents to the CRA for review during each visit. In addition, the 
investigator must submit a complete eCRF for each enrolled subject, regardless of the 
duration of participation. The protocol number and subject numbers of all supporting 
documents (such as laboratory records or hospital records) submitted with the eCRFs 
should be carefully verified. All the personal identities (including the subjects' names) 
should be deleted or made illegible to protect the privacy of the subjects. The investigator 
verifies that the record has been reviewed and ensures the accuracy of the recorded data 
by using an electronic signature. The electronic signature should be completed using the 
investigator's user ID and password. The system will automatically attach the date and 
time for signing to the signature. The investigator cannot share his/her user ID and 
password with others. If the data in the eCRFs is required to be changed, the change 
should be performed according to the procedure outlined by the EDC system. All the 


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changes and corresponding reasons should be recorded in the audit trail. 
AEs and concomitant diseases/history should be coded. The dictionary used for 
coding will be described in the CSR. 
10.3 
Quality Assurance Audits  
During the course of the study, the Sponsor or designee may conduct quality 
assurance audits of the study sites, database, and related research documents. At the same 
time, the corresponding regulatory authorities may also inspect the study sites, database, 
and related research documents at their own discretion. The investigator should notify the 
Sponsor immediately after being informed of an inspection from regulatory authorities. 
The Sponsor's quality assurance department will audit the clinical study sites. The 
audits include the supply of drugs, required trial documents, records of the informed 
consent process, as well as the consistency of the CRFs with the source documents. The 
content and scope of the audit can also be increased as the circumstances require. After 
reasonable notice, the investigator should allow auditors commissioned by the Sponsor 
and the regulatory authorities access to the site so that they can conduct inspections. The 
primary purpose of an audit or an inspection is to verify that the rights or health of the 
trial subjects are protected, the informed consent form is properly signed, the trial process 
is correctly implemented, and all data related to the evaluation of the investigational drug 
is collected and, if necessary, reported. In addition, the audit will ensure that ethical 
standard operating procedures, GCP and applicable regulatory requirements are used. The 
investigators should have direct accesses to all trial files, original records, and raw data. 
11. Ethics  
11.1 
Ethics Committee  
The Sponsor or designee will prepare the relevant documents including the study 
protocol, ICF, Investigator’s Brochure, subject recruitment materials or advertisements, 
and other documents required by regulations, which are to be submitted to the 
corresponding EC of the study site for approval. Prior to the start of the trial, written 
approval from the EC must be obtained and submitted to the Sponsor. The written 
approval from the EC should specify the name, number, version number of the protocol 
and other documents (such as ICF), and the date of approval. The investigator is required 
to notify the Sponsor of the EC's written comments regarding delay, interruption, and re-


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approval of the study. 
The study site must follow the requirements of the corresponding EC. The 
modifications of protocol, ICF, or recruitment materials should be submitted to the EC 
for approval. Local safety reports should be drafted and updated regularly in accordance 
with the regulations from the EC, and the final report should be submitted. All the above 
documents with EC approvals must be provided to the Sponsor or designee. 
11.2 
Ethics of this Study  
The study process and ICF aquisition are subject to the Declaration of Helsinki, GCP 
requirements, as well as laws and regulations of drug and data protection in China. 
GCP provides ethical, scientific, global quality standards for the design, 
implementation, documentation, and report of clinical studies involving human subjects. 
This study will be conducted in accordance with the GCP and relevant national 
regulations and in accordance with the relevant ethical principles of the Declaration of 
Helsinki to protect the rights, safety, and health of the subjects. 
The investigator is required to follow the procedures specified in this protocol and 
cannot change the procedures without the permission from the Sponsor. Any protocol 
deviations must be reported to the EC, Sponsor, or regulatory authorities. 
11.3 
Subject Information and Informed Consent  
Prior to the start of any study procedure, the ICF is to be introduced to potential 
participants to explain the risks and benefits of this study, and the language in the ICF 
should be straightforward. The ICF statement should clarify that this ICF signing is 
voluntary, and the risks and benefits of participating in this study should be clearly 
outlined. The subject can withdraw from the study at any time. Subjects can only be 
enrolled if he/she fully understands the study in detail, has received satisfactory answers 
to his/her queries, and has sufficient time for consideration. Written consent must be 
obtained from the subject or his/her legal representative. All signed ICFs must be kept in 
the investigator's files or in the subject's folder. 
It is the responsibility of the investigator to explain the content of the informed 
consent to the subject and to obtain a signed and dated informed consent form from the 
subject or the subject's legally acceptable representative prior to the start of the study. 
After signing, the investigator should send the subject a copy of the signed informed 


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consent form. The investigator should record the informed consent process in the study 
source documents.  
11.4 
Data Protection for Subjects  
Information on data protection and privacy protection will be included (or in some 
cases, along with the use of separate files) in the ICF.  
Take preventive measures to ensure the confidentiality of the document and prevent 
the identification of the subject. However, under special circumstances, some people may 
see a subject's genetic data and personal identification number. For example, in the event 
of medical emergency, the Sponsor, its physician or investigator may know the subject 
identification number and have access to the subject's genetic data. In addition, relevant 
regulatory authorities may require access to relevant documents.  
12. Study Management  
12.1 
Data Processing and Record Keeping  
The documents in the clinical study (protocol and protocol amendment, completed 
eCRF, signed ICF, etc.) should be preserved and managed according to the requirements 
of GCP. The site will retain these documents for 5 years after the end of the study.  
Study documents should be reasonably maintained for later access or data 
traceability. Safety and environmental risks should be considered when saving documents.  
No study documents may be destroyed without the written permission of the Sponsor 
and the investigator. The investigator/local site will forward the study documents to 
another party who complies with the document retention requirements or to another 
location that meets the requirements for retention only after notification to and written 
consent from the Sponsor.  
12.2 
Access to Raw Data/Documents  
The investigator agrees that the Sponsor, CRO and relevant authorized regulatory 
authorities will have direct access to all study-related documents, including the subject's 
medical records.  
12.3 
Protocol Amendment  
Any potentially appropriate amendments to the protocol during the conduct of the 


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study will be communicated and agreed by the Sponsor to the investigator. The Sponsor 
should ensure timely submission of protocol amendments to the regulatory authority.  
All amendments to the protocol should be kept as protocol amendments. Any 
amendment to the protocol should be submitted to the Ethics Committee for approval or 
filing according to the regulations of the Ethics Committee. If necessary, it should also 
be submitted to the regulatory authority for review and approval, and can be implemented 
only after approved by EC and regulatory authority (if necessary) (except for changes to 
the protocol to eliminate immediate hazards to study subjects).  
12.4 
Responsibilities of Investigators  
The investigator will conduct this study in accordance with the protocol, ethical 
principles of Declaration of Helsinki, Chinese GCP and corresponding regulatory 
requirements.  
The detailed responsibilities of relevant investigators are listed in Chapter 5 
(Responsibilities of Investigators) of China GCP (CFDA Order No. 3).  
12.5 
Publication Policy  
All data generated from this study are confidential information of the Sponsor. The 
Sponsor has the right to publish the study results. Information regarding the Sponsor's 
and investigator's publication policy will be described in the clinical study agreement.  
All information related to this study (not limited to the following documents: 
protocol, Investigator's Brochure) must be kept strictly confidential. The investigator 
must recognize that the scientific or medical information derived from this study may be 
of commercial value to the Sponsor. The investigator should keep the information and 
data related to this study confidential. In order to publish the information related to this 
study or the conclusions drawn from the study, it is necessary to negotiate with the 
Sponsor in advance and obtain the written consent of the Sponsor. In order to protect their 
rights and interests, the Sponsor may require the investigator not to publish the 
information about the study before the product is approved.  
The Sponsor has the right to publish the information or data related to this study or 
submit it to the drug administration department. If the Sponsor needs to display the name 
of the investigator in a publication or advertisement, the consent of the investigator should 
be obtained. 


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12.6 
Finance and Insurance  
The Sponsor will purchase insurance for subjects participating in this study in 
accordance with local regulations and minimum requirements. The terms of the insurance 
will be maintained in the study binder.  


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13. References  
1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. 
Available from URL: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 9/9/2014. 
2. Chinese Cancer Registry Annual Report 2017. National Cancer Center, Disease Prevention and 
Control Bureau of Ministry of Health (2017). 
3. Zhi Xiuyi, Shi Yuankai, Yu Jinming. China Primary Lung Cancer Practice (2015 Edition). Chinese 
Journal of Oncology, 2015; 37 (1): 67-78. 
4. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort 
of the open-label KEYNOTE-021 study. Lancet Oncol, 2016; 17: 1497-508. 
5. Gandhi L, Rodríguez‑Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic 
Non–Small-Cell Lung Cancer. The New England Journal of Medicine, 2018; DOI: 10. 
1056/NEJMoa1801005.  
6. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. Journal of 
Clinical Investigation 2015,125:3384-3391. 
7. NCCN Guidelines Version 8.2017 Non-Small Cell Lung Cancer. 
8. Seymour L,Bogaerts J, Perrone A,et al. iRECIST: guidelines for response criteria for use in studys 
testing immunotherapeutics. Lancet Oncol.,2017; 18(3): e143–e152. 
9. Tazdait M, Mezquita L, Lahmar J, et al. Patterns of responses in metastatic NSCLC during PD-1 or 
PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria. European 
Journal of Cancer, 2018; 88: 38-47. 


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14. Appendix  
Appendix 1: ECOG PS  
Grade  
ECOG DESCRIPTION  
0  
Asymptomatic, fully active, and able to carry on 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 selfcare but unable to carry out any 
work activities, awake more than 50% of the time (< 50% of bed time during the 
day) 
3  
Symptomatic, capable of only limited selfcare, confined to bed or chair for > 50% 
of waking hours, but not yet bedridden 
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5  
Dead  


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Appendix 2: Calculation of creatinine clearance and body surface area  
Creatinine Clearance by Cockcroft-Gault Formula  
Formula for calculating serum creatinine concentration (mg/dL):  
Creatinine clearance in men (mL/min) =  
(140 - age) × (weight) a  
72 × serum creatinine  
 
Creatinine clearance in women (mL/min) =  
0.85 × (140 - age) × (weight) a  
72 × serum creatinine  
 
Formula for calculating serum creatinine concentration ( mol/L):  
Creatinine clearance in men (mL/min) =  
(140 - age) × (weight) a  
0.81 × serum creatinine  
 
Creatinine clearance in women (mL/min) =  
0.85 × (140-age) × (weight) A  
0.81 × serum creatinine  
 
a: Age in years and weight in kg.  
Formula for calculating body surface area  
Body surface area (m2 ) = 0.00616 height (cm) + 0.01286 weight (kg) − 0.1529  


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Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
The following is an excerpt from the RECIST v1.1. 
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
1.1.1 Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
 
10 mm by CT scan (CT scan slice thickness no more than 5 mm) 
 
10 mm by conventional instruments in clinical exam (lesions which cannot be 
accurately measured by 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 ≥ 15mm 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. 
1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodule with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses that cannot be diagnosed and followed by 
reproducible imaging techniques, and cystic lesions. 
1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 


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Bone lesions: 
1) 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; 
2) Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
3) Blastic bone lesions are non-measurable. 
Cystic lesions: 
1) 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; 
2) 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 subject, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
1.2 Specifications by methods of measurements 
1.2.1. Measurements of lesions 
All measurements should be recorded in metric notation when clinically assessed. All 
baseline measurements of tumor lesions should be performed as close as possible to the 
treatment start and must be within 28 days (4 weeks) before the beginning of the treatment. 
1.2.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 


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evaluation should always be done rather than clinical examination unless the lesion being 
followed cannot be imaged but is assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. When lesions can be evaluated by both clinical exam and imaging, 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, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. Lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is ≤ 5 mm. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). 
Ultrasound: Ultrasound should not be used as a method of measurement to assess lesion 
size. Ultrasound examinations cannot be reproduced for review at a later date and, 
because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If new lesions are identified 
by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there 
is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm CR when biopsies are 
obtained or to determine relapse in trials where recurrence following CR or surgical 
resection is an endpoint. 
2. Tumor Response Evaluation 
2.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 


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nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
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. (Note: the appearance of one or more new lesions is also considered 
progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
2.2 Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the "sum" of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm Electronic 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 case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned. (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned in 


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this circumstance as well). This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness). The measurement of these 
lesions is potentially non-reproducible, therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if 
the radiologist is able to provide an actual measure, that should be recorded, even if it is 
below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions "fragment", the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained 
that would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of the 
longest diameter should be the maximal longest diameter for the coalesced lesion. 
2.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response 
of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
Non-Complete Response/Non-Progressive Disease (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 progression. 
2.4 Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as 
follows: When the subject also has measurable disease. In this setting, to achieve 
"unequivocal progression" on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest "increase" in the size of one or more non-target 


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lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
When the subject only has non-measurable disease: This circumstance arises in some 
phase III trials when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing subjects for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable 
in magnitude to the increase that would be required to declare PD for measurable disease: 
i.e. an increase in tumor burden representing an additional 73% increase in "volume" 
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from "trace" to "large", an increase in 
lymphangitic disease from "localized" to "widespread", or may be described in protocols 
as "sufficient to require a change in therapy". Examples include an increase in a pleural 
effusion from "trace" to "large", an increase in lymphangitic disease from "localized" to 
"widespread", or may be described in protocols as "sufficient to require a change in 
therapy". If "unequivocal progression" is seen, the subject should be considered to have 
had overall PD at that point. While it would be ideal to have objective criteria to apply to 
non-measurable disease, the increase must be substantial. 
2.5 New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should 
be unequivocal. For example, progression 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 may be simply 
healing or flare of pre-existing lesions) This is particularly important when the subject’s 
baseline lesions show partial or complete response. For example, necrosis of a liver lesion 
may be reported on a CT scan report as a "new" cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate PD. An example of this is the 


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subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible "new" disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
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, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
2.6 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  
2.7 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
"normal" size (< 10 mm), they may still have a measurement reported on scans. This 


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


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


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duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = 
progressive disease, and NE = not evaluable. a: If a CR is truly met at first time point, 
then any disease seen at a subsequent time point, even disease meeting PR criteria relative 
to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD is met. However, 
sometimes "CR" may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the subject had PR, not CR at the first time point. Under 
these circumstances, the original CR should be changed to PR and the best response is 
PR. 
2.8 Confirmatory Measurement/Duration of Response 
2.8.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error.In r 
studies where stable disease or progression are the primary endpoints, confirmation of 
response is not required since it will not add value to the interpretation of trial results. In 
the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study 
protocol. 
2.8.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded 
on study). The duration of overall complete response is measured from the time 


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measurement criteria are first met for CR until the first date that recurrent disease is 
objectively documented. 
2.8.3 Duration of SD 
Stable disease is measured from the start of the treatment (in randomized trials, from date 
of randomization) until the criteria for progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD). The clinical relevance of the duration of SD varies in different studies 
and diseases. If the proportion of subjects achieving stable disease for a minimum period 
of time is an endpoint of importance in a particular trial, the protocol should specify the 
minimal time interval required between two measurements for determination of stable 
disease. 
Note: The 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 


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Appendix 4: Response Evaluation Criteria in Immune Solid Tumors (iRECIST)  
iRECIST: Efficacy Assessment Guidelines for Use in Clinical Trials Evaluating 
Immunotherapy (Appendix) (excerpt)  
1. Evaluation of iRECIST efficacy 
Immunotherapy may promote the infiltration of immue cells, leading to a temporary 
increase in the volume of tumors or detection of undetectable diseases. This criterion is 
identical to RECIST 1.1 in many respects, but it has been adjusted to assess cases that 
may not reflect the true progress of tumors, such as increased tumor load or new lesions. 
The key differences are described below. All efficacy indicators assessed with 
iRECIST are prefixed with the prefix “i”. The efficacy and best overall efficacy of 
iRECIST at each time point will be recorded separately. 
1.1 Confirmed Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression to rule out 
or confirm pseudoprogression. iRECIST defines iUPD (unconfirmed progression) and 
iCPD (confirmed progression). Scans to confirm progression can be performed as early 
as 4 weeks after iUPD and not later than 8 weeks after iUPD. 
Progressive disease is confirmed (iCPD) if the next imaging assessment confirms 
further increase in lesion size from last asseesment. The specific evidence refers to the 
following items: 
 On the basis of disease progression (compared with the lowest point) of target, 
non-target or new lesions defined by RECIST 1.1, the tumor burden continues to 
increase. 
 Target lesions deteriorated, showing an absolute increase of at least 5 mm in 
the sum of measurements. 
 The progression of non-target lesions is clear, showing an increase in tumor 
load. 
 Englargement of new lesions (absolute increase of the sum of new target 
lesions by at least 5 mm) or discovery of other new lesions. 
 


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 Other lesions (target lesions, non-target lesions or new lesions) that had not 
previously been found to progress were in line with RECIST 1.1 progress criteria, 
including the detection of other new lesions. 
If iUPD is not confirmed in the next evaluation, the outcome of the corresponding 
efficacy evaluation will be recorded (if it still meets iUPD and does not deteriorate, 
recorded as iUPD; if it meets iSD, iPR or iCR criteria compared with baseline, then 
recorded as iSD, iPR or iCR, respectively). As shown in Table 2, in the case that the next 
efficacy evaluation of iUPD did not reach iCPD, previous iUPD did not affect the 
recording of iCR, iPR or iSD at subsequent evaluation time points or at the best overall 
efficacy. 
1.2 New lesions  
New lesions should be measured and evaluated according to RECIST 1.1 criteria (up 
to 5 lesions, no more than 2 lesions per organ and at least 10 mm in the longest diameter, 
at least 15 mm in the short diameter of lymph node lesions). They should be clearly 
recorded as new target lesions and new non-target lesions to distinguish them from 
baseline target lesions and non-target lesions. 
New lesions should be in line with the definition of new target lesions and new non-
target lesions so as to be defined as iUPD (or iCPD). The measurements of such target 
lesions should not be counted into the sum of measurements of target lesions defined at 
baseline. Measurements of these new target lesions should be recorded in a separate CRF. 
Disease progression of new lesions can be confirmed in the following cases: 
imaging evaluation performed at least 4 weeks (not more than 8 weeks) after iUPD 
found that the absolute value of the sum of new target lesions increased by at least 5 mm 
or the volume of new non-target lesions increased (no clear increase) or other lesions 
appeared. 
The best overall immune response (iBOR) for all patients from the beginning of 
treatment to the end of treatment will be defined according to Table 3. 
2. Response and disease stabilization time (RECIST v1.1 and iRECIST)  
The response time will be counted from the time that the CR/PR or iCR/iPR criteria 
are met ( whichever happens first) until recurrence or disease progression. The minimum 


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measurements (including baselines) during the study period are also recorded for 
reference. 
The duration of disease stabilization will be counted from the start of treatment until 
the disease progresses, and the minimum measurements (including baselines) during the 
study period will also be recorded for reference. 
Table 1. Comparison of RECIST v1.1 and iRECIST  
 
RECIST 1.1 
iRECIST 
Definitons 
of 
measurable 
and 
non-measurable 
disease; numbers 
and site of target 
disease 
Measurable lesions are 10 mm in 
diameter (15 mm for nodal lesions); 
maxium of five lesions (2 per 
organ); 
all 
other 
disease 
is 
considered non-target (must be 10 
mm in short axis for nodal disease)  
No 
change 
from 
RECIST 
1.1; 
however, new lesions are assessed as 
per RECIST 1.1 but are recorded 
separately on the case report form (but 
not included in the sum of lesions for 
target lesions identified at baseline) 
 
 
Complete 
response, 
partial 
response , or stable 
disease 
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease 
Can have had iUPD (one or more 
instances), but not iCPD, before iCR, 
iPR, or iSD 
Confirmation 
of 
complete response 
or partial response 
Only required for non-randomised 
trials 
As per RECIST 1.1 
Confirmation 
of 
stable disease 
Not required 
As per RECIST 1.1 
New lesions 
Result in progression; recorded but 
not measured 
Results in iUPD but iCPD is only 
assigned on the basis of this category 
if at next assessment additional new 
lesions appear or an increase in size of 
new lesions is seen (5 mm for sum of 
new lesion target or any increase in 
new lesion non-target); the appearance 
of new lesions when none have 
previously been recorded, can also 


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confirm iCPD. 
Independent 
blinded review and 
central collection 
of scans 
Recommended 
in 
some 
circumstances—eg, in some trials 
with progression-based endpoints 
planned for marketing approval 
Collection 
of 
scans 
(but 
not 
independent review) recommended for 
all tirals. 
Confirmation 
of 
progression 
Not required (unless equivocal) 
Required 
Consideration 
of 
clinical status 
Not included in assessment 
Clinical stability is considered when 
deciding 
whether 
treatment 
is 
continued after iUPD 
CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progressive Disease; iCR: 
Immune Complete Response; iPR: Immune Partial Response; iSD: Immune Stable Disease; iUPD: 
Immune Unconfirmed Progression; iCPD: Immune Confirmed Progression.  
Table 2. Assignment of timepoint response per iRECIST  
 
Timepoint 
response 
with 
no 
previous 
iUPD in any category 
Timepoint response with previous iUPD 
in any category* 
Target lesions: i CR; non-target 
lesions: iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target 
lesions: 
non-iCR/non-iUPD; 
new lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target 
lesions: 
non-iCR/non-iUPD; 
new lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target 
lesions: 
non-iCR/non-iUPD; 
new lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease from 
last 
timepoint; 
non-target 
lesions: iUPD with no change, 
or decrease from last timepoint; 
new lesions: yes 
Not applicable 
New lesions confirm iCPD if new lesions 
were previously identified and they have 
increased in size ( ≥ 5 mm in sum of 
measures for new lesion target or any 
increase for new lesion non-target) or 
number; if no change is seen in new lesions 
(size or number) from last timepoint, 
assignment remains iUPD 


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Timepoint 
response 
with 
no 
previous 
iUPD in any category 
Timepoint response with previous iUPD 
in any category* 
Target lesions: iSD, iPR, iCR; 
non-target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed 
on the basis of a further increase in the size 
of non-target disease (does not need to meet 
RECIST 1.1 criteria for unequivocal 
progression) 
Target lesions: iUPD; non-
target lesions: non-iCR/non-
iUPD, or iCR; new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed 
on the basis of a further increase in sum of 
measures 
≥
 
5 
mm; 
otherwise, 
assignment remains iUPD 
Target lesions: iUPD; non-
target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed 
based on a further increase in previously 
identified target lesion iUPD in sum of 
measures > 5 mm or non-target lesion 
iUPD (previous assessment need not have 
shown unequivocal progression) 
Target lesions: iUPD; non-
target lesions: iUPD; new 
lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed 
on the basis of a further increase in 
previously identified target lesion iUPD 
sum of measures ≥ 5 mm, previously 
identified non-target lesion iUPD (does not 
need to be unequivocal), or an increase in 
the size or number of new lesions 
previously identified 
Target lesions: non-iUPD or 
progression; non-target lesions: 
non-iUPD or progression; new 
lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed 
on the basis of an increase in the size or 
number 
of 
new 
lesions 
previously 
identified  
ICR: immunologic complete response; iPR: immunologic partial response; iSD: immunologic stable 
disease; iUPD: immunologic unconfirmed progression; iCPD: immunologic confirmed progression; 
SOM: sum of measurements; NA: not applicable: NE: not assessable.  
Table 3. Best Overall Response per iRECIST Criteria  
Best overall response  
Timepoint 
response 1  
Timepoint 
response 2 
Timepoint 
response 3 
Timepoint 
response 4  
Timepoint 
response 5  
Immune 
Best 
Overall 


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Response  
iCR  
iCR, iPR, iUPD, 
NE  
iCR, iPR, iUPD, 
NE  
iUPD  
iCPD  
iCR  
iUPD  
iPR, iSD, NE  
iCR  
iCR, iUPD, 
NE  
iCR, 
iPR, 
iSD, iUPD, 
iCPD, NE  
iCR  
iUPD  
iPR  
iPR, iSD, iUPD, 
NE  
iPR, 
iSD, 
iUPD, NE, 
iCPD  
iPR, 
iSD, 
iUPD, 
NE, 
iCPD  
iPR  
iUPD  
iSD, NE  
iPR  
iPR, 
iSD, 
iUPD, NE  
iPR, 
iSD, 
iUPD, iCPD, 
NE  
iPR  
iUPD  
iSD  
iSD, iUPD, NE  
iSD, iUPD, 
iCPD, NE  
iSD, iUPD, 
iCPD, NE  
iSD  
iUPD  
iCPD  
Arbitrary  
Arbitrary  
Arbitrary  
iCPD  
iUPD  
iUPD 
(without 
iCPD)  
iCPD  
Any  
Any  
iCPD  
iUPD  
NE  
NE  
NE  
NE  
iUPD  
 For example only - more cases may exist but follow the same principle  
 This form assumes a randomized study design and does not require confirmation of CR or PR  
 For subjects with only non-target lesions at baseline, the evaluation at each time point is only 
recorded as iCR or non-CR/non-PD, but not shown in the table for convenience  
ICR: immunologic complete response; iPR: immunologic partial response; iSD: immunologic stable 
disease; iUPD: immunologic unconfirmed progression; iCPD: immunologic confirmed progression; 
SOM: sum of measurements; NA: not applicable: NE: not assessable.  


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Investigator Statement and Signature Page  
Study drug: Recombinant fully human anti-programmed death receptor-1 (PD-1) 
monoclonal antibody  
Study drug code: Sintilimab (R & D code: IBI308)  
Trial Name: A Randomized, Double-blind, Phase III Study Evaluating the Efficacy 
and Safety of Sintilimab or Placebo in Combination with pemetrexed and Platinum-based 
Chemotherapy in the First-line Treatment of Advanced or Recurrent Non-squamous Non-
small Cell Lung Cancer (ORIENT-11)  
Approval Letter No.: 2016L08025  
Protocol No.: CIBI308C302  
Investigator Statement  
I have received and read the investigator's Brochure for this study and understood 
recombinant fully human anti-programmed death receptor-1 monoclonal antibody 
injection relevant information about the nature, effect, efficacy and safety. I have read 
and understood the contents of this protocol in detail. It is approved that this clinical study 
is ethical. I will obtain the consent of relevant departments of my unit.  
In accordance with the provisions of GCP, I will earnestly perform the 
responsibilities of the investigator, agree to carry out this clinical study in accordance 
with the design and provisions of this protocol, and explain the materials, regulations and 
responsibilities of the study to all the personnel participating in this study. I will ensure 
that I have sufficient time to be responsible for and complete this clinical study within the 
time limit specified in the protocol, and ensure that all relevant information and data will 
be truthfully, accurately, completely, timely and legally recorded in the medical records 
and case report forms.  
I will strictly abide by the Declaration of Helsinki, explain the details of this clinical 
study approved by the Ethics Committee to the subjects, and obtain the informed consent. 
I will be responsible for making medical decisions related to this clinical study and 
ensuring that subjects receive appropriate treatment for adverse events during the study. 
If serious adverse events occur during the study, I will immediately take appropriate 
treatment measures to ensure the safety of subjects and report to the Sponsor.  
I agree to accept the monitoring and audit by the inspector or auditor designated by 


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the Sponsor and the inspection by drug regulatory authorities to ensure the quality of the 
clinical study.  
I agree to keep all information received or obtained in the study related to this 
protocol confidential.  
Clinical study institution:                            
Principal investigator (signature):                          Date: