Clinical trial NCT03629925
Conditions: Squamous NSCLC
Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
Start date: 2018-09-28; Completion date: 2021-09-30
Enrollment: 357 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Efficacy and Safety Evaluation of IBI308 in Patients with Advanced or Recurrent Squamous NSCLC

Detailed description:
The anti-tumor activity of anti-PD-1 therapy in previously untreated Chinese squamous NSCLC patients will be investigated in this clinical trial.

Arms: arm 1: Sintilimab combination arm: Sintilimab in combination with gemcitabine plus cisplatin or carboplatin arm 2: Placebo combination arm: Placebo in combination with gemcitabine plus cisplatin or carboplatin
Interventions: intervention 1: Sintilimab intervention 2: Gemcitabine intervention 3: Cisplatin intervention 4: Placebo intervention 5: Carboplatin
Intervention descriptions: intervention 1: 200mg, Q3W, day1, I.V.; consecutive cycles intervention 2: 1000mg/m\^2, Q3W, day 1and 8, I.V.; first 4 or 6 consecutive cycles. intervention 3: 75 mg/m\^2, Q3W, day1, I.V.; first 4 or 6 consecutive cycles. intervention 4: NA, Q3W, day1, I.V.; consecutive cycles intervention 5: AUC 5mg/ml/min, Q3W, day1, I.V.; first 4 or 6 consecutive cycles.

Protocol documents:
Prot_000.pdf: 
Investigational Drug: IBI308 
Innovent Biologics (Suzhou) Co., Ltd. 
CIBI308C303 
Nov. 27, 2019 Version 2.3 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized, Double-Blind, Phase III Study to Compare the 
Efficacy and Safety of IBI308 in Combination with Gemcitabine and 
Platinum-Based Chemotherapy Vs. Placebo in Combination with 
Gemcitabine and Platinum-Based Chemotherapy in the First-Line 
Treatment for Patients with Advanced or Metastatic Squamous 
Non-Small Cell Lung Cancer (ORIENT-12) 
Protocol Number: 
CIBI308C303 
Version and Date: 
Nov. 27, 2019/Version 2.3 
Product Name: 
Sintilimab (IBI308) 
Study Phase: 
Phase III 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China 
Sponsor Contact: 
Zhou Hui, Vice President of Medical Science and Strategic Oncology 
Department 
+ 86 021-31652896 
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 EC. 
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's Signature Page 
 
Protocol Title: A Randomized, Double-Blind, Phase III Study to Compare the Efficacy and 
Safety of IBI308 in Combination with Gemcitabine and Platinum-Based Chemotherapy Vs. 
Placebo in Combination with Gemcitabine and Platinum-Based Chemotherapy in the 
First-Line Treatment for Patients with Advanced or Metastatic Squamous Non-Small Cell 
Lung Cancer (ORIENT-12) 
Project Number: CIBI308C303 
 
Title 
Name (regular script) 
Signature 
 Date 
Vice President of 
Medical Science and 
Strategic Oncology 
Department 
Zhou Hui 
 
 
 
 
 
 
  
 
Senior Biostatistics 
Director 
 
Sun Xing 
 
 
 
 
 
 
  
 
 


Investigational Drug: IBI308 
Innovent Biologics (Suzhou) Co., Ltd. 
CIBI308C303 
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Protocol Synopsis 
Protocol no. 
CIBI308C303 
Sponsor 
Innovent Biologics (Suzhou) Co., Ltd. 
Investigational drug 
IBI308 
Active ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study title  
A Randomized, Double-Blind, Phase III Study to Compare the Efficacy and Safety of 
IBI308 in Combination with Gemcitabine and Platinum-Based Chemotherapy Vs. Placebo 
in Combination with Gemcitabine and Platinum-Based Chemotherapy in the First-Line 
Treatment for Patients with Advanced or Metastatic Squamous Non-Small Cell Lung 
Cancer (ORIENT-12) 
Study phase 
Phase III 
Expected study 
duration  
Approximately 23 months 
Study objectives 
Primary objective: 
 
To compare the progression free survival (PFS) of patients with advanced or 
metastatic squamous non-small cell lung cancer (NSCLC) receiving IBI308 in 
combination with gemcitabine and platinum-based chemotherapy vs. placebo in 
combination with gemcitabine and platinum-based chemotherapy as first-line 
treatment based on the "Response Evaluation Criteria in Solid Tumors" (RECIST, 
V1.1). 
Secondary objectives:  
 
To compare the overall survival (OS) between the two groups; 
 
To compare the objective response rate (ORR) between the two groups based on 
RECIST V1.1; 
 
To compare the disease control rate (DCR) between the two groups based on 
RECIST V1.1; 
 
To compare the time to response (TTR) between the two groups based on 
RECIST V1.1; 
 
To compare the duration of response (DOR) between the two groups based on 
RECIST V1.1; 
 
To evaluate the safety and tolerability characteristics of IBI308 in combination 
with gemcitabine and platinum-based chemotherapy. 
Exploratory objectives: 
 
To explore potential biomarkers in tumor tissues that can predict the efficacy of 
IBI308, including but not limited to immunohistochemistry assay of programmed 
cell death ligand 1 (PD-L1) expression and RNA assay in tumor samples; 


Investigational Drug: IBI308 
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 
To explore potential biomarkers in peripheral blood that can predict the efficacy 
of the IBI308 group, including but not limited to the T-cell receptor (TCR) and 
circulating tumor DNA (ctDNA) assay; 
 
To compare the quality of life of patients treated with IBI308 in combination with 
chemotherapy vs. placebo in combination with chemotherapy by using the "Lung 
Cancer Symptom Scale" (LCSS) and "European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire" (EORTC QLQ-C30); 
 
To explore the PFS of subjects in the control group after crossover treatment with 
IBI308; 
 
To explore the population PK characteristics of IBI308. 
Study design 
This is a randomized, double-blind, multi-center, phase III study to compare the efficacy 
and safety of IBI308 in combination with gemcitabine and platinum-based (cisplatin or 
carboplatin) chemotherapy vs. placebo in combination with gemcitabine and 
platinum-based (cisplatin or carboplatin) chemotherapy in first-line treatment of 
previously untreated Chinese subjects with advanced or metastatic squamous NSCLC. 
Subjects in this study will receive treatment with either IBI308 in combination with 
gemcitabine and platinum (cisplatin or carboplatin) or placebo in combination with 
gemcitabine and platinum (cisplatin or carboplatin) for 4 or 6 cycles, followed by 
maintenance therapy with IBI308 or placebo, respectively, until progressive disease (PD), 
intolerable toxicity, initiation of new anti-tumor therapy, withdrawal of informed consent 
form (ICF), loss to follow-up, death, or other conditions requiring treatment 
discontinuation as judged by the investigator, whichever occurs first. The maximum 
duration of treatment with IBI308 is 24 months. In this study, a total of 348 previously 
untreated subjects with advanced or metastatic squamous NSCLC will be randomized in a 
1:1 ratio to the test group and the control group, 174 subjects in the test group and 174 
subjects in the control group (in the actual study, if the actual number of enrolled subjects 
is different from the number of planned enrollment due to unforeseen reasons, such as the 
enrollment speed faster than the requirements of the protocol, the end date of screening 
should be determined in advance to ensure that the number of actually enrolled subjects 
does not exceed the number of planned enrollment by 10%, i.e., a maximum of 382 
subjects should be enrolled, 191 in each group). Randomization stratification factors 
include staging (stage IIIB/IIIC vs. stage IV), platinum-based medications (cisplatin vs. 
carboplatin), and PD-L1 expression level (< 1% vs. ≥ 1%). The primary study endpoint is 
PFS assessed by the Independent Radiographic Review Committee (IRRC) based on 
RECIST V1.1. 
An interim analysis will be performed during the study and the results and reports will be 
submitted to the Independent Data Monitoring Committee (IDMC), which will judge 
whether the trial is valid according to the estimated valid cut-off value and give advice to 
the sponsor on whether the study data can be submitted in advance. The IDMC charter will 
be finalized and approved by IDMC and sponsor prior to the interim analysis. The 
responsibilities of IDMC members and associated procedures will be defined in the IDMC 
charter. 


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Sample estimation 
IBI308 is expected to prolong PFS of subjects from 5.5 months to 7.9 months (HR = 0.7). 
With the enrollment time of 15 months, the total study time of 23 months, power of 82%, 
one-sided α = 0.025 and considering a monthly dropout rate of 0.5%, a total of 348 
subjects (174 in the test group and 174 in the control group) are needed to be randomized 
to achieve the 264 PFS events required in the trial. In the actual study, if the actual number 
of enrolled subjects is different from the number of planned enrollment due to unforeseen 
reasons, such as the enrollment speed faster than the requirements of the protocol, the end 
date of screening should be determined in advance to ensure that the number of actually 
enrolled subjects does not exceed the number of planned enrollment by 10%, i.e., a 
maximum of 382 subjects should be enrolled, 191 in each group. 
An interim analysis will be performed when 70% of PFS events (i.e., 185 PFS events) 
occur. Superiority in efficacy of the test group over the control group will be determined 
using Lan-deMets spending function and O'Brien-Fleming boundary in the interim 
analysis. One-sided P value for the interim analysis is 0.0074. If the actual interim analysis 
time point in the study differs from the planned (185 PFS events), the P value for the 
interim analysis should be adjusted according to the Lan-deMets spending function and 
O'Brien-Fleming. Final PFS analysis is expected to be performed about 8 months after 
enrollment of the last subject. If the interim analysis results fail to reach statistical 
significance, and the PFS events at the final analysis are significantly more than the 
estimated, the P value of the final analysis will be recalculated using the Flexible spending 
function according to the α value actually spent in the interim analysis, so as to ensure that 
the overall type I error is controlled at a one-sided level of 0.025. 
In the interim analysis, with one-sided α = 0.0074, if HR ≤ 0.698 is observed for the test 
group of IBI308 in combination with gemcitabine and cisplatin or carboplatin 
chemotherapy vs. the control group of placebo in combination with gemcitabine and 
cisplatin or carboplatin chemotherapy, it is demonstrated that the superiority has been 
concluded in the interim analysis. 
For the secondary endpoint OS, no formal sample size calculation will be made, and the 
analysis is expected to be performed 1 year after the last subject is enrolled. 
This study is expected to be conducted in 30–40 sites of China. 
Inclusion criteria 
1) 
Sign the written informed consent form (ICF) prior to any trial-related procedure; 
2) 
Aged ≥ 18 years and ≤ 75 years; 
3) 
With a life expectancy of more than 3 months; 
4) 
With at least one measurable lesion confirmed by the investigator according to 
RECIST V1.1. Measurable lesions located in the radiation field of previous 
radiotherapy or subjected to locoregional therapy can be selected as target lesions if 
PD is confirmed; 
5) 
Patients with histologically or cytologically confirmed locally advanced (stage 
IIIB/IIIC), metastatic or recurrent (stage IV) squamous NSCLC who cannot receive 
surgery or radical concurrent chemoradiotherapy, based on the "8th Edition of the 
TNM Classification for Lung Cancer" issued by the International Association for the 
Study of Lung Cancer and the American Joint Committee on Cancer Classification; 
6) 
With an Eastern Cooperative Oncology Group Performance Status score (ECOG PS 
score) of 0 or 1; 


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7) 
Have not received any prior systemic anti-tumor therapy for advanced/metastatic 
disease; for patients who have received prior platinum-based adjuvant 
chemotherapy/radiotherapy, neoadjuvant chemotherapy/radiotherapy, or radical 
chemoradiotherapy for PD, they are eligible for the study if PD occurs at > 6 months 
after the last treatment; 
8) 
With adequate hematologic function, defined as ANC ≥ 1.5 × 109 /L, platelet count ≥ 
100 × 109 /L, and hemoglobin ≥ 90 g/L (no blood transfusion history within 7 days); 
9) 
With adequate hepatic function, defined as TBIL level ≤ 1.5 × upper limit of normal 
(ULN) and aspartate amino transferase (AST) and alanine transaminase (ALT) levels 
≤ 2.5 × ULN for all patients, or AST and ALT levels ≤ 5 × ULN for patients with 
liver metastases; 
10) With adequate renal function, defined as clearance of creatinine (CCr) ≥ 50 mL/min 
(Cockcroft-Gault formula);  
11) With adequate coagulation function, defined as international normalized ratio (INR) 
or prothrombin time (PT) ≤ 1.5 × ULN; for subjects receiving anticoagulant therapy, 
INR/PT within the range proposed for anticoagulant drugs is acceptable; 
12) Female subjects of childbearing age should be tested negative for urine or serum 
pregnancy within 3 days before the first dose of the study drugs. A blood pregnancy 
test is required if the urine pregnancy test is inconclusive; 
13) For male and female patients at risk of conception, highly effective contraception 
measures (failure rate < 1% per year) should be taken until at least 180 days after 
discontinuation of the study treatment; 
Note: Abstinence is acceptable as a method of contraception if it is the usual lifestyle 
and preferred method of contraception for the subject. 
Exclusion criteria 
1) 
Non-squamous NSCLC in histology. The dominant cell morphology must be 
identified for mixed cell type (patients with squamous cell carcinoma components > 
50% can be enrolled); patients with small cell carcinoma, neuroendocrine carcinoma, 
and sarcoma components cannot be included; 
2) 
Patients with known epidermal growth factor receptor (EGFR)-sensitive mutation or 
anaplastic lymphoma kinase (ALK) rearrangement; 
3) 
Currently participating in an interventional clinical study, or treated with another 
study drug or investigational device within 4 weeks before the first dose; 
4) 
Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 
agents or agents targeting another stimulation or synergistically inhibiting T-cell 
receptor (TCR) (e.g., CTLA-4, OX-40, and CD137); 
5) 
Received proprietary Chinese medicines with anti-tumor indications or 
immunomodulators (thymosin, interferon, interleukin, etc.) within 2 weeks prior to 
the first dose, or received a major surgery within 3 weeks prior to the first dose; 
6) 
With active hemoptysis, active diverticulitis, abdominal abscess, gastrointestinal 
obstruction, and peritoneal metastases requiring clinical intervention; 
7) 
Have undergone solid organ transplantation or hematologic transplantation; 
 


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8) 
With clinically uncontrolled pleural effusion/ascites (patients who do not need 
effusion drainage or have no significant increase in effusion 3 days after stopping 
drainage can be enrolled); 
9) 
With a tumor compressing the surrounding important organs (such as esophagus) 
with relevant symptoms, compressing the superior vena cava, or invading the 
mediastinal great vessels, heart, etc.; 
10) With Class III–IV congestive cardiac failure (based on New York Heart Association 
Classification) or poorly controlled and clinically significant arrhythmia; 
11) With any arterial thrombosis, embolism, or ischemia within 6 months prior to 
enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident, 
and transient ischemic attack. With a history of deep venous thrombosis, pulmonary 
embolism, or any other serious thromboembolic events within 3 months prior to 
enrollment (implantable port or catheter-related thrombosis, or superficial venous 
thrombosis is not considered as "serious" thromboembolism); 
12) With known allergy to the active ingredients and/or any excipient of IBI308, 
gemcitabine, cisplatin, or carboplatin; 
13) With active autoimmune disease requiring systemic treatment (e.g., use of 
disease-modifying drugs, corticosteroids, or immunosuppressive agents) within 2 
years before the first dose. Replacement therapy (e.g., thyroxine, insulin, or 
physiologic doses of corticosteroids for adrenal or pituitary insufficiency) is not 
considered systemic; 
14) Patients requiring long-term systemic use of corticosteroids. Patients requiring 
intermittent use of bronchodilators, inhaled corticosteroids, or local injection of 
corticosteroids for COPD or asthma can be included in the study; 
15) Full recovery (i.e., ≤ grade 1 or reaching the baseline, excluding asthenia or alopecia) 
from toxicity and/or complications caused by any intervention has not achieved 
before the start of treatment; 
16) Diagnosed with other malignant tumors within 5 years before the first dose, 
excluding radically cured cutaneous basal cell carcinoma, cutaneous squamous cell 
carcinoma, and/or radically resected carcinoma in situ. For other malignant tumors or 
lung cancer diagnosed more than 5 years before the first dose, pathological or 
cytological diagnosis should be performed for recurrent and metastatic lesions; 
17) Symptomatic central nervous system (CNS) metastasis. Patients with asymptomatic 
brain metastases or with stable symptoms after treatment of brain metastases are 
allowed to participate in this study as long as meeting all of the following criteria: 
presence of measurable lesions outside the CNS; absence of metastases in midbrain, 
pons, cerebellum, meninges, medulla oblongata, or spinal cord; maintain clinical 
stable condition for at least 2 weeks; discontinue hormone therapy 14 days prior to 
the first dose of the study drugs; 
18) With a history of non-infectious pneumonia requiring corticosteroid therapy within 1 
year prior to the first dose or with non-infectious pneumonia at present; 
19) With an active infection requiring treatment or have used systemic anti-infective 
drugs within one week prior to the first dose; 
 


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20) With known psychiatric disorder or substance abuse that could affect the compliance 
with trial requirements; 
21) With a known history of human immunodeficiency virus (HIV) infection (i.e., HIV 
1/2 antibody positive), known syphilis infection (syphilis antibody positive), and 
active pulmonary tuberculosis; 
22) With untreated active hepatitis B; 
Note: Subjects with hepatitis B who meet the following criteria are also eligible for 
inclusion: 
Hepatitis B virus (HBV) load must be less than 1000 copies/mL (200 IU/mL) or 
below the lower limit of detection (LLD) prior to the first dose, and subjects should 
receive anti-HBV treatment to avoid virus reactivation throughout the 
chemotherapeutic period of the study; 
For subjects with HBcAb (+), HBsAg (−), HBsAb (−), and HBV load (−), close 
monitoring is required instead of prophylactic anti-HBV treatment to avoid virus 
reactivation; 
23) Subjects with active hepatitis C virus (HCV) infection (HCV antibody positive and 
HCV-RNA level above the LLD); 
24) Have received live vaccines within 30 days prior to the first dose; 
Note: Seasonal inactivated influenza virus vaccines for injection are allowed, while 
live attenuated influenza vaccines for intranasal use are not acceptable; 
25) With any medical history, disease, treatment, or laboratory abnormal finding that 
would interfere with the trial results or prevent the subject from participating in the 
whole trial, or the investigator believes that participation in this study is not in the 
best interest of the subject; 
26) With local or systemic diseases not attributable to malignancy, or with cancer-related 
secondary diseases, which would result in a high medical risk and/or uncertainty in 
survival evaluation. 
Study drugs and 
administration 
1. 
IBI308: 10 mL:100 mg, 200 mg, IV infusion on day 1, Q3W. 
2. 
IBI308 placebo: 10 mL/vial, 2 vials, IV infusion on day 1, Q3W. 
3. 
Gemcitabine: 200 mg/vial or 1 g/vial, 1 g/m2, IV infusion on day 1 and day 8, Q3W. 
4. 
Cisplatin: 20 mg/vial, 75 mg/m2, IV infusion on day 1, Q3W. 
5. 
Carboplatin: AUC 5 mg/mL/min, IV infusion on day 1, Q3W. 
Evaluation criteria 
Efficacy evaluation: 
 
Efficacy evaluation is based on RECIST V1.1. PFS, OS, ORR, TTR, DOR, and 
DCR after administration will be evaluated. 
Safety evaluation: 
 
Incidence, relationship with the investigational drug, and severity level of all 
adverse events (AEs), treatment related adverse events (TRAEs), immune 
related adverse events (irAEs), and serious adverse events (SAEs); 


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 
Number of subjects discontinuing study treatment due to the above AEs; 
 
Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies 
(NAbs); 
 
Changes in vital signs, physical examination, and laboratory tests results before, 
during, and after the study treatment will be evaluated. 
Statistical methods 
The primary objective of this study is to confirm that compared with placebo in 
combination with gemcitabine and cisplatin or carboplatin chemotherapy, IBI308 in 
combination with gemcitabine and cisplatin or carboplatin chemotherapy can prolong the 
progression free survival (PFS). The primary endpoint PFS is analyzed at approximately 
23 months after the start of the trial (i.e., at the end of the study, expected to be at 
approximately 8 months after randomization of the last subject). An interim analysis will 
be performed when 70% of PFS events (i.e., 185 PFS events) occur. In order to strictly 
control the overall type I error rate at a one-sided level of 0.025, superiority in efficacy of 
the test group over the control group will be determined using Lan-deMets spending 
function and O'Brien-Fleming boundary in the interim analysis. One-sided P value for the 
interim analysis is 0.0074. 
Efficacy evaluation: 
A stratified log-rank test will be used to compare the OS between groups. The median PFS 
and corresponding 95% CI will be estimated via the Kaplan-Meier method, and survival 
curves will be plotted. The between-group HR and corresponding 95% CI will be 
estimated with a stratified COX proportional hazards model, with the randomization 
stratification factor as the stratification factor. The COX proportional hazards model will 
also be used to assess the effects of various covariates possibly related to prognosis and 
efficacy prediction on the estimated treatment effect HR. 
A stratified log-rank test will be used to compare the OS between groups. The median OS 
and corresponding 95% CI will be estimated via the Kaplan-Meier method, and survival 
curves will be plotted. The between-group HR and corresponding 95% CI will be 
estimated with a stratified COX proportional hazards model, with the randomization 
stratification factor as the stratification factor. The COX proportional hazards model will 
also be used to assess the effects of various covariates possibly related to prognosis and 
efficacy prediction on the estimated treatment effect HR. 
For endpoints DOR and TTR, the Kaplan-Meier method will used to estimate medians and 
provide survival curves. 
The ORRs, DCRs, and corresponding 95% CIs of tumor response evaluation in each 
treatment cycle will be estimated for test group and control group. The difference between 
groups and corresponding 95% CI will be calculated. 
The quality of life scores will be standardized to convert raw scores into standardized 
scores ranging between 0–100. The results will be subjected to descriptive statistics and 
Wilcoxon test. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
scores will be analyzed also using descriptive statistics and Wilcoxon test. 
Safety evaluation: 
The exposure of subjects to study drugs, the number of cycles completed by subjects in the 
two groups, dose adjustments during treatment, cumulative number of dose adjustments 
during treatment, etc. will be summarized. 


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All AEs will be coded and categorized according to codes in the "Medical Dictionary for 
Regulatory Activities" (MedDRA), and graded by severity level according to the 
"Common Terminology Criteria for Adverse Events" (CTCAE V4.03). The incidences of 
AEs, TRAEs, irAEs, AEs leading to treatment discontinuation, AEs leading to study 
termination, AEs leading to death, grade 3 or greater AEs, and SAEs will be summarized; 
the number of subjects and percentages will be summarized by system organ classification 
(SOC), preferred term (PT), and group, and these AEs will be summarized by SOC, PT, 
severity level, and group. 
Measured values and changes from baseline of laboratory tests, vital signs, and ECG will 
be summarized using descriptive statistics. Baseline results and worst results during the 
study will be presented in cross tabulation. 
Immunogenicity data will be presented with descriptive statistics. The number and 
percentage of subjects who develop ADAs and NAbs during the study will be summarized 
by group. 
The analysis of pharmacokinetic (PK) data will include, but is not limited to, descriptive 
statistical analysis of IBI308 trough concentrations in cycles 1/3/11. 


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Table 1. Schedule of study visits 
Stage 
Screening 
period 
Combination therapy (21 days per cycle) 
Maintenance 
therapy 
(21 days per 
cycle) 
Safety 
visit22 
Survival 
visits23 
C1/D1 C1/D8 C2/D1 C2/D8 C3/D1 C3/D8 C4/D1 C4/D8 C5/D1 C5/D8 C6/D1 C6/D8 
Day 
-28 
~-1 
1 
8 
22 
29 
43 
50 
64 
71 
85 
92 
106 
113  
Day 30 
after the 
last dose 
Every 
90 days 
Time window (day) 
NA 
＋2 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
± 3 days 
± 3 days ± 7 days 
Standard study 
procedures 
 
Written ICF1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/previous 
therapies for lung 
cancer2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs3 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Weight/height4 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Comprehensive 
physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG5 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Survival condition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Stage 
Screening 
period 
Combination therapy (21 days per cycle) 
Maintenance 
therapy 
(21 days per 
cycle) 
Safety 
visit22 
Survival 
visits23 
C1/D1 C1/D8 C2/D1 C2/D8 C3/D1 C3/D8 C4/D1 C4/D8 C5/D1 C5/D8 C6/D1 C6/D8 
Day 
-28 
~-1 
1 
8 
22 
29 
43 
50 
64 
71 
85 
92 
106 
113  
Day 30 
after the 
last dose 
Every 
90 days 
Time window (day) 
NA 
＋2 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
± 3 days 
± 3 days ± 7 days 
Laboratory 
evaluation 
 
Routine blood test6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry6 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urinalysis6 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Coagulation function7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Thyroid function9 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Virological antibody 
test (HIV, HBV, and 
HCV)10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test HCV-RNA if 
positive for HCV 
antibody11 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Test HBV-DNA if 
positive for HBsAg 
and/or HBcAb12 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood myocardial 
enzyme and troponin13 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 


Investigational Drug: IBI308 
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Stage 
Screening 
period 
Combination therapy (21 days per cycle) 
Maintenance 
therapy 
(21 days per 
cycle) 
Safety 
visit22 
Survival 
visits23 
C1/D1 C1/D8 C2/D1 C2/D8 C3/D1 C3/D8 C4/D1 C4/D8 C5/D1 C5/D8 C6/D1 C6/D8 
Day 
-28 
~-1 
1 
8 
22 
29 
43 
50 
64 
71 
85 
92 
106 
113  
Day 30 
after the 
last dose 
Every 
90 days 
Time window (day) 
NA 
＋2 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
± 3 days 
± 3 days ± 7 days 
Safety monitoring 
 
ECOG PS score 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
AE evaluation14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality-of-life 
questionnaires15 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Subsequent anti-tumor 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Efficacy evaluation 
 
Tumor imaging 
evaluation16 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
PK and 
immunogenicity 
 
Immunogenicity17 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
 
PK18 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Administration of 
study drugs19 
 
IBI308 or placebo 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Gemcitabine 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Cisplatin or 
carboplatin 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 


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Stage 
Screening 
period 
Combination therapy (21 days per cycle) 
Maintenance 
therapy 
(21 days per 
cycle) 
Safety 
visit22 
Survival 
visits23 
C1/D1 C1/D8 C2/D1 C2/D8 C3/D1 C3/D8 C4/D1 C4/D8 C5/D1 C5/D8 C6/D1 C6/D8 
Day 
-28 
~-1 
1 
8 
22 
29 
43 
50 
64 
71 
85 
92 
106 
113  
Day 30 
after the 
last dose 
Every 
90 days 
Time window (day) 
NA 
＋2 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
±3 
±2 
± 3 days 
± 3 days ± 7 days 
Biomarker study 
 
Archived or fresh 
tumor tissue sample20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood21 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Note: 
1. 
The ICF should be signed by subjects prior to any procedures outlined in the protocol. 
2. 
Previous therapies for lung cancer: all treatments for lung cancer, including chemotherapy, radiotherapy, and surgery. 
3. 
Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. 
4. 
Height is measured during screening period only. Body weight is measured prior to each dose. If the body weight of a subject fluctuates by less than 10% 
from the baseline (the day when the first dose of study drugs is given), the baseline body weight will be used to calculate the chemotherapeutic dose. 
Otherwise, the actual dose will be calculated based on the weight of scheduled dosing days. 
5. 
Time of 12-lead ECG examinations: within 7 days before the first dose of study drugs during screening, within 3 days before each administration of study 
drugs from cycle 2 onwards, and during safety follow-up. 
6. 
Routine blood test: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell (WBC), platelet (PLT), and WBC differential 
[lymphocyte, neutrophil, monocyte, eosinophil, and basophil]. Blood chemistry: hepatic function [TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, and 
CK], renal function (UREA or BUN, and Cr), blood electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Urinalysis: pH, 
UWBC, UPRO, URBC, UGLU, and specific gravity. Subjects with ≥ 2+ urine protein in urinalysis during screening should undergo a 24-h urine protein 
quantitation test. The tests will be conducted within 7 days before the first dose of study drugs during screening, within 3 days before each administration of 
study drugs from cycle 2 onwards, and during safety follow-up. Tests will be conducted at each study site. 


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7. 
Coagulation function test: PT and INR. The test will be conducted within 7 days before the first dose of study drugs during screening and during the safety 
follow-up. Tests will be conducted at each study site. 
8. 
Women of childbearing age will undergo urine or serum pregnancy test within 3 days before the first dose during screening and during the safety follow-up. 
If the urine pregnancy test is not conclusive, then blood pregnancy test should be performed. The conclusion should be based on the blood pregnancy test. 
Tests will be conducted at each study site. 
9. 
The thyroid function test will be conducted within 28 days before the first dose, within 3 days before each administration of study drugs from cycle 2 
onwards, and during the safety follow-up. T3/FT3, FT4, and TSH are examined during screening, and only TSH is examined from cycle 2 onwards. In case 
of any abnormalities, the examination of other thyroid function parameters should be considered. During study treatment, the study drugs can be 
administered before the test results are accessible. Tests will be conducted at each study site. 
10. This item involves the testing of HIV and HCV antibodies as well as hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), and should be 
completed within 28 days before the first dose. The test will be conducted at the study site during screening. 
11. Anti-HCV antibodies will be tested at the screening visit. For subjects tested positive for HCV antibodies, HCV-RNA load should be determined during 
screening, within 3 days before each administration of study drugs from cycle 2 onwards, or at an earlier time if clinically indicated. During study treatment, 
the study drugs can be administered before the test results are accessible. 
12. Hepatitis B panel will be tested at the screening visit. For subjects tested positive for HBsAg and/or HBcAb, HBV-DNA load should be determined during 
screening, within 3 days before each administration of study drugs from cycle 2 onwards, or at an earlier time if clinically indicated. During study treatment, 
for patients previously tested negative for HBsAg, the study drugs can be administered before the HBV-DNA load test results are accessible. 
13. The blood myocardial enzyme and troponin tests should at least include: creatine phosphokinase (CK), creatine phosphokinase isoenzyme (CK-MB), and 
troponin (troponin T or troponin I). The tests will be conducted within 7 days before the first dose of study drugs during screening and within 3 days before 
each administration of study drugs from cycles 2 and 3 onwards. The conduct or not of subsequent tests will be decided by the investigator. 
14. AEs and laboratory safety assessments will be performed based on CTCAE V4.03. Refer to Section 8 for definitions, recording, causality determination, 
severity level, reporting deadlines, and treatment of AEs and SAEs. 
15. Quality-of-life questionnaires include LCSS and EORTC QLQ-C30 (V3.0 Chinese version), which will be completed on the day of the first dose (predose), 
at each imaging evaluation (during the visit), and at the safety follow-up (during the visit). If an unscheduled imaging evaluation is performed, the 
quality-of-life questionnaires should also be completed. 
16. Tumor assessment includes the assessment based on RECIST V1.1. Tumor imaging examinations usually include contrast-enhanced CT or MRI of chest, 
abdomen, and pelvic cavity. Contrast-enhanced MRI of head should also be performed at baseline for subjects with signs or symptoms of suspected CNS 
metastasis. The same subject should receive the same type of imaging examination during the study. The baseline evaluation will be performed within 28 
days before randomization. Tumor imaging evaluation will be performed at week 6 (± 7 days) and week 12 (± 7 days) since randomization, every 9 weeks 


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(± 7 days) thereafter until week 48, and every 12 weeks (± 7 days) after week 48. After the first assessment of imaging PD (PD) by the investigator based on 
RECIST V1.1, if the subject has SD clinically, the current treatment can be continued and the imaging evaluation should be performed again 4–6 weeks 
later for confirmation (based on RECIST V1.1). If PD is not confirmed, the study treatment should be continued and imaging evaluations should be 
performed at the protocol-specified time points until imaging-confirmed PD. If a subject discontinues study treatment for a reason other than objective PD, 
the imaging evaluation should be performed at the end of treatment and then at the protocol-specified time points thereafter until one of the following events 
occurs: initiation of new anti-tumor therapy, objective PD, loss to follow-up, death, or withdrawal of ICF, whichever occurs first. Unscheduled imaging 
evaluations can be performed at any time during the study if the patient develops clinically unstable disease. If the subject has clinically unstable disease 
after the first assessment of imaging PD, the confirmation 4–6 weeks later is not required and the study treatment should be discontinued. 
17. Immunogenicity assays will be performed within 1 h prior to IBI308/placebo infusion in cycles 1/2/4/8/12/16, then every 8 cycles (cycle 24, 32, and so on) 
thereafter, and during the safety visit. If an infusion-related reaction occurs during IBI308 or placebo administration, blood samples should be taken near the 
start and end of this event and around 30 days after the reaction, for comparative analysis of immunogenicity. Tests will be conducted in the central 
laboratory. 
18. PK samples will be collected at the following time points: within 1 h before and immediately (+ 5 min) after IBI308 or placebo infusion in cycle 1, and 
within 1 h before IBI308 or placebo infusion in cycles 2/4/12. Tests will be conducted in the central laboratory. 
19. Subjects will receive treatment with either IBI308 in combination with gemcitabine and platinum (cisplatin or carboplatin) or placebo in combination with 
gemcitabine and platinum (cisplatin or carboplatin) for 4 or 6 cycles, followed by maintenance therapy with IBI308 or placebo, respectively. After the first 
assessment of imaging PD by the investigator based on RECIST V1.1, if the subject has SD clinically, the current treatment can be continued and the 
imaging evaluation should be performed again 4–6 weeks later for confirmation (based on RECIST V1.1). If PD is confirmed, unblinding should be 
performed and subjects of IBI308 in combination with chemotherapy group (test group) should end the study treatment, while subjects of placebo in 
combination with chemotherapy group (control group) can be conditionally crossed over to receive monotherapy of IBI308 based on the judgment of the 
investigator and the willingness of the subjects; if PD is not confirmed, the study treatment will be continued until imaging-confirmed PD followed by 
unblinding and other subsequent processing same as above. If the subject has clinically unstable disease after the first assessment of imaging PD, the 
confirmation 4–6 weeks later is not required and unblinding can be directly performed followed by processing same as above. During the study, the 
treatment should be discontinued if one of the following occurs: clinically unstable disease, intolerable toxicity, receipt of new anti-tumor therapy, 
withdrawal of ICF, loss to follow-up, death, or other conditions requiring treatment discontinuation as judged by the investigator, whichever occurs first. 
The maximum duration of treatment with IBI308 is 24 months in both groups. 
20. Each subject is required to provide at least 10 sections of archived or fresh tumor tissue samples meeting test requirements during screening. 
21. Each subject is also required to provide 10 mL of whole blood samples for tumor biomarker testing at the following time points: prior to the first dose, every 
time when imaging evaluation is performed but before the next treatment is started in the treatment period, the time when PD is confirmed, and during 
safety visit. Tests will be conducted in the central laboratory. 


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22. A safety follow-up visit will be carried out on day 30 (± 3 days) after the last dose or before initiation of new anti-tumor therapy, whichever occurs first. All 
AEs that occur prior to the safety follow-up visit should be documented until the events recover to grade 0–1 or the baseline level, or until the investigator 
believes that no further follow-up is required for reasonable reasons (e.g., the event cannot be resolved or has already been improved), whichever occurs 
first. All SAEs that occur within 90 days after the last dose or before initiation of new anti-tumor therapy (whichever occurs first) should be followed up and 
documented. 
23. Survival follow-ups: once every 90 days (± 7 days) after the safety follow-up. Telephone follow-ups are allowed. 


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Table 2. Schedule of visits during crossover treatment with IBI308 
Stage 
Crossover treatment (21 days per cycle)1 
Safety visit17 
Survival visits18 
C1 
C2 
C3 
C4 
C5 
C6 
C7 and later 
Time window (day) 
＋3 
±3 
±3 
±3 
±3 
±3 
±3 
Day 30 (± 3) after 
the last dose 
Every 90 days  
(± 7) 
Standard study procedures 
 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/height3 
X 
 
 
 
 
 
 
X 
 
Comprehensive physical 
examination 
X 
 
 
 
 
 
 
X 
 
ECOG PS score 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Routine blood test/blood 
chemistry/urinalysis5 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation function6 
X 
 
 
 
 
 
 
X 
 
Pregnancy test7 
X 
 
 
 
 
 
 
X 
 
Thyroid function8 
X 
X 
X 
X 
X 
X 
X 
X 
 
Virological antibody test (HIV, 
HBV, and HCV)9 
X 
 
 
 
 
 
 
 
 
Test HCV-RNA if positive for HCV 
antibody10 
X 
X 
X 
X 
X 
X 
X 
X 
 
Test HBV-DNA if positive for 
HBsAg and/or HBcAb11 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood myocardial enzyme and 
troponin12 
X 
X 
X 
 
 
 
 
 
 
AE evaluation13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Stage 
Crossover treatment (21 days per cycle)1 
Safety visit17 
Survival visits18 
C1 
C2 
C3 
C4 
C5 
C6 
C7 and later 
Time window (day) 
＋3 
±3 
±3 
±3 
±3 
±3 
±3 
Day 30 (± 3) after 
the last dose 
Every 90 days  
(± 7) 
Quality-of-life questionnaires14 
X 
 
 
X 
 
 
X 
X 
 
Subsequent anti-tumor therapy 
 
 
 
 
 
 
 
X 
X 
Survival condition 
 
 
 
 
 
 
 
 
X 
Efficacy evaluation 
 
Tumor imaging evaluation15 
X 
 
 
X 
 
 
X 
X 
X 
Administration of study drugs 
 
IBI308, 200 mg i.v. Q3W 
X 
X 
X 
X 
X 
X 
X 
 
 
PK and immunogenicity 
 
Immunogenicity16 
 
 
 
 
 
 
 
 
 
Note: 
1. 
Only after all patients in the control group have been assessed for overall status by the investigator and confirmed to have PD by the IRRC and meet the 
requirements for administration of IBI308, can they be crossed over to receive treatment with IBI308. The imaging results obtained at the end of the last 
dose can be used for the evaluation before crossover treatment. Regardless of the confirmation date of PD, subjects must start the administration of IBI308 
at least 21 days after the last chemotherapy. 
2. 
Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. 
3. 
Body height is measured only before the first dose. 
4. 
Time of 12-lead ECG examinations: within 7 days before the first dose of IBI308, within 3 days before each administration from cycle 2 onwards, and 
during safety follow-up. 
5. 
Routine blood test: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell (WBC), platelet (PLT), and WBC differential 
[lymphocyte, neutrophil, monocyte, eosinophil, and basophil]. Blood chemistry: hepatic function [TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, and 
CK], renal function (UREA or BUN, and Cr), blood electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Urinalysis: pH, 
UWBC, UPRO, URBC, UGLU, and specific gravity. Subjects with ≥ 2+ urine protein in urinalysis during screening should undergo a 24-h urine protein 


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quantitation test. The tests will be conducted within 7 days before the first dose of IBI308, within 3 days before each administration of study drugs from 
cycle 2 onwards, and during safety follow-up. Tests will be conducted at each study site. 
6. 
Coagulation function test: PT and INR. The test is conducted within 7 days before the first dose of IBI308 and during safety follow-up. Tests will be 
conducted at each study site. 
7. 
Women of childbearing age will undergo urine or serum pregnancy test within 3 days before the first dose of IBI308 and during the safety follow-up. If the 
urine pregnancy test is not conclusive, then blood pregnancy test should be performed. The conclusion should be based on the blood pregnancy test. Tests 
will be conducted at each study site. 
8. 
The thyroid function test will be conducted within 21 days before the first dose, within 3 days before each administration from cycle 2 onwards, and during 
the safety follow-up. During study treatment, the study drugs can be administered before the test results are accessible. Tests will be conducted at each study 
site. 
9. 
This item involves the testing of HCV antibodies and hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), and should be completed within 21 
days before the first dose. Tests will be conducted at each study site. 
10. For subjects tested positive for HCV antibodies, HCV-RNA load should be determined within 3 days before administration of study drugs in each cycle, or 
at an earlier time if clinically indicated. During study treatment, the study drugs can be administered before the test results are accessible. 
11. For subjects tested positive for HBsAg and/or HBcAb, HBV-DNA load should be determined within 3 days before administration of study drugs in each 
cycle, or at an earlier time if clinically indicated. During study treatment, for patients previously tested negative for HBsAg, the study drugs can be 
administered before the HBV-DNA load test results are accessible. 
12. The blood myocardial enzyme and troponin tests should at least include: creatine phosphokinase (CK), creatine phosphokinase isoenzyme (CK-MB), and 
troponin (troponin T or troponin I). The tests are performed within 7 days before the first dose of IBI308 during crossover treatment and within 3 days 
before each administration of study drugs from cycles 2 and 3 onwards. The conduct or not of subsequent tests will be decided by the investigator. 
13. AEs and laboratory safety assessments will be performed based on CTCAE V4.03. Refer to Section 8 for definitions, recording, causality determination, 
severity level, reporting deadlines, and treatment of AEs and SAEs. 
14. Quality-of-life questionnaires include LCSS and EORTC QLQ-C30 (V3.0 Chinese version), which will be completed on the day of the first dose (predose), 
at each imaging evaluation (during the visit), and at the safety follow-up (during the visit). 
15. Tumor assessment includes the assessment based on RECIST V1.1. Tumor imaging examinations usually include contrast-enhanced CT or MRI of chest, 
abdomen, and pelvic cavity. Contrast-enhanced MRI of head should also be performed at baseline for subjects with signs or symptoms of suspected CNS 
metastasis. The same subject should receive the same type of imaging examination during the study. Subjects in the stage of crossover treatment with 
IBI308 will be assessed every 9 weeks (± 7 days) since the first dose until the occurrence of imaging PD (based on RECIST V1.1). For patients who 


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discontinue the treatment for reasons other than objective PD, an imaging evaluation should be performed at the end of treatment and then at the 
protocol-specified time points thereafter until one of the following events occurs: initiation of new anti-tumor therapy, PD, loss to follow-up, death, or 
withdrawal of ICF, whichever occurs first. Unscheduled imaging evaluations can be performed at any time during the study if the patient develops clinically 
unstable disease. 
16. If an infusion-related reaction occurs during IBI308 infusion, blood samples should be taken near the start and end of this event and around 30 days after the 
reaction and used for comparative analysis of immunogenicity. Tests will be conducted in the central laboratory. 
17. A safety follow-up visit will be carried out on day 30 (± 3 days) after the last dose or before initiation of new anti-tumor therapy, whichever occurs first. 
18. Survival follow-ups: once every 90 days (± 7 days) after the safety follow-up. Telephone follow-ups are allowed. 
 


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TABLE OF CONTENTS 
Protocol Synopsis .......................................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................... 22 
List of Tables ............................................................................................................................... 25 
List of Figures .............................................................................................................................. 26 
1 
BACKGROUND ................................................................................................................. 29 
1.1 
Disease Background .................................................................................................. 29 
1.2 
IBI308 ........................................................................................................................ 33 
1.3 
Risk/Benefit Assessment ........................................................................................... 35 
2 
STUDY OBJECTIVES ....................................................................................................... 36 
2.1 
Primary Objectives .................................................................................................... 36 
2.2 
Secondary Objectives ................................................................................................ 36 
2.3 
Exploratory Objectives .............................................................................................. 36 
3 
Study design ......................................................................................................................... 37 
3.1 
Overall Design ........................................................................................................... 37 
3.2 
Design Principles ....................................................................................................... 41 
3.3 
Independent Data Monitoring Committee (IDMC) ................................................... 42 
4 
STUDY POPULATION ..................................................................................................... 42 
4.1 
Inclusion Criteria ....................................................................................................... 42 
4.2 
Exclusion criteria ....................................................................................................... 44 
4.3 
Restrictions During the Study .................................................................................... 46 
4.4 
Criteria for Discontinuation/Withdrawal ................................................................... 47 
5 
STUDY DRUG AND OTHER TREATMENTS .............................................................. 49 
5.1 
Use of Study Drugs .................................................................................................... 50 
5.2 
Dose adjustments ....................................................................................................... 51 
5.3 
Principles of Managing Immune Checkpoint Inhibitor Toxicities ............................ 57 
5.4 
Concomitant Treatments ............................................................................................ 58 
5.5 
Drug Management ..................................................................................................... 60 


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5.6 
Study drug-related records ......................................................................................... 61 
5.7 
Complaint handling.................................................................................................... 61 
6 
STUDY PROCEDURE ....................................................................................................... 61 
6.1 
Subject Screening and Randomization Procedures ................................................... 61 
6.2 
Study Plan and Schedule............................................................................................ 62 
6.3 
Initiation of Crossover Treatment in Subjects of Control Group After Objective 
Progressive Disease................................................................................................... 65 
6.4 
Other Procedures........................................................................................................ 69 
7 
STUDY EVALUATIONS ................................................................................................... 71 
7.1 
Efficacy evaluation .................................................................................................... 71 
7.2 
Safety evaluation........................................................................................................ 73 
7.3 
Pharmacokinetics: ...................................................................................................... 76 
7.4 
Immunogenicity ......................................................................................................... 76 
7.5 
Quality-of-Life Evaluation ........................................................................................ 77 
7.6 
Biomarker analysis .................................................................................................... 77 
7.7 
Storage and Destruction of Biological Samples ........................................................ 78 
8 
Safety Reports and AE Management ................................................................................ 79 
8.1 
Definition of AEs ....................................................................................................... 79 
8.2 
Definition of Serious Adverse Events ....................................................................... 79 
8.3 
Evaluation of Adverse Events.................................................................................... 80 
8.4 
Documentation of Adverse Events ............................................................................ 83 
8.5 
Expedited Reporting of SAEs and Pregnancy ........................................................... 85 
8.6 
Abnormal Hepatic Function....................................................................................... 86 
8.7 
Management of Drug-Related Toxicities .................................................................. 87 
8.8 
Emergency Unblinding .............................................................................................. 88 
9 
STATISTICAL ANALYSIS .............................................................................................. 88 
9.1 
Statistics analysis plan ............................................................................................... 88 
9.2 
Statistical Hypothesis and Sample Size ..................................................................... 88 
9.3 
Definition of Analysis Sets ........................................................................................ 89 
9.4 
Statistical Analysis Methods ...................................................................................... 89 


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10 
Quality assurance and quality control .............................................................................. 96 
10.1 Clinical monitoring .................................................................................................... 96 
10.2 Data Management/Coding ......................................................................................... 97 
10.3 Quality Control Audit ................................................................................................ 98 
11 
Ethics .................................................................................................................................... 99 
11.1 Ethics committee........................................................................................................ 99 
11.2 Ethics ......................................................................................................................... 99 
11.3 Informed Consent of Subjects.................................................................................... 99 
11.4 Data Protection of Subjects...................................................................................... 100 
12 
STUDY MANAGEMENT ................................................................................................ 100 
12.1 Data Processing and Record Keeping ...................................................................... 100 
12.2 Source Data/File Access .......................................................................................... 100 
12.3 Protocol Revisions ................................................................................................... 101 
12.4 Responsibilities of the Investigator.......................................................................... 101 
12.5 Publishing Policy ..................................................................................................... 101 
12.6 Financing and Insurance .......................................................................................... 101 
13 
REFERENCES .................................................................................................................. 102 
14 
APPENDIX ........................................................................................................................ 104 
Appendix 1: Signature Page for Investigator ................................................................ 104 
Appendix 2: Performance Status Scoring Criteria (ECOG PS) ................................. 105 
Appendix 3: Calculation of Clearance of Creatinine and Body Surface Area .......... 106 
Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST), V1.1 
(Excerpts) .................................................................................................... 107 
Appendix 5: EORTC QLQ-C30 V3.0 ............................................................................ 117 


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List of Tables 
Table 1. Schedule of study visits .................................................................................................... 11 
Table 2. Schedule of visits during crossover treatment with IBI308 ............................................ 18 
Table 3. Effective contraceptive methods (at least 1 method must be used) ................................ 47 
Table 4. Study therapeutic drugs ................................................................................................... 49 
Table 5. Dose adjustment protocol for irAEs of IBI308 ............................................................... 53 
Table 6. Guidelines for management of IBI308 infusion-related reactions .................................. 54 
Table 7. Dose adjustments of chemotherapeutics ......................................................................... 56 
Table 8. Dose adjustments based on chemotherapy-related hematological toxicities  
in previous cycle ............................................................................................................. 56 
Table 9. Dose adjustments based on chemotherapy-related non-hematological toxicities in 
previous cycle ................................................................................................................. 57 
Table 10. Laboratory test .............................................................................................................. 75 
Table 11. Detailed rules for AE evaluation ................................................................................... 81 
Table 12. Liver injuries required to be reported as SAEs ............................................................. 87 
 


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List of Figures 
Figure 1. Schematic of study design ............................................................................................. 39 
 


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List of Abbreviations 
Abbreviation 
Full name (English) 
ADA 
Anti-drug antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
ALT 
Alanine Transaminase 
ALK 
Anaplastic Lymphoma Kinase 
AST 
Aspartate Amino Transferase 
BOR 
Best Overall Response 
 
 
CNS 
Central Nervous System 
CR  
CRA 
CRO 
Complete Response 
Clinical Research Associate  
Clinical Research Organization 
Cr 
CI 
Creatinine 
Confidence Interval 
CRF 
Ecrf 
CT 
Case Report Form 
Electronic Case Report Form 
Computed Tomography 
CTLA-4 
CTCAE 
 
Cytotoxic T Lymphocyte Antigen 4 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DLT 
Dose-Limiting Toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
EDC 
Eastern Cooperative Oncology Group 
Electronic Data Capture  
EGFR 
Epidermal Growth Factor Receptor 
EORTC 
QLQ 
EMA 
MedDRA 
MRI 
FDA 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
European Medicines Agency 
Medical Dictionary for Regulatory Activities 
Magnetic Resonance Imaging 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 


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Abbreviation 
Full name (English) 
HR 
Hazard Ratio 
ICF 
IDMC 
INR 
Informed Consent Form 
Independent Data Monitoring Committee 
International Normalized Ratio 
irAE 
Immune Related Adverse Event 
IRRC 
Independent Radiographic Review Committee 
irRESICT 
Immune-Related Response Evaluation Criteria in Solid Tumors 
LCSS 
Lung Cancer Symptom Scale 
MTD 
MDSC 
NAb 
Maximal Tolerated Dose 
Myeloid-Derived Suppressor Cells 
Neutralizing Antibody 
NSCLC 
NCI 
Non-Small Cell Lung Cancer 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Pharmacodynamics 
PD-1 
PD-L1 
Programmed Cell Death 1 
Programmed Cell Death Ligand 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR   
Partial Response  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D  
PT 
PT 
Recommended Phase II Dose  
Prothrombin Time 
Preferred Term 
SAE 
SAP 
Serious Adverse Event 
Statistics Analysis Plan 
SD 
SOC 
Stable Disease 
System Organ Classification 
TBIL 
Total Bilirubin 
TCR 
T-Cell Receptor 
ctDNA 
Circulating Tumor DNA 
TMB 
Tumor Mutation Burden 
TTR 
Time to Response 
UADR 
Unexpected Adverse Drug Reaction 
ULN 
VEGF 
Upper Limit of Normal 
Vascular Endothelial Growth Factor  
 


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1 BACKGROUND 
1.1 
Disease Background 
Cancer has been one of the leading causes of death worldwide, and China is also facing 
increasing challenges from the cancer. Among all cancer deaths, the leading death cause is lung 
cancer (25.2%), where non-small cell lung cancer (NSCLC) accounts for about 80–85%. About 70% 
of patients with NSCLC, at diagnosis, suffers from locally advanced or metastatic disease that is 
unresectable1. In addition, 30–60% of patients with stage I–III NSCLC undergoing radical 
surgery may eventually develop recurrence or distant metastasis2. 
In the past two decades, the advances of NSCLC drugs mainly focus on non-squamous NSCLC, 
including pemetrexed maintenance therapy3, anti-angiogenic anti-vascular endothelial growth 
factor (VEGF) monoclonal antibody (bevacizumab)4, and TKI drugs that drive the mutations of 
epidermal growth factor receptor (EGFR) gene or the rearrangement of anaplastic lymphoma 
kinase (ALK)5, 6. Squamous still accounts for about 30% of new cases, despite the annual decline 
of its proportion in NSCLC. The research and development of drugs for squamous has been 
stagnating due to the specific epidemiological, histopathological, and molecular characteristics 
thereof. Currently, the first-line regimen for patients with advanced squamous NSCLC is still 
platinum-based doublet chemotherapy (paclitaxel or gemcitabine in combination with platinum), 
which has a response rate (RR) of about 30%, a progression free survival (PFS) of about 5.5 
months, and an overall survival (OS) of about 10.8 months7, 8. Therefore new treatment models 
and drugs are urgently needed for advanced squamous NSCLC to improve the efficacy and 
survival. Recent years have experienced rapid advancement of studies on inhibiting immune 
checkpoints to activate the human immune system and enable the effect of attacking the tumor 
cells. The applying of immune checkpoint inhibitors (such as programmed cell death receptor 
1/ligand 1 (PD-1/PD-L1) antibody) provides a new clinical pathway for the treatment of NSCLC, 
especially for the first-line treatment of advanced or metastatic NSCLC9. At present, PD-1 
/PD-L1 monoclonal antibodies with marketing approval for advanced NSCLC mainly include 
nivolumab (trade name: OPDIVO®, from BMS), pembrolizumab (trade name: KEYTRUDA®, 
from MSD), atezolizumab (trade name: TECENTRIP®, from Roche) and durvalumab (trade 
name: IMFINZI®, from AstraZeneca) worldwide. 
Monotherapy of anti-PD-1 /PD-L1 monoclonal antibodies is more effective and safe than 
chemotherapy in the second-line treatment of advanced NSCLC. The CheckMate 017 study, a 
randomized, open, phase III clinical study, compared the efficacy and safety between nivolumab 
and docetaxel in advanced squamous NSCLC patients who failed platinum-based chemotherapy. 
The results showed OS of 9.2 and 6 months for nivolumab and docetaxel groups, respectively, 
death risk decrease of 41% (HR 0.59; P < 0.001) for nivolumab treatment, and a PFS of 


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nivolumab superior to that of docetaxel10. In addition, the incidence of adverse reactions of 
nivolumab treatment was significantly lower than that of docetaxel. Based on this study, 
nivolumab was approved for second-line treatment of advanced squamous NSCLC on Mar. 4, 
2015; and in Oct. 2015, CheckMate 057 study results made nivolumab approved for second-line 
treatment of advanced non-squamous NSCLC11. Moreover, KEYNOTE-010, a phase II/III 
clinical study, indicated that patients with PD-L1 positive advanced NSCLC experienced better 
OS benefits from second-line treatment with pembrolizumab compared with docetaxel. Based on 
the results of POPLAR study and OAK study, both of which were randomized controlled trials 
comparing atezolizumab and docetaxel in the treatment of second-line and above NSCLC, with 
OS of 12.6 vs. 9.7 months and 13.8 vs. 9.6 months, respectively, Roche's anti-PD-L1 antibody 
(atezolizumab) was approved by the Food and Drug Administration (FDA) for second-line 
treatment of NSCLC in 2016. 
The situation is the same for Chinese population that the efficacy and safety of anti-PD-1 
monoclonal antibodies in the second-line treatment of advanced NSCLC are better than 
chemotherapy. CheckMate 078 was a registered clinical study of nivolumab in China. This 
multicenter, randomized phase III trial compared the efficacy and safety of nivolumab and 
docetaxel in stage IIIb/IV NSCLC patients who experienced PD after platinum-based doublet 
chemotherapy. In the Checkmate 078 study, a total of 504 squamous and non-squamous NSCLC 
patients (451 from China, 45 from Russia, and 8 from Singapore) were enrolled, and then 
patients were randomized in a 2:1 ratio to receive nivolumab and docetaxel, respectively, until 
occurrence of PD or unacceptable toxicities. The primary end point was overall survival (OS). 
Compared with docetaxel, nivolumab significantly prolonged survival, with a hazard ratio (HR) 
of 0.68 (97.7% CI: 0.52–0.90; P = 0.0006); nivolumab also significantly prolonged PFS of 
patients; and compared with chemotherapy, nivolumab reduced the PD risk by 23% (HR = 0.77; 
95% CI: 0.62–0.95; P = 0.0147). For the secondary end point, nivolumab group had a 
significantly better ORR compared with the docetaxel group (17% vs. 4%). In the safety, the 
nivolumab was also superior to docetaxel. Subgroup analysis showed that OS benefits were 
observed in patients with different PD-L1 expression levels and tumor histological types. 
Compared with chemotherapy, the HR of OS was 0.61 (95% CI: 0.42–0.89) for squamous 
NSCLC patients and 0.76 (95% CI: 0.56–1.04) for non-squamous NSCLC patients, more 
significant benefit for squamous NSCLC patients. 
For advanced NSCLC patients with high expression of PD-L1, first-line monotherapy with 
anti-PD-1 monoclonal antibody is superior to platinum-based doublet chemotherapy. KEYNOTE 
024 was a phase III randomized controlled study to evaluate and compare the efficacy and safety 
of pembrolizumab with that of standard platinum-based chemotherapy in previously untreated 
patients with advanced NSCLC, who showed no EGFR or ALK variations but high PD-L1 


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expression (≥ 50% positive PD-L1 expression in tumor cells)12. In this study, a total of 305 
patients were enrolled and randomized in a 1:1 ratio to pembrolizumab group and 
platinum-based doublet chemotherapy group, respectively; the patients in the chemotherapy 
group can cross to the pembrolizumab group in case of PD. The primary endpoint was PFS. The 
study showed that, compared with chemotherapy, pembrolizumab prolonged PFS by nearly 4 
months (10.3 vs. 6.0 months, HR = 0.50, P < 0.001); the secondary endpoint OS was also 
significantly prolonged (HR = 0.60, P = 0.005); and compared with chemotherapy, 
pembrolizumab showed an overall RR of 45% (45% vs. 28%, P = 0.0011) and its safety was 
superior. Subgroup analysis showed that the HR of PFS for squamous cell carcinoma was 0.35 
(0.17–0.71) and for non-squamous cell carcinoma was 0.55 (0.39–0.76). In order to further 
expand the indication population, MSD conducted the KEYNOTE 042 study. KEYNOTE 042 
was a randomized, open-label phase III clinical trial and indicated that pembrolizumab was 
superior to standard platinum-based doublet chemotherapy for PD-L1 positive (TPS > 1%) and 
EGFR-/ALK-NSCLC (non-squamous or squamous) patients and could significantly prolonged 
the OS of patients. 
Anti-PD-1 monoclonal antibody and combination immunotherapy might be superior to the 
platinum-based doublet regimen in the first-line treatment of advanced NSCLC with high tumor 
mutation burden (TMB). Although CheckMate 026 indicated no advance of nivolumab in 
efficacy even for the patients with PD-L1 expression of > 50%, a retrospective study showed that 
nivolumab treatment was superior to chemotherapy in ORR (47% vs. 28%) and PFS (9.7 months 
vs. 5.8 months) in patients with high TMB expression13. The CheckMate 227 study showed that, 
compared with chemotherapy, nivolumab in combination with ipilimumab (anti-cytotoxic T 
lymphocyte antigen 4 (CTLA-4) monoclonal antibody) significantly improved PFS in advanced 
NSCLC patients who had high TMB expression (TMB ≥10 mut/mb, regardless of PD-L1 
expression) and showed equal benefit for squamous and non-squamous cell carcinoma14. 
For the entire advanced NSCLC population, PD-1 monoclonal antibody in combination with 
chemotherapy may also be superior to chemotherapy. Chemotherapy has traditionally been 
regarded as a treatment having immunosuppressive effect, but more and more basic and clinical 
studies have shown that some chemotherapeutics that induce DNA damage can promote immune 
effect15. Based on the results of KEYNOTE 021G study that pembrolizumab significantly 
improved ORR and prolonged PFS, on May 10, 2017, FDA accelerated the approval of 
pembrolizumab in combination with emetaxel and carboplatin for treatment of previously 
untreated patients with advanced NSCLC (non squamous) and without EGFR-sensitive 
mutations/ALK rearrangement. Subsequent KEYNOTE 189 further demonstrated its survival 
benefits16. KEYNOTE 189 was a randomized, double-blind, placebo-controlled phase III study 
to evaluate the efficacy of pembrolizumab in combination with pemetrexed and platinum-based 


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chemotherapy as the first-line treatment for patients with non-squamous NSCLC (without 
EGFR-sensitive mutations/ALK rearrangement). A total of 614 patients were randomized in a 
2:1 ratio to receive pembrolizumab in combination with pemetrexed and cisplatin/carboplatin as 
well as placebo in combination with pemetrexed and cisplatin/carboplatin, followed by 
pembrolizumab or placebo in combination with pemetrexed maintenance, respectively. The OS 
(HR 0.49, P < 0.00001) and PFS (HR 0.52, P < 0.00001) were significantly improved in the 
pembrolizumab group compared with the placebo group. Patients in the pembrolizumab group 
had not yet achieved median OS, compared with 11.3 months for the placebo group, with median 
PFS of 8.8 and 4.9 months, respectively. Subgroup analysis showed that subgroups with different 
PD-L1 expression levels could benefit from pembrolizumab treatment. The ORR of the 
pembrolizumab and placebo groups was 47.6% and 18.9% (P<0.00001), respectively, and the 
safety was comparable16. The KEYNOTE 407 study evaluated the efficacy of pembrolizumab in 
combination with carboplatin and paclitaxel/albumin paclitaxel as the first-line treatment of 
metastatic squamous NSCLC compared with carboplatin and paclitaxel/albumin paclitaxel. The 
first interim analysis achieved the pre-determined secondary end point of ORR (58.4% vs. 
35.0%, P = 0.0004), and the second interim analysis achieved the primary study end point of PFS 
(6.4 vs. 4.8 months, HR 0.56, P < 0.0001) and OS (15.9 vs. 11.3 months, HR 0.64, P < 0.0008). 
Currently, the first-line chemotherapy regimen for patients with advanced squamous NSCLC is 
still doublet regiment of taxol or gemcitabine in combination with platinum (cisplatin or 
carboplatin), while anti-PD-1 monoclonal antibody in combination with gemcitabine and 
platinum-based regimen may be one of the preferred regimens. Nonclinical studies have shown 
that gemcitabine can eliminate immunosuppressive cells such as myeloid-derived suppressor 
cells (MDSCs)17, and platinum-based drugs can induce immunogenic tumor cell death18. Phase 
Ib clinical studies have shown that nivolumab in combination with gemcitabine and cisplatin as 
the first-line treatment of NSCLC has a RR of 50%. InnoventBio CIBI308A101 phase Ib cohort 
E studied the safety and preliminary efficacy of IBI308 in combination with gemcitabine and 
cisplatin chemotherapy used as first-line treatment for advanced squamous cell NSCLC, and as 
of Jun. 11, 2018, 16 subjects had completed at least one efficacy evaluation, of which 10 had 
achieved partial response (PR), 6 had stable disease (SD), indicating a RR of 62.5%, a disease 
control rate (DCR) of 100%, and the grade ≥ 3 TRAEs of 36.4% and thus showing good efficacy 
and safety. 
Based on the above clinical study results, squamous NSCLC may be the benefit population of 
immunotherapy, and PD-1 monoclonal antibody has a definite efficacy in advanced squamous 
NSCLC patients; the toxicity of first-line treatment in combination with platinum-based 
chemotherapy was controllable and combination therapy may be synergistic in improving 
efficacy. Patients with low expression of PD-L1 can also benefit from the combination therapy 


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of PD-1 monoclonal antibody and platinum-based chemotherapy, and therefore relevant studies 
in Chinese patients with advanced squamous NSCLC should be encouraged, so as to fill the gap 
in the first-line treatment of immunoantitumor therapy for lung squamous carcinoma patients in 
China as soon as possible. 
1.2 
IBI308 
1.2.1 Mechanism of action 
Tumor treatment via immune checkpoints has been a research hotspot in recent years, and 
tremendous breakthroughs have been made in this field. Unlike cytotoxic drugs, monoclonal 
antibodies or small molecule tyrosine kinase inhibitors that target oncogenes, immune 
checkpoint therapy of tumors does not directly target tumor cells, but rather improve the function 
of T cells, remove the tolerance of the immune system to tumor cells, and improve the effective 
recognition and killing of tumor cells by T cells via blocking the inhibitory signals against T cell 
proliferation and activation. Currently, the immune checkpoint targets showing significant 
clinical efficacy in tumor treatment include CTLA-4 and PD-1/PD-L119. 
So far, five PD-1/PD-L1 monoclonal antibody products have been approved by FDA for 
marketing, including nivolumab (tread name: OPDIVO®, from BMS), pembrolizumab 
(KEYTRUDA®, from MSD), atezolizumab (trade name: TECENTRIP®, from Roche), avelumab 
(BAVENCIO®, from Pfizer/Merck Drugs & Biotechnology), and durvalumab (trade name: 
IMFINZI®, from AstraZeneca); indications include advanced melanoma, advanced NSCLC, 
advanced classic Hodgkin's lymphoma, advanced renal cell renal carcinoma, advanced urothelial 
carcinoma, advanced head and neck tumors, etc20. In addition, many indications have been under 
phase III clinical studies or have been submitted for approval. The marketing of the above drugs 
confirms the important role of PD-1 /PD-L1 antibody drugs in tumor immunotherapy. 
Sintilimab (R&D code: IBI308) is a recombinant fully human IgG4 PD-1 monoclonal antibody. 
Multiple nonclinical in vitro and in vivo trials have shown the blockade function of IBI308 of the 
PD-1 pathway, and completed nonclinical studies on pharmacodynamics, animal PK and 
toxicology indicated that IBI308 was characterized by clear targets, reliable source of cell lines, 
and good stability and activity. Refer to "Investigator's Brochure" for detailed study results. 
1.2.2 Phase Ia clinical results of IBI308 
A phase Ia dose-escalation trial of IBI308 was initiated in Sep. 2016 (study code CIBI308A101 
1a). Subjects with advanced solid tumors who had failed standard treatment was enrolled in 
phase Ia and the dose escalation decision followed the standard "3 + 3" design to evaluate 4 dose 
levels (1 mg/kg, 3 mg/kg, 200 mg and 10 mg/kg) of IBI308. After the completion of 1 mg/kg 
dose administration, subjects were randomized in a 1:1 ratio to either 3 mg/kg or 200 mg group 


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for independent evaluations. DLT is observed for 28 days after the first dose for each dose group. 
After completion of DLT observation, subjects are treated with IBI308 Q2W (1 mg/kg, 3 mg/kg, 
or 10 mg/kg) or Q3W (200 mg) until PD, intolerable toxicity, withdrawal of ICF, or other 
reasons requiring treatment discontinuation (whichever occurs first). 
PK studies of patients with advanced solid tumors in phase Ia showed that the serum drug 
concentration of IBI308 (administered by intravenous infusion) gradually increased after the start 
of infusion, reached Cmax after the end of infusion, and then slowly decreased. Within the dose 
range of 1–10 mg/kg, the IBI308 exposure in vivo had a dose-proportional increase, suggesting 
linear kinetic characteristics. In subjects with solid tumors, after the single dose of IBI308, the 
elimination half-life (Geo.Mean (CV%)) was 14.4 (28.9%) days, the clearance rate was 11.5 
(42.5%) mL/h, the steady-state distribution volume was 5.43 (34.4%) L, and apparent 
distribution volume was 5.77 (33.2%) L, showing comparable PK characteristics to similar 
marketed anti-PD-1 antibodies (nivolumab, pembrolizumab). 
In a phase Ia pharmacodynamic study of patients with advanced solid tumors, single dose of 
IBI308 at 1 mg/kg (N = 3) could achieve rapid (24 h) saturation (mean ≥ 95%) of the PD-1 
receptors on the surface of peripheral CD3T cells of solid tumor subjects and could maintain the 
occupancy level during the study period (28 days) of continuously reducing drug concentrations 
and in a therapy of multiple doses that were given consecutively. The dose groups of 3 mg/kg (N 
= 3), 200 mg (N = 3), and 10 mg/kg (N = 3) showed comparable results of PD-1 occupancy to 
the 1 mg/kg, suggesting no dose and concentration dependences within the range of 1–10 mg/kg 
for PD-1 receptor occupancy. IBI308 also showed good anti-tumor activity in subjects with 
multiple advanced solid tumors who had failed standard treatment. The evaluation as per 
RECIST V1.1 showed the best overall efficacy that 2 subjects achieved PR and 2 achieved SD, 
and the evaluation as per irRECIST showed that 2 subjects achieved irPR and 3 achieved irSD. 
A new subject (01002) with hepatocellular carcinoma who received failed treatment with 
sorafenib achieved irSD. The subject had been receiving IBI308 treatment after PD, and the 
tumor burden had continued to decrease compared with that at PD. After 3 cycles of continuous 
treatment, the subject was evaluated as irSD according to irRECIST. As of Oct. 30, 2017, the 
subject was still receiving IBI308 treatment. Subjects receiving tumor immunotherapy may 
experience tumor pseudoprogression, which is significantly different from the efficacy 
characteristics of traditional chemotherapy. One of the 12 subjects receiving IBI308 treatment 
was observed increased and then decreased tumor burden. In clinical trials after IBI308 study, 
the efficacy criteria for immune solid tumors have been referenced to further explore the trend of 
changes in tumor pseudoprogression. As of Oct. 30, 2017, deaths (due to PD) were observed in a 
total of 3 subjects during follow-up visits. 


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1.2.3 Phase Ib study results of IBI308 in first-line patients with squamous NSCLC 
CIBI308A101 phase Ib cohort E mainly enrolled patients with advanced, recurrent, or metastatic 
squamous NSCLC who had not received previous systematic anticancer therapy. The patients 
were treated with IBI308 in combination with gemcitabine and cisplatin, and as of Jun. 11, 2018, 
16 subjects completed at least one efficacy evaluation, of which 10 achieved PR, 6 achieved SD, 
indicating a RR of 62.5%, DCR of 100%, grade ≥3 TRAE of 36.4% and thus showing good 
efficacy and safety. 
1.3 
Risk/Benefit Assessment 
Considering the mechanism of action of IBI308 and the clinical safety information of drugs with 
similar mechanism, the AEs during this clinical trial will possibly be immune-mediated 
inflammatory resulted from the activation of immune system, e.g. pneumonia, thyroiditis, 
hepatitis, dermatitis/skin lesions, etc. According to the available clinical data, anti-PD-1 
monoclonal antibodies are well-tolerated despite of high incidence of adverse reactions. 
Treatment discontinuation due to adverse reactions only occur in a small number of subjects, and 
most events resolve after appropriate interventions. Early symptoms of immune related adverse 
events (irAEs) vary. Therefore, investigators must closely monitor early signs and symptoms of 
irAEs during the trial, make correct judgments timely, adjust the dose according to Section 5.2.2 
in the protocol, and provide effective treatment measures to reduce risks to subjects. Besides, 
subjects with autoimmune diseases shall be excluded from the trial to avoid exacerbation of the 
original disease due to the activation of immune system. 
Gemcitabine in combination with platinum is the current standard chemotherapy regimen for 
first-line treatment of patients with advanced squamous NSCLC in China. This study will apply 
IBI308 or not on the basis of this regimen to the first-line treatment of patients with advanced 
squamous NSCLC. Therefore, this study will provide patients with standard effective first-line 
chemotherapy to ensure the clinical benefit of patients. Phase Ia and Ib clinical data of IBI308 
suggested that IBI308 had definite pharmacological activity and good tolerability in patients with 
advanced tumors, and preliminarily showed ideal anti-tumor activity in previously untreated 
patients with advanced squamous NSCLC. We intended to conduct further large-scale 
multicenter, randomized, phase III clinical studies in patients with advanced, recurrent, or 
metastatic squamous NSCLC who have not received previous systematic anticancer therapy, so 
as to clarify the efficacy and safety of IBI308 in combination with standard chemotherapy in 
such population and to provide a data basis for relevant indications for marketing. 


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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
Based on RECIST V1.1, to compare the PFS of IBI308 in combination with gemcitabine and 
platinum-based chemotherapy with that of placebo in combination with gemcitabine and 
platinum-based chemotherapy in the first-line treatment of patients with advanced or metastatic 
squamous NSCLC. 
2.2 
Secondary Objectives 
 
To compare the OS of the subjects between the two groups; 
 
Based on RECIST V1.1, to compare the ORR of the subjects between the two groups; 
 
Based on RECIST V1.1, to compare the DCR of the subjects between the two groups; 
 
Based on RECIST V1.1, to compare the TTR of the subjects between the two groups; 
 
Based on RECIST V1.1, to compare the DOR of the subjects between the two groups; 
 
To evaluate the safety and tolerability characteristics of IBI308 in combination with 
gemcitabine and platinum-based chemotherapy. 
2.3 
Exploratory Objectives 
 
To explore potential biomarkers in tumor tissues that can predict the efficacy of IBI308: 
including but not limited to immunohistochemistry assay of PD-L1 expression and 
RNA assay in tumor specimens; 
 
To explore potential biomarkers in peripheral blood that can predict the efficacy of 
IBI308 group, including but not limited to TCR and ctDNA assay; 
 
To compare the quality of life of patients treated with IBI308 in combination with 
chemotherapy vs. placebo in combination with chemotherapy by using LCSS and 
EORTC QLQ-C30 questionnaires; 
 
To explore the PFS of subjects in the control group after crossover treatment with 
IBI308; 
 
To explore the population PK characteristics of IBI308. 


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3 
Study design 
3.1 
Overall Design 
This study is a multicenter, randomized, double-blind, phase III study to compare the efficacy 
and safety of IBI308 in combination with gemcitabine and platinum-based (cisplatin/carboplatin) 
chemotherapy vs. placebo in combination with gemcitabine and platinum-based 
(cisplatin/carboplatin) chemotherapy in first-line treatment of previously untreated Chinese 
subjects with advanced or metastatic squamous NSCLC. 
In this study, a total of 348 previously untreated subjects with advanced or metastatic squamous 
cell NSCLC will be randomized in a 1:1 ratio to the test group and the control group, 174 cases 
in the test group and 174 cases in the control group (in the actual study, if the actual number of 
enrolled subjects is different from the number of planned enrollment due to unforeseen reasons, 
such as the enrollment speed is faster than the requirements of the protocol, the end date of 
screening should be determined in advance to ensure that the number of actually enrolled 
subjects does not exceed the number of planned enrollment by 10%, i.e., a maximum of 382 
subjects shall be enrolled, 191 in each group). Randomization stratification factors include 
staging (stage IIIB/IIIC vs. stage IV), platinum-based medications (cisplatin vs. carboplatin), and 
PD-L1 expression level (< 1% vs. ≥ 1%). In this study, the parallel control is placebo in 
combination with gemcitabine and platinum-based (cisplatin/carboplatin) chemotherapy and the 
test group will receive IBI308 in combination with gemcitabine and platinum-based 
(cisplatin/carboplatin) treatment. Both groups will receive the corresponding treatment for 4 or 6 
cycles, followed by IBI308 or placebo maintenance therapy, respectively. 
The primary objective of the study is to compare the PFS of IBI308 in combination with 
gemcitabine and platinum-based (cisplatin/carboplatin) chemotherapy with that of placebo in 
combination with gemcitabine and platinum-based (cisplatin/carboplatin) chemotherapy in the 
first-line treatment of patients with advanced or metastatic squamous NSCLC by Independent 
Imaging Review Board (IRRC) based on RECIST V1.1. Tumor imaging evaluation will be 
performed at week 6 (± 7 days) and week 12 (± 7 days) since randomization, every 9 weeks (± 7 
days) thereafter until week 48, and every 12 weeks (± 7 days) after week 48.  
After the first assessment of imaging PD by the investigator based on RECIST V1.1, if the 
subject has SD clinically, the current treatment can be continued and the imaging evaluation 
should be performed again 4–6 weeks later for confirmation (based on RECIST V1.1). If PD is 
confirmed, unblinding should be performed and subjects of IBI308 in combination with 
chemotherapy group (test group) should end the study treatment, while subjects of placebo in 
combination with chemotherapy group (control group) can be conditionally crossed to 
monotherapy of IBI308 based on the judgment of the investigator and the willingness of the 


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subjects, until PD, toxicity intolerability, receiving new anti-tumor therapy, withdrawal of ICF, 
loss of follow-up or death, or other reasons requiring termination of study treatment, whichever 
occurs first; if PD is not confirmed, the study treatment will be continued until 
imaging-confirmed PD followed by unblinding and other subsequent processing same as above. 
If the subject has clinically unstable disease (refer to Section 7.1.3) after the first assessment of 
imaging PD, the confirmation 4–6 weeks later is not required and unblinding can be directly 
performed followed by processing same as above. During the study, the treatment should be 
discontinued if one of the following occurs: clinically unstable disease, intolerable toxicity, 
receipt of new anti-tumor therapy, withdrawal of ICF, loss to follow-up, death, or other 
conditions requiring treatment discontinuation as judged by the investigator, whichever occurs 
first. The maximum duration of treatment with IBI308 is 24 months in both groups. 
During the study, subjects should receive continual treatment until objective PD, intolerable 
toxicity, withdrawal of ICF, loss of follow-up or death, withdrawal of the subjects from the trial 
based on the decision of the investigator or the sponsor, pregnancy of the subjects, poor 
compliance to the study, management-related reasons, or receiving the study drug for up to 24 
months. For patients who discontinue the treatment for reasons other than PD, an imaging 
evaluation should be performed at the end of treatment, and during follow-up the imaging 
evaluation should be performed according to imaging examination scheduled time points 
specified in the protocol until one of the following events occurs: start of new anti-tumor 
therapy, objective PD, loss of follow-up or death, withdrawal of ICF by the subjects, whichever 
occurs first. 
The investigator will monitor potential AEs throughout the trial and grade the severity level of 
AEs according to the National Cancer Institute (NCI) General Term Standard for Adverse Events 
(CTCAE) Guidelines, V4.03. After the end of treatment, a 30-day safety follow-up will be 
conducted for subjects to monitor AE. If the patient does not receive new anti-tumor therapy 
within 90 days after the last dose, serious adverse events (SAE) within 90 days after the last dose 
will be collected; and if the subject has started a new anticancer therapy, SAE before the new 
anticancer therapy will be collected, whichever occurs first. 
This study will be conducted in accordance with the Good Clinical Practice (GCP). 


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Figure 1. Schematic of study design 
 
Notes: In the actual study, if the actual number of enrolled subjects is different from the number of planned 
enrollment due to unforeseen reasons, such as the enrollment speed is faster than the requirements of the protocol, 
the end date of screening should be determined in advance to ensure that the number of actually enrolled subjects 
does not exceed the number of planned enrollment by 10%, i.e., a maximum of 382 subjects shall be enrolled, 191 in 
each group. 
3.1.1 Trial blinding 
IBI308 and placebo will be in the same packages to ensure blindness. The subjects, investigators, 
and sponsor staff or designee participating in the treatment or clinical evaluation of the subjects 
should be unknown about the grouping. 
Refer to section 6.4.3 for a description of the unblinding method for subjects during the trial (if 
required). 
3.1.2 Sample size estimation 
IBI308 is expected to prolong PFS of subjects from 5.5 months to 7.9 months (HR = 0.7), and 
with the enrollment time of 15 months, the total study time of 23 months, power of 82%, 
one-sided α = 0.025 and considering a monthly dropout rate of 0.5%, a total of 348 subjects (174 
in the test group and 174 in the control group) are needed to be randomized to achieve the 264 
PFS events required in the trial. In the actual study, if the actual number of enrolled subjects is 
different from the number of planned enrollment due to unforeseen reasons, such as the 
enrollment speed is faster than the requirements of the protocol, the end date of screening should 
be determined in advance to ensure that the number of actually enrolled subjects does not exceed 
Treatment-naive patients 
with advanced or 
metastatic squamous 
non-small cell lung cancer, 
ECOG PS 0–1, with at 
least one measurable lesion 
(RECIST V1.1) 
Randomization  
in a 1:1 ratio, 
double-blind  
(N = 348) 
IBI308 200mg d1/q3w 
Gemcitabine, 1 g/m2 d1, 8/q3w 
Cisplatin, 75 mg/m2 d1/q3w 
or carboplatin, AUC 5 d1/q3w 
Combination treatment for 4 or 
6 cycles, followed by 
maintenance treatment with 
IBI308 
Placebo, d1/q3w 
Gemcitabine, 1 g/m2 d1, 8/q3w 
Cisplatin, 75 mg/m2 d1/q3w 
or carboplatin, AUC 5 d1/q3w 
Combination treatment for 4 or 
6 cycles, followed by 
maintenance treatment with 
placebo 
(Optional) 
Follow-up 
visit 


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the number of planned enrollment by 10%, i.e., a maximum of 382 subjects shall be enrolled, 
191 in each group. 
An interim analysis will be performed in this study when 70% of PFS events (i.e., 185 PFS 
events) occur. Superiority in efficacy of the test group over the control group will be determined 
using Lan-deMets spending function and O'Brien-Fleming boundary in the interim analysis. 
One-sided P value for the interim analysis is 0.0074. If the actual interim analysis time point in 
the study differs from the planned (185 PFS events), the P value for the interim analysis should 
be adjusted according to the Lan-deMets spending function and O'Brien-Fleming. 
In the interim analysis, with one-sided α = 0.0074, if HR ≤ 0.698 is observed for the test group of 
IBI308 in combination with gemcitabine and cisplatin or carboplatin chemotherapy vs. the 
control group of placebo in combination with gemcitabine and cisplatin or carboplatin 
chemotherapy, it is demonstrated that the superiority has been concluded in the interim analysis. 
For the secondary endpoint OS, no formal sample size calculation will be made, and the analysis 
is expected to be performed 1 year after the last subject is enrolled. 
This study is expected to be conducted in 30–40 sites of China. 
3.1.3 Study randomization 
The randomization method of this study is as follows: Subjects are randomized in a 1:1 ratio to 
the test group and the control group, receiving IBI308 in combination with chemotherapy and 
placebo in combination with chemotherapy, respectively. The central randomization method is 
adopted with competitive enrollment for each center. The central randomization procedure will 
use an interactive web response system (IWRS), which can generate and dispense a random 
number to subjects who have completed all of the screening assessment items of the study and 
meet the inclusion criteria. The random number will connect the subjects into a designed 
treatment group (IBI308 in combination with chemotherapy group or placebo in combination 
with chemotherapy group) and can assign investigational drugs to subjects as per required 
quantity. For subjects withdrew from the study, whatever the reason of withdrawal, their random 
numbers will be retained. IWRS staff will only write randomized table and will not be involved 
in any specific trial operation. The assigned study drug must be administered within 48 hours of 
randomization. 
In this trial, the settings of IWRS will be used to fulfill the following requirements in the 
randomly enrolled patients: patients with PD-L1 expression of < 1% do not exceed 35% of the 
total randomization population; patients with PD-L1 expression of ≥ 1% are not less than 65% of 
the total random population. 


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3.1.4 Stratification 
The stratification of randomization is based on the following factors: 
• 
Staging (stage IIIB/IIIC vs. stage IV) 
• Platinum-based medications (cisplatin vs. carboplatin) 
• The expression level of PD-L1 (< 1% vs. ≥ 1%), the patients whose expression level of 
PD-L1 cannot be evaluated are classified into the < 1% group. 
3.2 
Design Principles 
3.2.1 Basis for selection of randomized double-blind study design 
This study intends to adopt a randomized double-blind design, where blinding can reduce bias 
due to human error, make the study results more reliable, and improve the compliance of 
subjects. 
3.2.2 Basis for selection of IBI308 administration regimen and dosage 
According to current national and international guidelines, platinum-based doublet chemotherapy 
is still the standard first-line treatment for advanced squamous NSCLC population. The 
KEYNOTE 407 study evaluated the efficacy of pembrolizumab in combination with carboplatin 
and paclitaxel/albumin paclitaxel compared with carboplatin and paclitaxel/albumin paclitaxel 
first-line treatment for metastatic squamous NSCLC. The interim analysis reached the primary 
study end points of PFS and OS. IBI308 is an anti-PD-1 monoclonal antibody, and multiple 
immune-functioning mouse models has demonstrated the anti-tumor activity of monotherapy of 
IBI308 (see the Investigator's Brochure). In the phase Ia clinical study of IBI308 (CIBI308A101 
Ia/b), pharmacodynamic results showed that IBI308 had a definite blocking effect on PD-1 
receptor in the body, and satisfactory efficacy was achieved after treatment of IBI308 in 
combination with gemcitabine and cisplatin in the phase Ib cohort E first-line previously 
untreated population with advanced squamous NSCLC. Therefore, this trail will study the 
efficacy and safety of IBI308 in combination with gemcitabine and platinum 
(cisplatin/carboplatin) chemotherapy and placebo in combination with gemcitabine and platinum 
(cisplatin/carboplatin) chemotherapy in first-line treatment in previously untreated population 
with advanced or metastatic squamous NSCLC. 
In this study, IBI308 is intended to be administered at a dosage of 200 mg Q3W. The selection of 
this administration method is mainly based on the safety and exposure (concentration)-response 
(PD-1 receptor occupancy) relationship data currently completed in the previous study, 
combined with the nonclinical in vitro/in vivo pharmacodynamic data and relevant comparison 


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data to similar drugs. Under the premise that no significant variation occurs in drug clearance 
characteristics of subjects, IBI308 of 200 mg Q3W is administered continuously for 84 days (4 
times) can achieve steady state with steady trough concentration of about 26 μg/mL and can 
maintain peripheral and target PD-1 receptor occupancy. 
3.2.3 Basis for selection of PFS as primary study end point 
For a novel anti-tumor therapy, PFS is a widely accepted indicator of clinical efficacy in 
randomized phase III clinical studies and is able to demonstrate satisfactory risk-benefit 
characteristics of new therapies. In recent years, the FDA and the European Medicines Agency 
(EMA) have also identified it as one of the most important registration end points for clinical 
studies on NSCLC. PFS can be assessed by IRRC according to RECIST V1.1, thereby 
minimizing bias as much as possible. Therefore, PFS is intended to serve as primary study end 
point of this study. 
3.2.4 Basis of allowing the control group to cross to IBI308 after progressive disease 
Multiple studies have demonstrated the efficacy of anti-PD-1 monoclonal antibody in NSCLC 
patients who have failed first-line platinum-based chemotherapy, and the benefit and good 
tolerability in the NSCLC patients who have failed first-line platinum-based chemotherapy after 
subsequently receiving IBI308 monotherapy have also been demonstrated in the CIBI308A101 
Ib cohort E (result has not yet been formally published). Based on the above results, subjects in 
the control group are allowed to cross to the treatment with IBI308 monotherapy after imaging 
PD based on the judgment of the investigator. 
3.3 
Independent Data Monitoring Committee (IDMC) 
An independent data monitoring committee (IDMC) is set up to conduct an interim analysis of 
the primary efficacy endpoint (PFS) and safety. The personnel composition, responsibilities, and 
procedures of the IDMC are detailed in the IDMC regulations. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Subjects shall meet the following criteria: 
1) Subjects must sign written ICF prior to the implementation of any procedures related to the 
trial; 
2) Aged ≥ 18 years and ≤ 75 years; 
3) With a life expectancy of more than 3 months; 


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4) With at least one measurable lesion confirmed by the investigator according to RECIST 
V1.1. Measurable lesions located in the radiation field of previous radiotherapy or subjected 
to locoregional therapy can be selected as target lesions if PD is confirmed; 
5) Patients with histologically or cytologically confirmed locally advanced (stage IIIB/IIIC), 
metastatic or recurrent (stage IV) squamous NSCLC who cannot receive surgery or radical 
concurrent chemoradiotherapy, based on the "8th Edition of the TNM Classification for 
Lung Cancer" issued by the International Association for the Study of Lung Cancer and the 
American Joint Committee on Cancer Classification; 
6) With an Eastern Cooperative Oncology Group Performance Status score (ECOG PS score) 
of 0 or 1; 
7) Have not received any prior systemic anti-tumor therapy for advanced/metastatic disease; for 
patients who have received prior platinum-based adjuvant chemotherapy/radiotherapy, 
neoadjuvant chemotherapy/radiotherapy, or radical chemoradiotherapy for PD, they are 
eligible for the study if PD occurs at > 6 months after the last treatment; 
8) With adequate hematologic function, defined as ANC ≥ 1.5 × 109 /L, platelet count ≥ 100 × 
109 /L, and hemoglobin ≥ 90 g/L (no blood transfusion history within 7 days); 
9) Adequate hepatic function, defined as total bilirubin (TBIL) ≤ 1.5 × upper limit of normal 
(ULN) and AST as well as ALT ≤ 2.5 × ULN for all patients, or AST and ALT ≤ 5 × ULN 
for patients with liver metastasis; 
10) Adequate renal function, defined as clearance of creatinine (CCr) ≥ 50 mL/min 
(Cockcroft-Gault formula);  
11) Adequate coagulation function, defined as international normalized ratio (INR) or 
prothrombin time (PT) ≤ 1.5 × ULN; for the subject who is receiving anticoagulant therapy, 
INR or PT within the proposed scope of the anticoagulant medication is acceptable; 
12) Female subjects of childbearing age should be tested negative for urine or serum pregnancy 
within 3 days before the first dose of the study drugs. A blood pregnancy test is required if 
the urine pregnancy test is inconclusive; 
13) For male and female patients at risk of conception, highly effective contraception measures 
(failure rate < 1% per year) should be taken until at least 180 days after discontinuation of 
the study treatment; 
Note: Abstinence is acceptable as a method of contraception if it is the usual lifestyle and 
preferred method of contraception for the subject. 


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4.2 
Exclusion criteria 
Subjects cannot be enrolled if any of the followings is met: 
1) Non-squamous NSCLC in histology. The dominant cell morphology must be identified for 
mixed cell type (patients with squamous cell carcinoma components > 50% can be enrolled); 
patients with small cell carcinoma, neuroendocrine carcinoma, and sarcoma components 
cannot be included; 
2) Patients with known EGFR-sensitive mutations or ALK rearrangement; 
3) Currently participating in an interventional clinical study, or treated with another study drug 
or investigational device within 4 weeks before the first dose; 
4) Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 agents or 
agents targeting another stimulation or synergistically inhibiting T-cell receptor (TCR) (e.g., 
CTLA-4, OX-40, and CD137); 
5) Received proprietary Chinese medicines with anti-tumor indications or immunomodulators 
(thymosin, interferon, interleukin, etc.) within 2 weeks prior to the first dose, or received a 
major surgery within 3 weeks prior to the first dose; 
6) With active hemoptysis, active diverticulitis, abdominal abscess, gastrointestinal obstruction, 
and peritoneal metastases requiring clinical intervention; 
7) Have undergone solid organ transplantation or hematologic transplantation; 
8) With clinically uncontrolled pleural effusion/ascites (patients who do not need effusion 
drainage or have no significant increase in effusion 3 days after stopping drainage can be 
enrolled); 
9) With a tumor compressing the surrounding important organs (such as esophagus) with 
relevant symptoms, compressing the superior vena cava, or invading the mediastinal great 
vessels, heart, etc.; 
10) With Class III–IV congestive cardiac failure (based on New York Heart Association 
Classification) or poorly controlled and clinically significant arrhythmia; 
11) With any arterial thrombosis, embolism, or ischemia within 6 months prior to enrollment, 
such as myocardial infarction, unstable angina, cerebrovascular accident, and transient 
ischemic attack. With a history of deep venous thrombosis, pulmonary embolism, or any 
other serious thromboembolic events within 3 months prior to enrollment (implantable port 
or catheter-related thrombosis, or superficial venous thrombosis is not considered as 
"serious" thromboembolism); 


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12) With known allergy to the active ingredients and/or any excipient of IBI308, gemcitabine, 
cisplatin, or carboplatin; 
13) With active autoimmune disease requiring systemic treatment (e.g., use of disease-modifying 
drugs, corticosteroids, or immunosuppressive agents) within 2 years before the first dose. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic doses of corticosteroids for 
adrenal or pituitary insufficiency) is not considered systemic; 
14) Patients requiring long-term systemic use of corticosteroids. Patients requiring intermittent 
use of bronchodilators, inhaled corticosteroids, or local injection of corticosteroids for 
COPD or asthma can be included in the study; 
15) Full recovery (i.e., ≤ grade 1 or reaching the baseline, excluding asthenia or alopecia) from 
toxicity and/or complications caused by any intervention has not achieved before the start of 
treatment; 
16) Diagnosed with other malignant tumors within 5 years before the first dose, excluding 
radically cured cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and/or 
radically resected carcinoma in situ. For other malignant tumors or lung cancer diagnosed 
more than 5 years before the first dose, pathological or cytological diagnosis should be 
performed for recurrent and metastatic lesions; 
17) Symptomatic central nervous system (CNS) metastasis. Patients with asymptomatic brain 
metastases or with stable symptoms after treatment of brain metastases are allowed to 
participate in this study as long as meeting all of the following criteria: presence of 
measurable lesions outside the CNS; absence of metastases in midbrain, pons, cerebellum, 
meninges, medulla oblongata, or spinal cord; maintain clinical stable condition for at least 2 
weeks; discontinue hormone therapy 14 days prior to the first dose of the study drugs; 
18) With a history of non-infectious pneumonia requiring corticosteroid therapy within 1 year 
prior to the first dose or with non-infectious pneumonia at present; 
19) With an active infection requiring treatment or have used systemic anti-infective drugs 
within one week prior to the first dose; 
20) With known psychiatric disorder or substance abuse that could affect the compliance with 
trial requirements; 
21) Known history of human immunodeficiency virus (HIV) infection (i.e. HIV 1/2 antibody 
positive), known syphilis infection (syphilis antibody positive), or active tuberculosis; 
22) With untreated active hepatitis B; 


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Note: Subjects with hepatitis B who meet the following criteria are also eligible for 
inclusion: 
HBV viral load must be less than 1000 copies/mL (200 IU/mL) or below the lower limit of 
detection (LLD) prior to the first dose, and subjects should receive anti-HBV treatment to 
avoid virus reactivation throughout the chemotherapeutic period of the study; 
For subjects with HBcAb (+), HBsAg (−), HBsAb (−), and HBV load (−), close monitoring 
is required instead of prophylactic anti-HBV treatment to avoid virus reactivation; 
23) Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the 
LLD); 
24) Have received live vaccines within 30 days prior to the first dose; 
Note: Seasonal inactivated influenza virus vaccines for injection are allowed, while live 
attenuated influenza vaccines for intranasal use are not acceptable; 
25) With any medical history, disease, treatment, or laboratory abnormal finding that would 
interfere with the trial results or prevent the subject from participating in the whole trial, or 
the investigator believes that participation in this study is not in the best interest of the 
subject; 
26) With local or systemic diseases not attributable to malignancy, or with cancer-related 
secondary diseases, which would result in a high medical risk and/or uncertainty in survival 
evaluation. 
4.3 
Restrictions During the Study 
4.3.1 Pregnancy 
Since it is known that human IgG1 and IgG4 are able to penetrate the placental barrier, 
administration during pregnancy is not recommended. Pregnant women are not allowed to be 
included in this study. 
4.3.2 Childbearing age 
For female subjects of childbearing age who are sexually active with male partners who have 
not undergone sterilization, and male subjects who have not undergone sterilization and are 
sexually active with female partners of childbearing age, such subjects and their partners must 
use one of the acceptable methods of contraception listed in Table 3 from screening to 180 
days after the last dose of study treatment, and then discuss with a responsible physician about 
the discontinuation of contraception after this time point. Periodic abstinence, calendar-based 
method, and withdrawal method are not the acceptable forms of contraception. Women of 


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childbearing age is defined as females who have experienced menarche, have not undergone 
surgical sterilization (bilateral tubal ligation, bilateral salpingectomy, or panhysterectomy), and 
are not postmenopausal. 
Table 3. Effective contraceptive methods (at least 1 method must be used) 
Barrier methods 
Intrauterine Devices (IUDs) 
Hormonal Methods 
Male condom with spermicide 
Copper-T IUD 
Implant 
Cervical cap with spermicide 
Progesterone-T IUDa 
Hormonal injection 
Diaphragm with spermicide 
Levonorgestrel-releasing intrauterine 
system (e.g. Mirena®)a 
Combined oral contraceptive pill 
Low-dose oral contraceptive pill 
Contraceptive patch 
a Also considered as a hormonal method. 
Menopause is defined as 12 months of amenorrhea of a woman without any other medical 
reasons. Age requirements are as follows: 
 
Females ≥ 50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, and luteinizing hormone and follicle stimulating 
hormone levels within the postmenopausal range, are considered menopausal. 
 
Females < 50 years old who have 12 months of amenorrhea or above after stopping 
hormone replacement therapy, radiation-induced ovariectomy and the time from the last 
menorrhea > 1 year, chemotherapy-induced amenorrhea and the time from the last 
menorrhea > 1 year, or surgical sterilization (bilateral ovariectomy or hysterectomy), 
are considered menopausal. 
4.3.3 During Lactation 
IBI308 is unknown for secretion from breast milk. Considering the presence of multiple drugs 
in breast milk, IBI308 may have potential toxicity for infants. Therefore, lactating women 
should not be enrolled into this study. 
4.4 
Criteria for Discontinuation/Withdrawal 
4.4.1 Treatment Discontinuation 
Treatment discontinuation is not the same as withdrawal from the study. Since data on some 
clinical events after treatment discontinuation may be important to the study, these information 
must be collected until the subject's last scheduled visit, even if the treatment has already been 
discontinued. 


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The treatment can be discontinued by a subject at any time for any reasons, or determined by 
the investigator in the case of any AEs. In addition, the investigator or sponsor may discontinue 
the treatment of a subject if the subject is not suitable for treatment or violates study protocol, 
or for administrative and/or other safety reasons. 
A subject must discontinue the treatment in the case of any one of the followings, but can 
continue to be monitored during the study: 
o 
Treatment discontinuation required by the subject or his/her legal representative. 
o 
Occurrence of an AE that requires discontinuation due to protocol-specified reasons 
(refer to Section 5.2). 
o 
Onset of another malignant tumor that requires active treatment. 
o 
Onset of a concurrent disease that interferes further treatment. 
o 
Subject withdrawal determined by the investigator. 
o 
Positive serum pregnancy test results. 
o 
Poor compliance of the subject. 
o 
Unnecessary risks of study drug continuation to the subject determined by the 
investigator and/or sponsor according to subject's disease status and condition. 
o 
Completion of the 24-month treatment of study drug (a maximum of 24 months for 
patients in the control group who were cross-treated with IBI308 after objective PD). 
For subjects who have discontinued treatment but continue to receive visits in the study, all 
visits and procedures listed in the schedules of activities (Tables 1 and 2) shall be completed. 
4.4.2 Withdrawal 
A subject must withdraw from the study if the subject or his/her legal representative withdraws 
the ICF of participating in the study. A subject will not continue to receive treatment or 
scheduled visits if he/she withdraws from the study. A subject can receive survival visits after 
withdrawal from the study with his/her consent. A subject must withdraw from the study if 
he/she is lost to follow-up. 
4.4.3 Clinical criteria for premature discontinuation of study 
The study will be discontinued prematurely if the following criteria are met: 
 
Inaccurate or incomplete of quality and quantity of data records 


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 
Poor compliance to the study protocol and regulatory requirements 
 
Potential hazard to the subjects' health as suggested by the adverse drug reaction (ADR) 
incidence or severity level in this or other studies 
 
Planned changes or discontinuation of study drug development 
If the sponsor decides not to continue the supply of the study drugs, sufficient notice will be 
made to facilitate the appropriate adjustments to the subject's treatment. 
5 
STUDY DRUG AND OTHER TREATMENTS 
Study drugs are defined as IBI308, placebo, gemcitabine, and cisplatin or carboplatin in this 
study. The first dose of study treatment should be started on the day of randomization (day 1 of 
cycle 1), and no later than 48 h after the randomization. The sponsor should be notified if the 
first dose is not administered after 48 h. Every effort should be made to start the study 
treatment on the day of randomization. As determined by the investigator and for 
administrative reasons, the study treatment can be administered before the scheduled day 1 of 
cycles or within 3 days thereafter. 
Table 4. Study therapeutic drugs 
Study drug 
Dose 
Frequency 
Route of 
administration 
Treatment cycle 
Usage 
IBI3081 
200mg 
Q3W 
Intravenous 
infusion 
Once Q21D, administered on 
day 1, consecutive cycles 
Test group 
Placebo1 
NA 
Q3W 
Intravenous 
infusion 
Once Q21D, administered on 
day 1, consecutive cycles 
Control group 
Gemcitabine2 
1.0g/m2 
Q3W 
Intravenous 
infusion 
Once Q21D, administered on 
days 1 and 8, a maximum of 6 
consecutive cycles 
Test/Control 
group 
Cisplatin2 
75mg/m2 
Q3W 
Intravenous 
infusion 
Once Q21D, administered on 
day 1, a maximum of 6 
consecutive cycles 
Test/Control 
group 
Carboplatin2 
AUC 5 
Q3W 
Intravenous 
infusion 
Once Q21D, administered on 
day 1, a maximum of 6 
consecutive cycles 
Test/Control 
group 
1. IBI308 should be administered by infusion prior to the administration of chemotherapeutics. 
2. If the weight fluctuation is less than 10% compared to baseline (the day of the first dose), use the baseline 
weight to calculate the body surface area, and then calculate the chemotherapeutic dose based on the body 
surface area. Otherwise, use the weight on the scheduled day of administration to calculate the 
chemotherapeutic dose. The maximum body surface area adopted in the protocol is 2.0 m2. For subjects with a 
body surface area of > 2.0 m2, the staff of the study center will calculate the dose based on a body surface area 
of 2.0 m2. For convenience, the protocol allows for a deviation of ± 5% of the total infusion dose each time.  


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All the study drugs in Table 4 are provided by the sponsor, and the product/batch numbers of 
all procured drugs are accessible. The study sites are responsible for recording the batch 
numbers, manufacturers, and expiry dates. 
5.1 
Use of Study Drugs 
5.1.1 Use of IBI308 
The main active ingredient of IBI308 is the recombinant fully human anti-PD-1 monoclonal 
antibody, with a concentration of 10 mg/mL. IBI308 is a clear, colorless liquid and is free of 
foreign matters, flocs, and precipitation. The excipients include 140 mmol/L mannitol, 25 
mmol/L histidine, 20 mmol/L dihydrate sodium citrate, 50 mmol/L sodium chloride, 0.02 
mmol/L disodium edetate (ethylenediaminetetraacetic acid disodium salt), and 0.2 mg/mL 
polysorbate 80, pH 6.0. 
The smallest packaging unit is one box. Each box contains 2 vials of sintilimab (IBI308) 
injection. The package contains the drug name, dosage form, strengths, drug code, batch 
number, expiry date, storage conditions, and sponsor's information. The label on the vial 
contains the same information as the outer package except for dosage form, precautions, and 
dosage and administration. The package and vial should be both labeled "use for clinical study 
only". IBI308 drug product should be stored at 2–8 °C away from light. The shelf life is 24 
months. If quality issues such as turbidity and precipitation are observed in the injection, seal 
the vial immediately and notify the sponsor. 
The preparation and infusion of IBI308 are as follows: 
1. 
Completely withdraw the contents of 2 vials of IBI308 injection and transfer them into a 
100 mL IV infusion bag containing 0.9% (w/v) sterile normal saline, then document the 
start time of the preparation. 
2.  The IV bag is gently inverted to mix the solution, ensuring the uniformity of the contents. 
No vigorous shaking is allowed to avoid foam. If large amount of foam forms, stand the IV 
bag until the foam disappears. 
3.  Administer with a 0.2–1.2 μm in-line filter (suggested infusion time is 30–60 minutes). 
Document the start and stop time of infusion. 
Note: Before preparation, make sure that the IBI308 injection is clear without any quality 
issues such as turbidity or precipitation; make sure that the time from withdrawing IBI308 from 
the first vial to the end of infusion is no more than 24 h (storage conditions for the prepared 
solution is 2–8 °C in the fridge); avoid mixing with other drugs; do not administer as an IV 
push. 


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5.1.2 Use of chemotherapeutics 
Standard chemotherapeutics used in combination are prepared according to the description in 
the approved product specification and the selected dose is as follows: 
 
Gemcitabine: 1000 mg/m2 d1, 8/q3w 
 
Cisplatin: 75 mg/m2 d1/q3w 
 
Carboplatin: AUC 5 (calculated by Calvert formula) d1/ q3w, and the dosage of 
carboplatin shall not exceed 750 mg. 
Calvert formula 
Total dose (mg) = (target AUC) × (CCr + 25) 
The estimated CCr used in the Calvert formula shall not exceed 125 mL/min 
Maximum carboplatin dose (mg) = target AUC 5 (mg·min/mL) × (125 + 25) = 5 × 
150 mL/min = 750 mg 
Full hydration is required to prevent the renal toxicity of cisplatin: During the use of cisplatin, 
a hydration of 3 days is required, and potassium chloride, mannitol, and furosemide should be 
used to maintain the daily urine volume at 2000–3000 mL. Cisplatin is a chemotherapeutic 
drug which carries high likeliness to induce vomiting, and therefore antiemetic drugs such as 
5-HT3 receptor antagonist, dexamethasone (or other glucocorticoids), dopamine receptor 
blockers (methoxychlor amine), and antihistamines (such as promethazine hydrochloride and 
diphenhydramine) are recommended, and NK-1 receptor antagonist (aprepitant) are 
recommended to prevent chemotherapy-associated vomiting when conditions allow. 
5.2 
Dose adjustments 
5.2.1 General principles 
The dose adjustment must be based on the most severe drug toxicity occurred in the previous 
administration cycle. Before the administration of each study drug on day 1, the subjects' 
hematologic, hepatic and renal function must meet the requirements for administration, and all 
other toxicities must resolve to CTCAE grade 0–1 or baseline level (excluding alopecia, 
fatigue, specific stipulations in the protocol, or other circumstances of no clinical significance 
as determined by the investigator; when chemotherapy-related myelosuppression resolves to 
grade 2 or below, IBI308 therapy can be resumed). 
For chemotherapy, administration requirements for hematologic function were defined as the 
absolute count of central granulocytes ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and 


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hemoglobin ≥ 90 × 109/L; for hepatic function were defined as TBIL ≤ 1.5 × ULN, AST and 
ALT ≤ 2.5 × ULN (all patients) or ≤ 5 × ULN (patients with liver metastasis); for renal 
function were defined as CCr ≥ 50 mL/min prior to the first dose (Cockcroft-Gault formula) 
followed by CCr ≥ 45 mL/min in subsequent cycles. For IBI308/placebo administration, 
chemotherapy-associated myelosuppression should resolve to grade 2 or below, and the 
administration requirements in case of immune-related hepatic dysfunction and renal 
insufficiency refer to Section 5.2.2 and Table 5 in this protocol. In clinical practice, 
administration may be acceptable based on the judgment of the investigator despite the 
presence of a deviation from the scope of above requirements. If the subject can tolerate the 
study drug as determined by the investigator, the administration of study drug can be 
conducted after the communication with the sponsor by e-mail, while the close follow-up is 
required to deal with any subsequent changes in a timely manner. 
If the subject fails to meet the administration criteria after the scheduled interval of the 
administration cycle due to drug toxicity, the next administration is allowed to be delayed. The 
administrations of IBI308 and chemotherapeutics should be kept in synchronization as far as 
possible by adjusting the window period of ± 3 days. If these study drugs need to be 
interrupted/permanently discontinued due to the toxicity associated with a certain or multiple 
study drugs, AEs related to therapeutic drugs, or other reasons, the other study drugs (IBI308 
or chemotherapy) can be used alone in conditions that corresponding administration criteria are 
met. 
All dose adjustments should be documented, including reasons and processings. 
5.2.2 Dose adjustment of IBI308 
Does adjustments of IBI308 are not permitted throughout the trial. The principles of 
interruption and permanent discontinuation of IBI308 are shown in Table 5. If the 
administration delay occurs in a 3-week treatment cycle for IBI308, all the subsequent 
administration days should be delayed to ensure that a dosing interval of 21 ± 3 days. 
IBI308-related AEs are usually immune related adverse events (irAEs). For suspension due to 
irAEs, hormone therapy may be used to resolve the AEs to grade 1 or 0 based on their type and 
severity, and administration can be resumed after 4 weeks or above of reduction of hormone 
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Table 5. Dose adjustment protocol for irAEs of IBI308 
irAEs 
Severity level 
Dose adjustments 
Pneumonia 
Grade 2 pneumonia 
Interruptiona 
Recurrent grade 2 pneumonia, grade 3 or 4 
pneumonia 
Permanent discontinuation 
Diarrhea/enterocolitis 
Grade 2 or 3 diarrhea or enterocolitis 
Interruptiona 
Grade 4 diarrhea or enterocolitis 
Permanent discontinuation 
Dermatitis 
Grade 3 dermatitis 
Interruptiona 
Grade 4 dermatitis 
Permanent discontinuation 
Hepatitis 
Grade 2 AST, ALT, or TBIL elevation for 
subjects with normal AST, ALT or TBIL at 
baseline; AST, ALT, or TBIL elevation of ≥ 50% 
(reaching the requirement of grade 2) for < 7 
days for subjects with AST, ALT, or TBIL > 
ULN at baseline 
Interruptiona 
Grade 3 or 4 AST, ALT, or TBIL elevation for 
subjects with normal AST, ALT or TBIL at 
baseline; AST, ALT, or TBIL elevation of ≥ 50% 
(reaching the requirements of grade 3 or 4) for ≥ 
7 days for subjects with AST, ALT, or TBIL > 
ULN at baseline 
Permanent discontinuation 
Hypophysitis 
Grade 2 hypophysitis 
Interruptionb 
Grade 3 or 4 hypophysitis 
Interrupt or permanently discontinue 
Adrenocortical 
insufficiency 
Grade 2 adrenocortical insufficiency 
Interruptionb 
Grade 3 or 4 adrenocortical insufficiency 
Interrupt or permanently discontinue 
Hyperthyroidism 
Grade 3 or 4 hyperthyroidism 
Interrupt or permanently discontinue 
Hypothyroidism 
Grade 2-4 hypothyroidism 
Continue 
Type I diabetes 
Grade 3 hyperglycemia 
Interruptionb 
Grade 4 hyperglycemia 
Interrupt or permanently discontinue 
Renal insufficiency 
Grade 2 or 3 Cr elevation 
Interruptiona 
Grade 4 Cr elevation 
Permanent discontinuation 
Neurotoxicity 
Grade 2 neurotoxicity 
Interruptiona 
Grade 3 or 4 neurotoxicity 
Permanent discontinuation 
Other irAEsc, d 
Intolerance/persistent grade 2 AE 
Interruptiona 
 
Grade 3 AE 
Interrupt or permanently discontinue 
 
Grade 4 AE or recurrent Grade 3 AE 
Permanent discontinuation 
a: Resume the administration after symptoms improve to grade 0–1 or baseline levels. 
b: Resume the administration if hypophysitis, adrenocortical insufficiency, hypothyroidism/thyroid dysfunction, or 
type I diabetes is adequately controlled and only physiological hormone replacement therapy is required. 
c: Interruption or permanent discontinuation for an abnormal laboratory test result should be determined based on 
the concomitant clinical symptoms/signs and the investigator's clinical judgment. 


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d: In case of immune-related blood amylase and lipase elevations (grade 3 or 4), which are simply abnormal results 
of laboratory tests and have no clinical symptoms/signs, the investigator can resume the administration of 
IBI308/placebo after the indicators improve. The investigator can determine the subsequent administration based on 
the comprehensive considerations of the patients' concomitant symptoms/signs, the instructions for IBI308, and the 
relevant guidelines. 
IBI308 is allowed to be interrupted for up to 12 weeks. If the symptoms do not resolve to the 
level, at which the treatment can be resumed, within 12 weeks, the subject must permanently 
discontinue IBI308 treatment and enter the follow-up phase of the study, except for the 
following two cases: 
 
IBI308 interruption > 12 weeks due to dose reduction of glucocorticoid that is used to 
treat irAEs. Consult the sponsor's medical manager prior to resuming IBI308. Imaging 
examination for efficacy should not be affected by treatment interruption and should be 
performed as scheduled. 
 
IBI308 interruption is over 12 weeks due to the treatment of AEs unrelated to IBI308. 
Consult the sponsor's medical manager prior to resuming IBI308. Imaging examination 
for efficacy should not be affected by treatment interruption and should be performed as 
scheduled. 
5.2.3 Management of IBI308 infusion-related reactions 
IBI308 may cause severe or life-threatening infusion-related reactions, including severe 
hypersensitivity reactions or allergic reactions. Signs and symptoms usually occur during or 
after drug infusion and usually resolve within 24 h after the infusion completion. Refer to 
Table 6 for the guidelines for management of IBI308 infusion-related reactions. 
Table 6. Guidelines for management of IBI308 infusion-related reactions 
NCI CTCAE grade 
Treatments 
Premedications for 
subsequent infusions 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
According to subject's medical indications, 
monitor the vital signs closely until the 
subject is stable as determined by the 
investigator. 
Absent 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment required 
(e.g., antihistamines, non-steroidal 
anti-inflammatory drugs 
(NSAIDs), anesthetics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours 
Stop the infusion and monitor symptoms. 
Other appropriate treatments include but are 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Anesthetics 
The following premedications 
are recommended within 1.5 h 
(± 30 min) prior to IBI308 
infusion: 
 
Diphenhydramine 50 mg PO 
(or equivalent antihistamines). 
 
 


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NCI CTCAE grade 
Treatments 
Premedications for 
subsequent infusions 
According to subject's medical indications, 
monitor the vital signs closely until the 
subject is stable as determined by the 
investigator. 
If symptoms resolve within 1 h after 
interrupting the infusion, then the infusion 
will be resumed at 50% of the original 
infusion rate (e.g. from 100 mL/h to 50 
mL/h). Otherwise, interrupt the treatment 
until symptoms resolve. Premedications 
should be given before next scheduled 
administration. 
If grade 2 toxicities occur despite of 
adequate premedications, the study drugs 
should be permanently discontinued. 
Acetaminophen 500–1000 mg 
PO (or antipyretics at 
equivalent effective dose). 
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 
infiltration) 
Grade 4: 
Life threatening; pressors or 
ventilatory support indicated 
Discontinue the infusion. 
Other appropriate treatments include but are 
not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Anesthetics 
Oxygen 
Pressors 
Corticosteroids 
According to subject's medical indications, 
monitor the vital signs closely until the 
subject is stable as determined by the 
investigator. 
Hospitalization may be indicated. 
**Epinephrine should be used immediately 
for allergic reactions. 
The study drugs should be permanently 
discontinued. 
Not applicable 
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 "Common Terminology Criteria for Adverse Events" (CTCAE) V4.03 
(http://ctep.cancer.gov) 
 


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5.2.4 Dose adjustments of chemotherapeutics 
If the toxicity is mainly caused by a certain chemotherapeutic drug as confirmed by the 
investigator, dose reduction of a single medication can be acceptable; if the toxicity is uncertain 
and may be caused by two or more drugs, dose reductions of all relevant drugs are feasible. If 
administration delay of chemotherapeutics occurs in a 3-week treatment cycle, all the subsequent 
administration days should be delayed to ensure a dosing interval between chemotherapy 
treatments of 21 ± 3 days. If the administrat ion of gemcitabine on day 8 is delayed for more than 
7 days due to toxicity, skip the administration on day 8 and resume the treatment in the next 
cycle. The chemotherapy cycle and the IBI308 cycle should be kept in synchronization as far as 
possible by adjusting the permitted window period. The longest permitted discontinuation time 
period of chemotherapeutics is 6 weeks from the last chemotherapy. If the drug requirements of 
chemotherapy cannot be met after 6 weeks, chemotherapy shall be terminated permanently. 
Different dose levels of chemotherapeutics are shown below. If dose reduction is still required 
after reductions of two dose levels, the chemotherapy should be discontinued. 
Table 7. Dose adjustments of chemotherapeutics 
 
Initial dose 
Reduction by 1 dose level 
Reduction by 2 dose levels 
Gemcitabine 
1000mg/m2 
750mg/m2 
500mg/m2 
Cisplatin 
75mg/m2 
56mg/m2 
38mg/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 adjustments for chemotherapy-related hematotoxicities 
Table 8. Dose adjustments based on chemotherapy-related hematological toxicities in 
previous cycle 
 
 
Gemcitabine 
Cisplatin/Carboplatin 
Platelet 
Neutrophil 
Adjust the dose level according to Table 7 
≥ 50 × 109/L and 
≥ 0.5×10 9/L 
Initial dose 
Initial dose 
≥ 50 × 109/L and 
< 0.5×10 9/L 
Reduction by 1 dose level 
Reduction by 1 dose level 
< 50 × 109/L, without 
hemorrhage, and 
Any 
Reduction by 1 dose level 
Reduction by 1 dose level 
< 50 × 109/L, combined with 
hemorrhage of ≥ grade 2, and 
Any 
Reduction by 2 dose levels 
Reduction by 2 dose levels 
Any condition, and 
< 1 × 109/L, combined 
with fever ≥ 38.5 °C 
Reduction by 1 dose level 
Reduction by 1 dose level 


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Recommended dose adjustments for chemotherapy-related non-hematotoxicities 
Table 9. Dose adjustments based on chemotherapy-related non-hematological toxicities in 
previous cycle 
Adverse event 
CTCAE grade 
Gemcitabine 
Cisplatin 
Carboplatin 
Nausea or emesis 
Grade 3 or 4 
Initial dose 
Initial dose 
Initial dose 
Diarrhea 
Grade 3 or 4 
Reduction by 1 dose 
level 
Reduction by 1 dose 
level 
Initial dose 
Rash 
Grade 3 or 4 
Reduction by 1 dose 
level 
Initial dose 
Initial dose 
Neurotoxicity 
Grade 2 
Initial dose 
Reduction by 2 dose 
levels 
Initial dose 
Grade 3 or 4 
Discontinue 
Discontinue 
Reduction by 1 dose 
level 
Transaminase 
increased 
Grade 3 
Reduction by 1 dose 
level 
Reduction by 1 dose 
level 
Reduction by 1 dose 
level 
grade 4 
Discontinue 
Discontinue 
Discontinue 
Other 
non-hematological 
toxicity 
Grade 3 or 4 
Reduction by 1 dose 
level 
Reduction by 1 dose 
level 
Reduction by 1 dose 
level 
Clearance of creatinine (CCr): 
CCr is calculated by Cockcroft-Gault formula (Appendix 3), which is based on the standard 
body weight. The CCr must be ≥ 50 mL/min before the first administration of 
chemotherapeutics. A maximum of 6 weeks of administration delay of gemcitabine and/or 
platinum-based drugs is acceptable for waiting for recovery of CCr to required level in the 
subject; and if the recovery of CCr to a level of ≥ 45 mL/min is unachieved after more than 6 
weeks since the last administration, cisplatin or carboplatin and/or gemcitabine must be 
discontinued. 
5.3 
Principles of Managing Immune Checkpoint Inhibitor Toxicities 
AEs related to IBI308 exposure may be etiologically associated with immunity. These irAEs may 
occur within a short period after the first dose or within months after the last dose. They may 
influence more than one systems simultaneously. Therefore, early diagnosis and treatment are 
critical to reduce complications. Based on the existing clinical trial data, most irAEs are 
reversible, and can be managed through discontinuation of IBI308, administration of 
glucocorticoids, and/or other supportive therapies. For suspected irAEs, appropriate evaluations 
for confirmed pathogenesis or exclusion of other reasons should be ensured. Other procedures or 
examinations, such as bronchoscopy, endoscopy, or skin biopsy, may be included into this 
evaluation. Temporary or permanent discontinuation of IBI308 and administration of 


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glucocorticoids are adopted depending on the severity level of irAEs. Refer to the "Manual for 
Management of Immune Related Adverse Events" provided by the sponsor for dose adjustments 
and toxicity management of potential irAEs. 
5.4 
Concomitant Treatments 
5.4.1 Permitted concomitant treatments 
 
Medications that meet the protocol requirements, as determined by the investigator (e.g. 
concomitant medication used for disease-related symptoms and TRAEs). 
 
Subjects who need medications for a long time due to pre-existing diseases, such as 
hypertensive and diabetes mellitus, can continue the use of drug. 
 
Locoregional surgery, minimally invasive treatment, or radiotherapy used for isolated 
lesions (excluding target lesions) during the study treatment. 
 
Supportive care for relieving tumor-related symptoms, such as bisphosphonate treatment 
for bone metastases. 
 
Use of locoregional corticosteroids, such as dermal, ocular, nasal, and inhaled 
corticosteroids. 
5.4.2 Prohibited concomitant treatments 
The following treatments are prohibited during the study treatment (including the crossover 
monotherapy of IBI308 for subjects in the control group after objective PD): 
 
Any systemic chemotherapy or biotherapy (except for cytokine drugs to treat 
chemotherapeutics-induced AEs), as well as proprietary Chinese medicines, with 
anti-tumor effects. 
 
Immunomodulators, including but not limited to non-specific immunomodulators (such 
as thymosin, interferon, interleukin, immunoglobulin, and gamma globulin) as well as 
proprietary Chinese medicines with immunomodulating effects, etc. 
 
Chemotherapeutics not specified in this protocol. 
 
Any study drug other than IBI308. 
 
Radiotherapy to control tumors (palliative radiotherapy is allowed if not directed towards 
the target lesion, such as radiotherapy for relieving pain from bone metastasis and 
symptoms of brain metastasis). 


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 
Inoculation with live vaccine within 30 days prior to the first dose of study treatment and 
throughout the trial. Live vaccines include but are not limited to measles, epidemic 
parotitis, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette Guerin (BCG), 
and typhoid (oral) vaccines. Seasonal inactivated influenza virus vaccines are permitted, 
but live attenuated influenza vaccines are not. 
 
Corticosteroids. Inhaled steroids for subjects with asthma or chronic obstructive 
pulmonary disease (COPD) are permitted; temporary use of corticosteroids for relieving 
dyspnea are permitted; corticosteroids are permitted for the treatment of immune-related 
AEs; corticosteroids of physiologic dose can be approved after consulting the sponsor. 
o 
Note: Prophylactic corticosteroids to avoid allergic reactions (e.g. pretreatment 
prior to administration of IV contrast agent or chemotherapeutics) are permitted. 
Based on the assessment of the investigator, subjects requiring any one of the treatment methods 
above must be excluded from the trial. Subjects may receive other medically-necessary 
medications as determined by the investigator. 
It is very important for the investigator to review every drug (prescription and non-prescription) 
used by the subject prior to the trial and during each visit.  
 
During each visit, subjects must be asked about any new medications received.  
 
To minimize the risk of drug-drug interactions, every measure must be taken to limit 
the number of concomitant medications that are really necessary. 
 
Drugs of hepatotoxicity (i.e. those with warnings in the prescribing information) should 
be avoided during the treatment. The investigators are encouraged to review every 
potential hepatotoxic drug via www.livertox.nih.gov. 
 
Prohibited drugs listed in the exclusion criteria are not permitted. 
5.4.3 Drug-drug interactions 
 
IBI308: No information on drug-drug interaction of IBI308 is currently available. 
 
Gemcitabine: No information on drug-drug interaction of gemcitabine is currently 
available. 
 
Cisplatin: cisplatin in combination with aminoglycoside antibiotics, amphotericin B, or 
cefalotin may increase renal toxicity; cisplatin in combination with probenecid may 
induce hyperuricemia; chloramphenicol, furosemide, or ethacrynate sodium can 
increase the ototoxicity of cisplatin; antihistamine may cover up tinnitus, vertigo, and 
other symptoms caused by cisplatin. 


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 
Carboplatin: IBI308 may alter renal function. Although it is still inconclusive whether 
the nephrotoxicity of carboplatin would be increased when used in combination with 
aminoglycosides and other nephrotoxic drugs, the combination use with these drugs is 
recommended to be avoided. 
5.5 
Drug Management 
5.5.1 Drug management 
IBI308 should be refrigerated at 2–8 °C in a dry place and away from light. Do not freeze. 
Cold-chain should be maintained during transport, and the study drugs should be kept and 
dispensed by a designee. 
The study drugs should be stored in a refrigerator only accessible by the authorized personnel. 
After receiving the study drugs, the investigator should ensure that the temperature during 
transport is maintained within the specified range, sign for receipt upon verification, and store 
the study drugs at the specified temperature. If abnormalities of the storage temperature during 
either the transport or storage at the study site arise, the study drugs should be moved to an 
environment in the specified temperature as soon as possible and should not be administered. 
Notify the sponsor timely and follow the advice of the sponsor. 
All the investigational drugs provided by the sponsor should only be used for this clinical trial. 
Any purposes other than those specified in the protocol are not permitted. The investigator must 
agree not to provide the study drugs to anyone unrelated to this trial. 
Used IBI308 should be stored under the same storage conditions until verification by the clinical 
research associate (CRA), who will then arrange for the return of study drugs. 
5.5.2 Dispensation 
This trial will use stratified randomization. The randomization list will be generated by 
statisticians with SAS. After confirming that the subject meets all of the inclusion and exclusion 
criteria, the study site will log in the IWRS and enter the subject information into it. The IWRS 
will allocate a random number to the subject and provide a medication number. 
5.5.3 Return and destruction 
In this trial, the containers of used IBI308 should be returned, and those of chemotherapeutics 
can be destroyed on-site according to appropriate guidelines and operating procedures 
established by study sites and local agencies. If some study sites have difficulties in recovering 
the IBI308 containers, they are allowed to destroy the containers on-site according to the process 
of chemotherapeutics containers with the consent of the sponsor. 


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Upon the completion or discontinuation of the study, all unused or expired study drugs must be 
returned to the sponsor for destruction. Arrangements for the return of study drugs were made by 
the clinical research associate (CRA) designated by the sponsor. 
5.6 
Study drug-related records 
The designee of the study sites should make timely records of receiving, dispensing, using, 
storing, returning, and destroying the study drugs in accordance with the relevant regulations and 
guidelines. 
5.7 
Complaint handling  
To ensure the safety and proper monitoring of the subjects, and facilitate the improvement of trial 
process and drug product, the sponsor will collect complaints related to the study drugs. 
Complaints regarding concomitant medications will be directed to the manufacturer according to 
the prescribing information of the drugs. 
The investigator or designee completed the following procedures for product complaints in 
accordance with applicable requirements of the study: 
 A drug complaint form specific for clinical trials was used to document product 
complaints and relevant description completely. 
 The completed product complaint form should be submitted to the sponsor or 
designee by fax or email within 24 hours. 
 If the investigator was asked to return the product for further investigation, the 
investigator should return the product along with a copy of the complaint form. 
6 
STUDY PROCEDURE 
6.1 
Subject Screening and Randomization Procedures 
6.1.1 Subject screening and randomization 
The investigator enrolled the subjects by the following steps: 
1. Subjects should sign the ICF prior to any study-related procedures. 
2. Confirmed the subjects' eligibility by the principal investigator or trained designee after 
reviewing the inclusion/exclusion criteria. 
3. Central randomization is adopted, with the stratification factors of staging (stage 
IIIB/IIIC vs. stage IV), platinum-based medications (cisplatin vs. carboplatin), and 
PD-L1 expression level (< 1% vs. ≥ 1%). 


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Subjects who failed to meet the criteria (screen failures) were re-screened. If re-screening is 
considered, the investigator must contact the sponsor's medical manager. Each subject can be 
re-screened once. The subjects must sign the ICF again and receive a new identification number 
when they are re-screened. 
6.1.2 Enrollment error handling 
The inclusion/exclusion criteria must be followed strictly. If an ineligible subject is enrolled, the 
sponsor's medical manager and the investigator must discuss whether to allow the subject to 
continue participating in the study. If as determined by the investigator, allowing the subject to 
continue with the study is appropriate medically, which is also agreed with by the sponsor's 
medical manager, then the subject will continue participating in the study and receive the study 
drug; If the investigator considers that continued participation in the study is medically 
appropriate but the sponsor's medical manager disagrees with the decision, the subject cannot 
continue to participate in the study. The investigator must not allow the subject to continue with 
the study until receive the written approval from the sponsor. 
6.2 
Study Plan and Schedule 
6.2.1 Screening period 
The following procedures must be completed during the screening (day –28 to –1) to ensure 
subject eligibility: 
 
Signing of informed consent form 
 
Confirming the inclusion/exclusion criteria 
 
Recording the demographics, medical history, and previous therapies of lung cancer 
 
Previous and concomitant medications 
 
Recording the vital signs, height, and body weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead electrocardiogram (ECG) 
 
Routine blood test/blood chemistry/urinalysis/myocardial enzyme and troponin (within 
7 days prior to the first dose) 
 
Hemagglutination function tests (within 7 days prior to the first dose) 
 
Pregnancy test (within 3 days prior to the first dose) 


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 
Thyroid function (within 28 days prior to the first dose) 
 
HIV antibodies, hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) and 
HBV-DNA (if applicable), as well as HCV antibodies and HCV-RNA (if applicable) 
(within 28 days prior to the first dose) 
 
AE evaluation 
 
Concomitant medications 
 
Tumor imaging evaluation (within 28 days prior to the first dose) 
 
Archived or fresh tumor tissue sample 
Refer to Sections 7.1 and 7.2 for details regarding physical examination, tumor imaging 
evaluation, and safety evaluation. 
6.2.1.1 Medical history 
The medical history should be collected by the investigator or qualified designee. The medical 
history shall include all previous diseases and current active diseases. All autoimmune diseases 
should be documented, regardless of the date of onset. The medical history shall include the 
diagnosis and treatments for the disease. A detailed previous therapies of lung cancer (including 
chemotherapy, radiotherapy, and surgery) will be documented separately, which will not be listed 
in the medical history. 
6.2.1.2 Previous medication 
The investigator or qualified designee will review the previous medications of subjects 
(including any washout requirements specified in the protocol) and document the medications 
(including replacement/supplement drugs) used within 30 days prior to the first dose of 
investigational drug. 
6.2.1.3 Concomitant medications 
The investigator or qualified designee will document all concomitant medications used 
throughout the trial (from signing of the ICF to the safety follow-up visits). 
All medications related to SAE should be documented and reported according to the definition in 
Section 8.4. 
6.2.2 Treatment visits 
 
Recording the vital signs and body weight 
 
ECOG PS score 


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 
12-lead electrocardiogram (ECG) 
 
Routine blood test/blood chemistry/urinalysis/myocardial enzyme and troponin 
 
Thyroid function 
 
HBV DNA and/or HCV RNA (if applicable) 
 
PK and immunogenicity 
 
AE evaluation 
 
Concomitant medication 
 
Tumor imaging evaluation 
 
Administration of study drugs 
 
LCSS and EORTC QLQ-C30 
 
Full blood sampling for biomarkers 
Refer to Table 1 for the schedule of follow-up visits during the study treatment. Refer to 
Sections 7.1–7.4 for details regarding tumor imaging evaluation, safety evaluation, and blood 
sampling for PK/immunogenicity. 
6.2.3 Safety visits 
A safety follow-up should be carried out on day 30 (± 3 days) after the last dose or before the 
start of a new anti-tumor treatment, whichever occurs first. The following contents should be 
included: 
 
Recording the vital signs 
 
Body weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead electrocardiogram (ECG) 
 
Routine blood test/blood chemistry/routine urinalysis 
 
Hemagglutination function tests 
 
Thyroid function 
 
Pregnancy test 


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 
HBV DNA and/or HCV RNA (if applicable) 
 
AE evaluation 
 
Immunogenicity 
 
Concomitant medication 
 
Subsequent anti-tumor therapy (if applicable) 
 
Tumor imaging evaluation 
 
LCSS and EORTC QLQ-C30 
 
Full blood sampling for biomarkers 
All AEs prior to the safety follow-up visits should be documented until the events recover to 
grade 0–1 or the baseline level, or until the investigator believes that no further follow-up is 
required for reasonable reasons (e.g., the event cannot be resolved or has already been 
improved), whichever occurs first. 
6.2.4 Survival visits 
After completing the safety follow-up, the subject shall be contacted every 90 (± 7) days 
(telephone visits are acceptable) to obtain the survival information, any subsequent systemic 
anti-tumor therapy, and PD information (for subjects with no imaging PD). Long-term follow-up 
should be continued until death or end of study. 
6.2.5 Subsequent anti-tumor therapy 
The investigator or qualified designee will review all the new anti-tumor therapies initiated after 
the last dose. If the subject initiate a new anti-tumor therapy within 30 days after the last dose, 
the safety follow-up visit must be performed before initiation of the new therapy.  
The subject should be followed for survival after initiation of the new anti-tumor therapy. Refer 
to Section 6.2.4 "Survival visits" for details regarding survival follow-ups. 
6.3 
Initiation of Crossover Treatment in Subjects of Control Group After Objective 
Progressive Disease 
If confirmed objective PD occurs after treatment and the unblinding is completed, subjects in the 
control group can receive monotherapy of IBI308 for crossover treatment based on the judgment 
of the investigator and the consent of the sponsor, on the conditions of SD and meeting the 
criteria of crossover treatment. Subjects, other than those discontinue the treatment due to 
objective PD confirmed by imaging, shall not receive crossover treatment with IBI308. 


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Regardless of the onset date of objective PD, subjects who is about to receive crossover 
treatment must start the administration of IBI308 at least 21 days after the last chemotherapy. 
Criteria for crossover treatment are presented below: 
 
Evidence for objective PD is confirmed by IRRC according to RECIST V1.1; 
 
All AEs (except for alopecia and asthenia) must recover to ≤ grade 1 or the baseline 
level; 
 
Subjects who are clinically unstable due to new lesions or brain metastases cannot 
receive crossover treatment; 
 
An ECOG PS score of 0–1; 
 
Subjects have not received any systemic anti-tumor treatment other than 
chemotherapeutics in this study; 
 
Palliative radiotherapy (≤ 30 Gy) should be completed at least 7 days before the first 
dose of crossover therapy; 
The study plan for the open-label crossover treatment period is as follows. 
6.3.1 Evaluation before crossover treatment 
The following procedures must be completed prior to crossover treatment to ensure the eligibility 
of the subjects in this study, and the imaging results obtained at the end of the last dose can be 
used for the evaluation before crossover treatment: 
 
Verify whether the subjects meet the criteria for crossover treatment 
 
Recording the vital signs, height, and body weight 
 
Physical examination 
 
ECOG PS score 
 
12-Lead ECG (within 7 days before the first dose) 
 
Routine blood test/blood chemistry/routine urinalysis (within 7 days prior to the first 
dose) 
 
Hemagglutination function tests (within 7 days prior to the first dose) 
 
Pregnancy test (within 3 days prior to the first dose) 
 
Thyroid function (within 21 days prior to the first dose) 


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 
HIV antibodies, hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb) and 
HBV-DNA (if applicable), HCV antibodies and HCV-RNA (if applicable) (within 21 
days prior to the first dose) 
 
Blood myocardial enzyme and troponin (within 7 days prior to the first dose) 
 
AE evaluation 
 
Concomitant medications 
 
Tumor imaging evaluation 
Refer to Sections 7.1 and 7.2 for details regarding tumor imaging evaluation and safety 
evaluation. 
The investigator or qualified designee will document all the concomitant medication used 
throughout the trial (from the first dose of IBI308 to the safety visit). 
6.3.2 Visits during crossover treatment 
 
Recording the vital signs 
 
ECOG PS score 
 
12-lead electrocardiogram (ECG) 
 
Routine blood test/blood chemistry/routine urinalysis 
 
Thyroid function 
 
HBV DNA and/or HCV RNA (if applicable) 
 
Blood myocardial enzyme and troponin 
 
AE evaluation 
 
Concomitant medication 
 
Tumor imaging evaluation 
 
Administration of study drugs 
 
LCSS and EORTC QLQ-C30 
Refer to Table 2 for the schedule of visits during crossover treatment. Refer to Sections 7.1–7.2 
for details regarding tumor imaging evaluation and safety evaluation. 


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6.3.3 Safety visit after crossover treatment 
A safety follow-up will be carried out on day 30 (± 3 days) after the last dose or before initiation 
of new anti-tumor therapy, whichever occurs first. The following contents should be included: 
 
Recording the vital signs 
 
Body weight 
 
Physical examination 
 
ECOG PS score 
 
12-lead electrocardiogram (ECG) 
 
Routine blood test/blood chemistry/routine urinalysis 
 
Hemagglutination function tests 
 
Pregnancy test 
 
Thyroid function 
 
HBV DNA and/or HCV RNA (if applicable) 
 
AE evaluation 
 
Concomitant medication 
 
Subsequent anti-tumor therapy (if applicable) 
 
Tumor imaging evaluation 
 
Survival condition 
 
LCSS and EORTC QLQ-C30 
All AEs prior to the safety follow-up visits should be documented until the events recover to 
grade 0–1 or the baseline level, or until the investigator believes that no further follow-up is 
required for reasonable reasons (e.g., the event cannot be resolved or has already been 
improved), whichever occurs first. All SAEs that occur within 90 days after the last dose or 
before initiation of new anti-tumor therapy (whichever occurs first) should be followed up and 
documented. 


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6.3.4 Survival visits after crossover treatment 
After completing the safety follow-up, the subject shall be contacted every 90 (± 7) days 
(telephone visits are acceptable) to obtain the survival information, any subsequent systemic 
anti-tumor therapy, and PD information (for subjects with no imaging PD). Long-term follow-up 
should be continued until death or end of study. 
Note: If the safety visit on day 30 is not performed for a subject, then the date should be 
calculated from the end of treatment. 
6.3.5 Subsequent anti-tumor therapy after crossover treatment 
The investigator or qualified designee will review all the new anti-tumor therapies initiated after 
the last dose. If the subject initiates a new anti-tumor therapy within 30 days after the last dose, 
the safety follow-up visit must be performed before initiation of the new therapy.  
The subject should be followed for survival after initiation of the new anti-tumor therapy. Refer 
to Section 6.3.4 "Survival visits" for details regarding survival follow-ups. 
6.4 
Other Procedures 
6.4.1 Treatment discontinuation/withdrawal from study 
A subject who discontinues the treatment/withdraws from the study before the completion of the 
treatment should be encouraged to continue follow-up visits and complete all remaining study 
visits. 
When a subject discontinues the treatment/withdraws from the study, all procedures applicable to 
the end-of-treatment visit should be performed. All adverse events (AEs) present at the time of 
treatment discontinuation/withdrawal from the study should be followed up according to the 
safety requirements outlined in Section 8.4 (Documentation of Adverse Events). If a patient 
discontinues treatment/withdraws from the study for a reason other than objective PD, the patient 
should receive an imaging evaluation at the end of treatment. For a subject who has completed 
24 months of treatment with IBI308, the treatment can be discontinued. The subject who 
discontinues the treatment after receiving IBI308 for 24 months should return to the study site 
for a safety follow-up visit and then enter the follow-up phase of this study. 
6.4.2 Loss to follow-up 
If a subject fails to return to the clinic for required study visits and/or the study site is unable to 
reach a subject, the following procedures will be performed: 


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 The study site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, he/she should be informed of the importance of maintaining the 
protocol-defined visit schedule. 
 At each missed visit, the investigator or designee must make every effort to resume 
contact with the subject (e.g., by telephone and/or registered letter to the last known 
subject's mailing address or equivalent local method). These attempts to contact the 
subject should be documented in the subject's medical records. 
Note: A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject has been reached. The quantity of missing data for a subject should be 
managed according to pre-specified data processing and analysis guidelines. 
6.4.3 Unblinding 
Generally, the investigator will perform the first imaging evaluation for PD according to RECIST 
V1.1. After confirmation of PD 4–6 weeks later, individual unblinding can be performed with the 
permission of the sponsor; if the subject develops clinically unstable disease after the first 
assessment of imaging PD, the confirmation 4–6 weeks later is not required and unblinding can 
be directly performed. In case the investigator or sub-investigator needs to determine the drug 
and dose administered to a subject in an emergency (e.g., in case of an SAE), he/she will contact 
the sponsor and the Clinical Research Organization (CRO) by telephone and request emergency 
unblinding. Before unblinding, the investigator or sub-investigator must record the severity 
level/toxicity grade, relationship with study drugs, and causes of observed AEs in the medical 
records. Subjects whose treatment assignment has been unblinded must discontinue the 
administration of study drugs. 
In addition, the investigator must log into the IWRS system and perform unblinding in the IWRS 
system to update the medication assignment. If necessary for the safety of a subject, the 
emergency unblinding must be performed using IWRS. Subjects whose treatment assignment has 
been unblinded must discontinue the administration of study drugs. 
Once blinding is performed, the blinding-related information (such as date, cause, and personnel 
responsible for unblinding) must be recorded immediately, and the sponsor's medical manager 
must be informed as soon as possible. The unblinded information regarding corresponding 
subject code should be revealed to the principal investigator or designee only, but not to the staff 
of the study site or the sponsor who directly participate in this trial. Subjects whose treatment 
assignment has been unblinded must discontinue the administration of study drugs. 
The interim analysis will be performed by an independent statistician and the results will be 
submitted to the IDMC. The investigator, subjects, and the sponsor will remain blinded. 


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7 STUDY EVALUATIONS 
7.1 
Efficacy evaluation 
7.1.1 Tumor imaging and disease evaluation 
Tumor imaging examinations usually include contrast-enhanced computed tomography (CT) or 
magnetic resonance imaging (MRI) of chest, abdomen, and pelvic cavity. Head MRI should be 
performed at baseline for subjects with signs or symptoms of suspected CNS metastasis. The 
same subject should receive the same type of imaging examination during the study. 
During the screening, the investigator of the study site will confirm the presence of measurable 
lesions based on RECIST V1.1 to determine the eligibility of the subject. As defined in the 
RECIST V1.1, there are a total of up to 5 target lesions and 2 target lesions per organ. 
All planned imaging data of all subjects at the study site should be submitted to the IRRC service 
provider. Besides, additional imaging data (including other devices) obtained at unscheduled 
time points to determine PD and imaging data obtained for purposes other than recording the 
imaging PD should also be submitted to the IRRC service provider. 
7.1.2 Tumor imaging evaluation at baseline 
During screening, the first tumor imaging examination must be performed within 28 days before 
randomization. Before randomization, the investigator of the study site should confirm the 
subjects have measurable lesions based on the RECIST V1.1. 
As a clinical routine test, the imaging examination performed within 28 days prior to 
randomization, whose quality meets the diagnosis requirements, may be evaluated by the 
investigator for oncology assessment in the screening period. 
The method used for evaluation of tumor burden during each subsequent follow-up should be the 
same as the one used at the baseline (CT/MRI). Imaging examinations may be performed on 
other suspected involved sites (e.g., head) according to the clinical symptoms and signs of the 
subject. 
7.1.3 Tumor imaging evaluation during trial 
The imaging evaluations should be carried out at the time points specified in the protocol as far 
as possible throughout the study. Since randomization, the tumor imaging evaluation should be 
performed in week 6 (± 7 days) and week 12 (± 7 days), respectively. Afterwards, one tumor 
imaging evaluation should be performed every 9 weeks (± 7 days) until week 48, and then 
performed once every 12 weeks (± 7 days). After the first assessment of imaging PD by the 
investigator based on RECIST V1.1, if the subject has SD clinically, the current treatment can be 


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continued and the imaging evaluation should be performed again 4–6 weeks later for 
confirmation (based on RECIST V1.1). If PD is confirmed, unblinding should be performed and 
subjects of IBI308 in combination with chemotherapy group (test group) should end the study 
treatment, while subjects of placebo in combination with chemotherapy group (control group) 
can be conditionally crossed over to receive monotherapy of IBI308 based on the judgment of 
the investigator and the willingness of the subjects, until PD, intolerable toxicity, receipt of new 
anti-tumor therapy, withdrawal of ICF, loss to follow-up, death, or other reasons requiring 
discontinuation of study treatment, whichever occurs first; if PD is not confirmed, the study 
treatment will be continued until imaging-confirmed PD followed by unblinding and other 
subsequent processing same as above. If the subject has clinically unstable disease after the first 
assessment of imaging PD, the confirmation 4–6 weeks later is not required and unblinding can 
be directly performed followed by processing same as above. 
Unscheduled imaging evaluations can be performed at any time during the study if the patient 
develops clinically unstable disease. 
Clinically unstable disease is defined as follows: 
 
Clinically significant signs and symptoms suggesting PD (including worsening 
laboratory test values) 
 
ECOG PS decreased (score increased)  
 
Rapid PD  
 
Tumor progression at important anatomical sites that requires other urgent medical 
interventions (e.g., spinal cord compression) 
For patients discontinuing the treatment for reasons other than imaging PD, imaging evaluation 
should be performed at the end of treatment and at time points specified in the protocol until one 
of the following events occurs: initiation of new anti-tumor therapy, objective PD, withdrawal of 
ICF, loss to follow-up, or death. 
Head CT/MRI examinations should be performed at baseline before the start of study treatment 
for subjects with known or suspected brain metastases during the screening. Throughout the 
study, these subjects should also receive head CT/MRI examinations to evaluate brain metastases 
as non-target lesions. 
The subject may continue the treatment if PD cannot be confirmed by the investigator, especially 
for non-target lesions and new lesions, until the occurrence of clinical symptoms or the next 
scheduled evaluation time point when the imaging evaluation will be performed again. If PD is 
confirmed, the date of PD should be the date of initial discovery. 


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The tumor imaging evaluation in this study is based on IRRC following the RECIST V1.1. See 
Appendix 4 for evaluation methods. 
7.1.4 Tumor imaging evaluation at the end of treatment and in follow-up period 
For subjects who have completed treatment or who have discontinued treatment for reasons other 
than objective PD, a tumor imaging evaluation should be performed when the treatment is 
completed/discontinued. Subsequent imaging evaluations should be carried out at time points 
specified in the protocol until one of the following events occurs: initiation of new anti-tumor 
therapy, objective PD, death, or end of the study, whichever occurs first. 
7.2 
Safety evaluation 
The investigator or qualified designee will evaluate the AEs of each subject throughout the study 
and follow-up period as required by the study schedule. AEs are graded and documented 
according to NCI CTCAE (V4.03). AEs are characterized by severity level, causality, toxicity 
level, and measures taken for study treatment. 
All AEs of unknown causes during the treatment should be evaluated to determine whether the 
events are irAEs. 
Refer to Sections 8 for details regarding AE evaluation and documentation. 
7.2.1 Physical examination 
7.2.1.1 Comprehensive physical examination 
A comprehensive physical examination will be performed by the investigator or qualified 
designee during the screening, and abnormalities with clinical significance will be documented. 
In addition, the comprehensive physical examination should be performed at time points 
specified in the study schedule. After the first dose of the study drugs, any new clinically 
significant abnormalities indicated by physical examination should be documented as AEs. 
7.2.1.2 Targeted physical examination 
In cycles where a comprehensive physical examination is not required by the study schedule, 
targeted physical examination should be performed by the investigator or qualified designee if 
clinically indicated, scheduled prior to administration on day 1 of each treatment cycle. New 
clinically significant abnormalities should be documented as AEs. 


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7.2.1.3 Body height, body weight, and vital signs 
The investigator or qualified designee will document vital signs during screening, prior to each 
administration of the study drugs, and at the end of treatment in accordance with the instructions 
in the study schedule. Weight must be measured before every planned dose during the study. If 
the body weight of a subject fluctuates by less than 10% from the baseline (the day when the first 
dose of study drugs is given), the baseline body weight will be used to calculate the 
chemotherapeutic dose. Otherwise, the actual dose will be calculated based on the weight of 
scheduled dosing days. 
Height will be measured at baseline only. Vital signs include body temperature, pulse, respiratory 
rate, and blood pressure. 
7.2.1.4 12-lead electrocardiogram (ECG) 
A standard 12-lead electrocardiogram (ECG) will be recorded according to local standard 
procedures during screening. Abnormalities with clinical significance should be documented. 
ECG examinations can be performed at other time points as clinical indicated. 
7.2.1.5 Eastern Cooperative Oncology Group (ECOG) performance status scoring 
The investigator or qualified designee will evaluate the ECOG performance status during 
screening, prior to administration on day 1 of each treatment cycle, at the end of treatment, and 
in safety follow-up period in accordance with the instructions in the study schedule. 
7.2.2 Laboratory test and evaluation 
The items of laboratory test are presented below. Refer to the study procedure manual for the 
operation procedures of body fluid sample collection. Refer to the section of laboratory 
evaluation in the study schedule for the time of test. 
7.2.2.1 Laboratory safety evaluation (routine blood test, coagulation test, urinalysis, blood 
chemistry, etc.) 
Refer to Table 10 for laboratory test items including routine blood test, coagulation test, 
urinalysis, blood chemistry, etc. 


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Table 10. Laboratory test 
Routine blood test 
and coagulation test 
Blood chemistry 
Urinalysis 
Others 
Hemoglobin 
Albumin 
PH 
Pregnancy test (blood or 
urine)a 
Platelet count 
Alkaline phosphatase 
Glucose 
Total triiodothyronine (T3) 
or FT3, FT4, and TSHb  
WBC (total and 
differential)c 
Alanine aminotransferase 
Proteind 
Anti-HCV antibody 
RBC 
Aspartate amino 
transferase 
Specific gravity 
HCV-RNA 
Hematocrit 
Calcium 
Urinary white blood cell 
HBsAg  
INR 
Chloride 
Urine red blood cell 
HBV-DNA 
PT 
Cr 
 
Anti-HBc  
 
Blood glucose 
 
HBeAg 
 
Phosphorus 
 
HBsAb 
 
Magnesium 
 
HBeAb  
 
Potassium 
 
Anti-HIV antibody 
 
Sodium 
 
Creatine phosphokinase 
(CK) 
 
TBIL 
 
Creatine phosphokinase 
isoenzyme (CK-MB) 
 
Direct bilirubin 
 
Troponin T or troponin I 
 
Total protein 
 
 
 
Blood urea or blood urea 
nitrogen 
 
 
 
Amylase 
 
  
 
Lactate dehydrogenase 
 
 
 
γ-GT 
 
 
 
Creatine kinase 
 
 
FT4 = free thyroxine; HBc = hepatitis B core antigen; 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 
Applicable for women with child-bearing potential only, perform at 3 days before the first dose and during the 
safety follow-up period. 
b 
T3 is preferred. Free T3 can be detected in case T3 is not applicable. 
c 
WBC differential includes lymphocytes, neutrophils, monocytes, basophils, and eosinophils. 
d 
The 24-h urine protein quantitation test should be performed for subjects with urine protein of ≥ 2+ 


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The laboratory test during screening should be performed within 7 days before the first dose of 
study drugs. Exceptions include hepatitis and thyroid serology examinations, which can be 
performed within 28 days (close-label stage) or 21 days (IBI308 crossover treatment stage) 
before the first dose. After cycle 1, the pre-dose laboratory safety inspections can be performed 
within 3 days before administration, unless otherwise stated in the study schedule. 
The laboratory test results must be reviewed and confirmed to be acceptable by the investigator 
or qualified designee before each administration of study drugs, unless otherwise stated in the 
study schedule. The unresolved laboratory abnormalities that are classified as drug-related AEs 
should be followed up until remission. After the end of treatment, there is no need to repeat the 
laboratory test if the results are within the normal range. 
7.2.2.2 Pregnancy test 
All women considering participating in the trial who have not undergone surgical sterilization or 
who have not reached menopause must receive a pregnancy test within 3 days before the first 
dose of the study drugs. A serum test is required if the urine test is inconclusive. Subjects must be 
excluded/discontinued from the trial if test results are positive or critically positive. 
7.2.2.3 Samples tested by central laboratory 
Refer to the study procedure manual for details regarding the collection time, storage, and 
transportation of the samples to be tested by central laboratory. 
7.3 
Pharmacokinetics: 
PK samples will be collected at the following time points: within 1 h before the infusion of 
IBI308/placebo in cycle 1, immediately (+ 5 min) after the infusion of IBI308/placebo in cycle 1, 
and within 1 h before the infusion of IBI308/placebo in cycles 2/4/12. 
For PK analysis, 3.5 mL of whole blood is collected using vacutainers with clot activator. Serum 
is then separated, dispensed in aliquots, and frozen. Refer to the Laboratory Manual provided by 
the sponsor-designated central laboratory for sampling methods, sample storage, transport, and 
analysis. 
7.4 
Immunogenicity 
Immunogenicity samples will be collected within 1 h prior to IBI308/placebo infusion in cycles 
1/2/4/8/12/16, then every 8 cycles (cycles 24, 32, and so on) thereafter, and during the safety 
follow-up. If an infusion-related reaction occurs during IBI308 infusion, blood samples should 
be taken near the start and end of this event and around 30 days after the reaction and used for 
comparative analysis of immunogenicity. For subjects in the control group crossed over to 
receive monotherapy of IBI308, blood samples will be collected only in the presence of IBI308 


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infusion-related reactions. The blood samples collected near the start and end of the event and 
about 30 days after the event will be reserved for comparative analysis of immunogenicity. The 
collected blood samples will be analyzed for immunogenicity in the central laboratory. 
ADA titer should be tested for each subject. ADA-positive samples should be further tested for 
neutralizing antibodies (NAbs). For ADA and NAb assays, 5 mL of whole blood is collected 
using vacutainers with clot activator. Serum is then separated, dispensed in aliquots, and frozen. 
Refer to the Laboratory Manual provided by the sponsor-designated central laboratory for 
sampling methods, sample storage, transport, and analysis. 
7.5 
Quality-of-Life Evaluation 
The evaluation of quality of life will be performed based on the LCSS and EORTC QLQ-C30. 
Quality-of-life questionnaires should be completed on the day of the first dose, at the time of 
each imaging evaluation, during the first safety follow-up visit, and at the time when any 
unscheduled imaging evaluation is performed. 
The Lung Cancer Symptom Scale (LCSS) consists of 9 graphical subscales that measure the 
quality of life of patients over the last 24 h. This scale is divided into two parts that are filled by 
patients and physicians respectively. The patient part consists of 9 items, and the answer of each 
item is marked on a line segment. The physician part mainly evaluates the number and severity 
level of symptoms, which are presented by grading. The 9 subscales of the LCSS include six 
major symptoms of lung cancer patients: decreased appetite, fatigue, cough, dyspnea, 
hemoptysis, and pain. The remaining 3 subscales include patients' self-assessment regarding the 
grading of lung cancer symptoms and the impacts of the disease on daily activities. 
The EORTC QLQ-C30 is a core questionnaire for patients with cancer consisting of 30 items 
which are divided into 15 scales: 5 functional scales (physical, role, cognitive, emotional, and 
social), 3 symptom scales (fatigue, pain, and nausea and vomiting), 1 global health status/quality 
of life scale, and 6 single items. 
7.6 
Biomarker analysis 
7.6.1 Tissue biomarkers 
All eligible subjects should provide tumor tissue samples meeting requirements (tissue blocks or 
unstained sections) for analyses of PD-L1 immunohistochemical expression level, RNA 
detection, etc. The following two tissues are acceptable: 
1. 
Archived tumor tissues: Wax blocks should be kept for less than 1 year, and sections should 
be prepared within 6 months; 
2. 
Fresh tumor tissues collected during screening. 


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At least 10 unstained sections are needed, with the thickness of 4–5 μm. If the tissue sample size 
is too small to provide 10 archived or fresh tumor tissue sample sections meeting the test 
requirements during screening, please communicate with the sponsor timely, and explain and 
record the reasons clearly to obtain the consent of the sponsor. The sponsor may accept the 
situation where 10 sections are not available due to limited samples in clinical practice, but at 
least sufficient sections (5 sections) should be provided for the central laboratory to detect the 
expression of PD-L1. 
Refer to the "Laboratory Manual" provided by the sponsor-designated central laboratory for 
details regarding section sampling requirements, sample storage, transport, and analysis. 
The detection result of PD-L1 expression level is used for randomization stratification. The result 
will not be provided to the investigator or subjects but directly submitted to the randomization 
system so as to ensure the study compliance. 
7.6.2 Blood biomarkers 
Each subject needs to provide 10 mL of whole blood samples at the following time points: prior 
to the first dose, every time when efficacy evaluation is performed but before the next treatment 
is started in the treatment period, the time when PD is confirmed, and during safety visit. 
Biomarker studies include but are not limited to TCR and ctDNA detection. 
Refer to the Laboratory Manual provided by the sponsor-designated central laboratory for 
sampling methods, sample storage, transport, and analysis. 
7.7 
Storage and Destruction of Biological Samples 
Samples will be disposed or destroyed, pooled and anonymized. Additional analyses of pooled 
and anonymized samples may be performed to further evaluate and validate the analytical 
method. Results of these analyses may be published separately from the CSR. 
Reproducibility (if performed) will be assessed simultaneously with the biological analysis of the 
samples. The results of these evaluations will not be published in the clinical study report, but 
will be presented separately in a biological analysis report. 


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8 
Safety Reports and AE Management 
8.1 
Definition of AEs 
An adverse event (AE) is defined as any unfavorable and unexpected medical event that is 
observed in the clinical study subject since the signing of ICF, regardless of the causality to the 
study drugs. AEs include but are not limited to the followings: 
 
Worsening of pre-existing (prior to enrollment) medical conditions/diseases (including 
symptoms, signs, and laboratory test abnormalities); 
 
Any new adverse medical conditions (including symptoms, signs, and newly diagnosed 
diseases); 
 
Clinically significant laboratory test abnormalities. 
8.2 
Definition of Serious Adverse Events 
A SAE refers to an AE meeting at least one of the followings: 
 
Death, except for the cases caused by PD; 
 
Life-threatening (a life-threatening event is defined as an AE that exposes the subject to 
the risk of death, but does not include the AE that may lead to death only if the event 
exacerbates). 
 
Requires hospitalization or prolonged hospitalization, excluding the followings: 
 Hospitalization at a rehabilitation institution 
 Hospitalization at a sanatorium 
 General emergency admission 
 Day surgery (e.g. outpatient/same-day/ambulatory surgery) 
 Hospitalizations or prolonged hospitalizations due to worsening of an AE are not 
considered as SAEs. E.g., hospitalization due to pre-existing diseases, without new 
AEs or exacerbation of pre-existing diseases (e.g., hospitalization to examine 
laboratory abnormalities that have been persistent before the study starts); 
hospitalization for other reasons (e.g., annual routine physical examinations); 
hospitalization during the study as specified in the protocol (e.g., procedure as 
required by the study protocol); elective hospitalization unrelated to exacerbation of 
AEs (e.g., elective surgery); scheduled treatment or surgical procedures, which 
should be documented in the study protocol and/or individual subject's baseline 
information; hospitalization merely due to the use of blood products. 


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 
Resulting in permanent or severe disability/incapacity. 
 
Resulting in congenital abnormalities/birth defects. 
 
Other important medical events: defined as events that may jeopardize the subjects and 
require medical or surgical interventions to prevent one of the other outcomes listed in 
the definition above. 
8.3 
Evaluation of Adverse Events 
The investigator will evaluate all AEs according to the NCI "Common Terminology Criteria for 
Adverse Events" (CTCAE) V4.03. AEs with altered CTCAE grade will be documented in the AE 
case report form (CRF)/worksheet. 
All AEs, regardless of the CTCAE grade, must be assessed for whether they are SAEs or not. 


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Table 11. Detailed rules for AE evaluation 
V4.03 CTCAE 
Grade 
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 instrumental ADL 
Grade 3 
Severe or medically significant 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 
An SAE refers to any one of the following events at any dose or during the use of study drugs: 
 
†Leading to death; 
 
†Life-threatening; or as determined by the investigator, the subject is at immediate risk of death at the time of the event (Note: this does not 
include an AE that may lead to death if the event worsens); 
 
†Leading to permanent or serious disability/insufficiency; (substantial disruption of the subject's ability to conduct normal life); 
 
†Hospitalization or prolonged hospitalization; (defined as an inpatient admission, regardless of the length of stay, even if the hospitalization 
is a prophylactic measure for continuous observation. Note: Hospitalization due to pre-existing disease that does not worsen during the trial 
[including elective surgery] is not considered as an SAE. A pre-existing disease refers to clinical conditions diagnosed prior to the treatment 
with study drugs and documented in the subject's medical history); 
 
†Congenital anomalies/birth defects; (for the offspring of the subject using the product, regardless of the time of diagnosis); 
 
Other important medical events; events that are not fatal or life-threatening, and does not require hospitalization, but may jeopardize the 
subject and may require medical or surgical interventions to prevent one of the above outcomes (marked with †) based on appropriate medical 
judgment. 
Duration 
The start and end dates of AEs should be documented. Indicate the appropriate length of time and units if the duration is less than 1 day. 
Measures 
taken  
Does the AE lead to discontinuation of the study drugs? 
Relationship 
with the 
investigational 
drug 
Is the AE caused by the study drugs? A medically qualified investigator is required to assess the causality relationship between the study drugs 
and AEs. To ensure that causality is assessed by a medically qualified investigator, the investigator must sign/date (initials) the source 
document or worksheet to support the causality assessment on the AE form. This signed document must be retained within the period required 
by the regulations. The following criteria serve as a reference guide to assist the investigator in assessing the relationship between the 
investigational drug and AEs based on available information. 
The following factors are used to assess the relationship between the study drugs and AEs; if the correlation between each criterion and 
the corresponding factor increases (in terms of quantity and/or intensity), the likelihood that the AE is caused by the study drugs increases; 


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Exposure 
Is there any evidence that the subject is exposed to the investigational drug, e.g. a credible medical history, an 
acceptable compliance evaluation (drug count, daily log, etc.), expected pharmacological effect, and in vivo 
drug/metabolite measurement samples? 
Time course 
Does the AE have a reasonable time relationship with the administration of the investigational drug? 
Is the time of AE consistent with the criteria for drug-induced AEs? 
Possible causes 
Is the AE not be explained by other pathogenies, such as underlying disease, other drugs/vaccines, or other hosts or 
environmental factors? 
Dechallenge 
Is the study drugs discontinued or dose/exposure/frequency reduced? 
If yes, can the AE resolve or improve? 
If yes, then it is a positive dechallenge. If no, then it is a negative dechallenge. 
Note: The above is not applicable if the followings occur: (1) the AE results in death or permanent disability; (2) the 
AE resolves/improves despite continuing treatment with the study drugs; (3) the study is single-dose; (4) only one 
dose of the study drugs is administered. 
Rechallenge 
Is the subject re-exposed to the study drugs? 
If yes, does the AE reoccur or worsen? 
If yes, then it is a positive rechallenge. If no, then it is a negative rechallenge. 
Note: The above is not applicable if the followings occur: (1) the initial AE results in death or permanent disability, or 
(2) the study is single-dose, or (3) only one dose of the study drugs is administered. 
Note: A rechallenge is not recommended for an SAE that is possibly caused by the investigational drug or if 
re-exposure to the investigational drug may result in potentially serious risks to the subject. However, if continuing 
study treatment is beneficial to the subject and no replacement treatment is available, a rechallenge can be performed 
after the approval is obtained from the sponsor's clinical director. 
Consistency with the 
characteristics of 
investigational drug 
Is the clinical/pathological manifestation of the AE consistent with pharmacological or toxicological data of the study 
drugs or other similar drugs? 
Based on his/her best clinical judgment, the medically qualified investigator will consider the above factors and report the results of the causality assessment in 
the CRF/worksheet. 
Causality documentation 
The following table can be used to assess the causality (not all the criteria are required to be met) 
Related 
Evidence of exposure to study drugs. A reasonable time relationship between the occurrence of the AE and administration of 
the investigational drug. The AE is more likely to be attributed to the study drugs, rather than other causes. 
Unrelated 
The subject does not receive the study drugs, or the time relationship between the occurrence of the AE and the administration of 
the study drug is unreasonable, or other explanations are more likely to be attributed to (still applicable to overdosed subjects 
without relevant AEs). 


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8.4 
Documentation of Adverse Events 
The investigator should document AEs and SAEs using medical terms and concepts. Avoid 
colloquialisms/abbreviations. All AEs (including SAEs) should be documented in the AE forms 
of the electronic case report forms (eCRFs). 
8.4.1 Collection and time of adverse events 
The investigators learned about AEs by asking the subjects non-leading questions. 
All the AEs, including SAEs, that occurred from the signing of the ICF to 30 days after the last 
dose were collected, regardless of whether it was observed by the investigator or self-reported by 
the subject. 
The investigator needs to report all SAEs and the AEs related to the study drugs or study 
procedures from 30 days after the last dose to 90 days after the last dose. 
After 90 days since the last dose, the investigator should report the SAEs that are considered 
related to the study drugs or study procedures. 
If the subject initiates new anti-tumor therapy within 90 days after the last dose, then only SAEs 
related to the study drugs are required to be documented thereafter. 
8.4.2 Follow-up of adverse events 
The AE should be followed until the events return to the baseline values or grade 0–1, or until 
the investigator believes that no further follow-up is required for reasonable reasons (if the event 
cannot be resolved or has already been improved). If the event cannot be resolved, a reasonable 
explanation should be documented in the eCRF. The outcome of an AE/SAE and date should be 
documented in the eCRF and medical record, regardless of whether the event is related to the 
study drugs. 
8.4.3 Contents of AE documentation 
The investigator should document the complete information of any AE, including diagnosis (in 
the absence of diagnosis, symptoms and signs including laboratory test abnormalities should be 
documented), time and date of occurrence (if applicable), CTCAE severity grade and alteration 
(for events ≥ grade 3), whether it is an SAE, measures taken for the study drugs, treatment for 
the AE, outcome of the event, and causality between the event and study drugs. 
For an SAE, the investigator shall also provide the date when the AE meets the criteria for an 
SAE, the date when the investigator is informed of the SAE, the reason of being an SAE, date of 
hospitalization, date of hospital discharge, possible cause of death, date of death, whether an 
autopsy has been performed, causality assessment of the study procedures, causality assessment 


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of other drugs, and other possible causes of the SAE. The investigator shall provide the rationales 
of the causality and a description of the SAE. In the SAE description, the followings shall also be 
included: the subject number, age, gender, height, and weight; indication for receiving the 
investigational drug, cancer staging, and overall condition; SAE occurrence, development, 
outcome, and result; laboratory results related to the SAE (the time of the examination, units, and 
normal ranges must be provided); medical history, onset and duration of concurrent diseases 
related to the SAE; medication history and initiation, duration, and dosage of concomitant 
medications related to the SAE; initiation, duration, and dosage of the study drug. 
Descriptions of the AE are as follows: 
Diagnosis, signs, and symptoms 
In the presence of diagnosis, instead of individual symptoms and signs (including laboratory test 
results), the definite diagnosis should be documented in the eCRF. Signs and symptoms should 
be reported as separate AEs/SAEs if cannot be attributed to the diagnosis. If it is determined that 
the signs and symptoms are caused by the diagnosis, then only the diagnosis shall be reported, 
included the signs and symptoms. The record of signs and symptoms shall then be deleted. A 
follow-up SAE report shall be submitted. 
AEs secondary to other events 
Generally, AEs secondary to other events (such as result of another event or clinical sequelae) 
should be documented as the primary event, unless the event is severe or an SAE. However, 
clinically significant secondary events should be recorded as independent AEs in the eCRFs if 
they occur at different time than the primary event. If the relationship between events is unclear, 
document them as separate events in the eCRFs. 
Ongoing or recurrent AEs 
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment 
time points. 
Recurring AEs refer to AE that have resolved between the two time points of assessment but 
subsequently occur again. These events should be independently documented in the eCRFs. 
Laboratory test abnormalities 
All clinically significant laboratory test abnormalities were reported as AEs. The investigators 
had responsibilities to review all the laboratory test abnormalities and determine whether the 
abnormalities should be reported as AEs. 


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Death 
During the entire course of the study, all the deaths that occurred within 90 days after the last 
dose were documented in the Death Report Form in the eCRFs and reported to the sponsor 
timely, regardless of the causality with the study drug. 
When documenting death events, for the death with a known cause, the cause of death should be 
documented as an AE and the outcome of the AE should be death, and the event should also be 
reported as an SAE (death caused by tumor progression will not be documented and reported as 
an AE/SAE, but the investigator should document the death in the death report form of the eCRF 
and inform the sponsor promptly). For the death with an unknown cause, the AE should be 
documented as "death with an unknown cause" in the AE form of the eCRF, and reported as an 
SAE. Further investigation should be performed next to identify the exact cause of death. 
Pre-existing medical conditions 
Symptoms/signs presenting during the screening period will be recorded and reported as AEs 
only if their severity level, frequency, or property becomes aggravated (except for worsening of 
the studied disease). The relative change should be documented, such as increased frequency of 
headaches. 
Progressive disease 
A PD is defined as the worsening of subject condition caused by the primary tumor that the 
investigational drug is targeting, the appearance of new lesions, or the progression of the primary 
lesion. Expected PD should not be reported as an AE. Any deaths, life-threatening events, 
hospitalization or prolonged hospitalization, permanent or significant disability/incapacity, 
congenital anomaly/birth defects, or other important medical events caused by PD should not be 
reported as an SAE. 
New anti-tumor therapy 
If the subject initiates new anti-tumor therapy within 90 days after the last dose, then only SAEs 
considered related to the study drugs are required to be documented and reported. 
8.5 
Expedited Reporting of SAEs and Pregnancy 
SAE reporting: 
All SAEs that occur from the signing of ICF to 90 days (inclusive) after the last dose must be 
reported. The investigator must fill the "SAE Report Form" provided by the sponsor, regardless 
of whether it is the initial report or a follow-up report. The report should be sent to the sponsor 
(drugsafety@innoventbio.com) within 24 hours of noticing the event, as well as to national 


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regulatory authorities and EC in accordance with the laws and regulations of China. 
For SAEs occurring outside of the above period, those considered related to the study drugs 
should also be reported. 
The investigator must submit the completed SAE report form to the sponsor within 24 hours of 
noticing the event. The investigator should urgently perform visit on missing information and 
provide a complete SAE report for events that result in death or are life-threatening. The 
investigator should also report the events to the national regulatory authorities and EC in 
accordance with regulations. 
Pregnancy 
The risk of embryotoxicity exists for the similar kind of drugs. All the subjects with childbearing 
potential must take effective contraceptive measures. 
During the study, if a female subject exposed to the study drugs becomes pregnant, she must be 
excluded in the study. The investigator must report to the sponsor within 24 hours of noticing the 
event and submit the Innovent Clinical Study Pregnancy Report/Follow-Up Form. 
During the study, if a female partner of a male subject exposed to the study drugs becomes 
pregnant, the subject will continue in the study. The investigator must report to the sponsor 
within 24 hours of noticing the event and submit the "Innovent Clinical Study Pregnancy 
Report/Follow-Up Form". 
The investigator must continuously monitor and visit on the outcome of the pregnancy until 8 
weeks after the subject gives birth. The outcome should be reported to the sponsor. 
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any 
congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the 
event is required to be reported in accordance with SAE procedures and time limits. 
If the subject also experiences an SAE during the pregnancy, the event should be reported 
according to SAE procedures. 
8.6 
Abnormal Hepatic Function 
Drug-induced liver injury is considered if abnormal AST and/or ALT levels are accompanied 
with abnormal elevation of TBIL, and the following conditions are met without other possible 
causes. Such cases should always be considered as important medical events. 


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Table 12. Liver injuries required to be reported as SAEs 
Baseline 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment period 
ALT or AST ≥ 3 × ULN  
with TBIL ≥ 2 × ULN, 
ALP ≤ 2 × ULN, 
and no hemolysis 
AST or ALT ≥ 8 × ULN 
with TBIL increased by ≥ 1 × ULN or TBIL ≥ 
3 × ULN 
Once being notified with the abnormalities, the subject must return to the study site promptly 
(ideally within 48 hours) and receive an assessment. The assessment must include the laboratory 
tests, detailed medical history, and physical assessment, and the possibility of hepatic tumor 
(primary or secondary) shall be considered. 
Other than repeated AST and ALT tests, albumin, creatine kinase, TBIL, direct bilirubin, 
gamma-glutamyltransferase (γ-GT), PT/INR, and ALP should also be tested. Detailed medical 
history include history of alcohol, acetaminophen, soft drugs, various supplements, traditional 
Chinese medicine, chemical drug exposure, family diseases, occupational exposure, sexual 
behavior, travel, contact with patients with jaundice, surgery, blood transfusion, hepatic diseases 
or allergies, cardiac diseases, and immune diseases. Further tests may include the detection of 
acute hepatitis A, B, C and E, hepatic imaging (such as biliary tract), autoantibodies, and 
echocardiography. If a retest shows consistency with the criteria outlined in Table 12 and there 
are no other possible causes, the possibility of drug-induced liver injury should be considered 
before all the results of etiological tests are accessible. These potentially drug-induced liver 
injury should be reported as SAEs, and the "Abnormal Hepatic Function Monitoring and 
Follow-Up Report" should be submitted to the sponsor. 
8.7 
Management of Drug-Related Toxicities 
During the course of the trial, the sponsor will conduct regularly monitoring of safety. Detailed 
information regarding the frequency of review and type of data to be reviewed will be presented 
in a separate safety review plan. 
8.7.1 Immune related adverse events 
Since the mechanism of action of IBI308 involves T-cell activation and proliferation, immune 
related adverse events (irAEs) are likely to be observed during this study. Signs and symptoms of 
irAEs were monitored. If there are no definite alternative causes (e.g. infections), signs or 
symptoms of the subjects during the study may be related to the immune system. 
Refer to Sections 5.2 and 5.3 for dose adjustments of IBI308 and principles of AE management. 


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8.8 
Emergency Unblinding 
During the study, if there is a need for unblinding (e.g., occurrence of an SAE), the responsible 
investigator of the study site will submit a request, and the sponsor's medical director and 
principal investigator will decide together whether to carry out unblinding. If emergency 
unblinding is required, the investigator can discuss with the sponsor and submit a request to 
unblind. After approval, the subject's treatment allocation will be known through the IWRS. In 
case of emergency unblinding, relevant information must be documented in the eCRF and 
reported to the IWRS provider and the sponsor promptly. Upon unblinding, the subject should 
discontinue current study drugs while being followed up until tumor progression or death.  
9 
STATISTICAL ANALYSIS 
9.1 
Statistics analysis plan 
The drafting of a detailed statistics analysis plan (SAP) will be started after the enrollment of the 
first subject, and the final draft will be determined before database locking and unblinding. The 
SAP will contain details and result expression regarding the planned analyses. 
9.2 
Statistical Hypothesis and Sample Size 
This study mainly aims to confirm that IBI308 in combination with chemotherapy can prolong 
the progression free survival (PFS) of treatment-naive patients with advanced or metastatic 
squamous NSCLC compared with chemotherapy alone. The following statistical hypothesis tests 
will be performed in this study for the primary endpoint PFS: 
Null hypothesis H0: PFS (test group) ≠ PFS (control group) 
Alternative hypothesis H1: PFS (test group) > PFS (control group) 
IBI308 is expected to prolong PFS of subjects from 5.5 months to 7.9 months (HR = 0.7). 
Calculated with the enrollment time of 15 months and the total study time of 23 months, power = 
82% and one-sided α = 0.025. Besides, an interim analysis (Lan-deMets spending function 
combined with O'Brien-Fleming) will be performed when 70% of PFS events are observed. 
Considering a monthly dropout rate of 0.5%, a total of 348 subjects (174 in the test group and 
174 in the control group) are needed to be randomized to achieve the 264 PFS events required in 
the trial. In the actual study, if the actual number of enrolled subjects is different from the 
number of planned enrollment due to unforeseen reasons, such as the enrollment speed faster 
than the requirements of the protocol, the end date of screening should be determined in advance 
to ensure that the number of actually enrolled subjects does not exceed the number of planned 
enrollment by 10%, i.e., a maximum of 382 subjects should be enrolled, 191 in each group. 


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For the secondary endpoint OS, no formal sample size calculation will be made, and the analysis 
is expected to be performed 1 year after the last subject is enrolled. 
9.3 
Definition of Analysis Sets 
Full analysis set (FAS): The FAS consists of all randomized subjects based on an intend to treat 
(ITT) principle. The analysis of this population will be performed based on treatment groups to 
which subjects are randomized. The FAS is a main analysis set, which is applicable to the 
analyses regarding efficacy, subject distribution, protocol deviation, medical history, previous 
and concomitant medications, demographics, and baseline characteristics. 
Safety analysis set (SS): The SS consists of the randomized subjects who have received at least 1 
study treatment. In the analysis of this population, subjects will be grouped based on the 
treatment they actually received during the study. If a patient receives incorrect medication in 
one cycle while receiving correct medications in other cycles, the patient will be grouped based 
on the correct treatment. The SS is used to investigate drug exposure and used for all safety 
analyses. 
Per protocol set (PPS): The PPS is a subset of the FAS, which consists of randomized subjects 
who do not have major protocol deviations affecting efficacy evaluation and have completed at 
least 1 cycle of administration with available imaging evaluation results (or have failed to 
completed at least 1 cycle of administration due to PD and have clear evidence of imaging PD). 
The PPS is used for the sensitivity analyses of primary efficacy endpoints and key secondary 
efficacy endpoints. 
9.4 
Statistical Analysis Methods 
The statistical analysis endpoints of this study include 
Primary endpoints: 
 
Progression free survival (PFS) assessed by IRRC based on RECIST V1.1 
Secondary endpoints: 
 
Overall survival (OS) of subjects in the two groups; 
 
Objective response rate (ORR) of subjects in the two groups assessed based on RECIST 
V1.1; 
 
Disease control rate (DCR) of subjects in the two groups assessed based on RECIST 
V1.1; 
 
Time to response (TTR) of subjects in the two groups assessed based on RECIST V1.1; 


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 
Duration of response (DOR) of subjects in the two groups assessed based on RECIST 
V1.1; 
 
Safety and tolerability characteristics of IBI308 in combination with gemcitabine and 
platinum (cisplatin/carboplatin) chemotherapy. 
Exploratory endpoints 
 
To explore potential biomarkers in tumor tissues that can predict the efficacy of IBI308: 
including but not limited to immunohistochemistry assay of PD-L1 expression in tumor 
specimens; 
 
To explore potential biomarkers in peripheral blood that can predict the efficacy of 
IBI308 group, including but not limited to TCR and ctDNA assay; 
 
To compare the quality of life of patients treated with IBI308 in combination with 
chemotherapy vs. standard chemotherapy by using LCSS and EORTC QLQ-C30 
questionnaires; 
 
To explore the PFS of subjects in the control group after crossover treatment with 
IBI308; 
 
To explore the population PK characteristics of IBI308. 
9.4.1 General statistical analysis 
All statistical analyses should be performed by programming calculation using the SAS 9.2 (or 
later version) statistical analysis software. 
Except for the superiority hypothesis test of the primary efficacy endpoint PFS (one-sided α = 
0.0074) in interim analysis and PFS (one-sided α = 0.0228) in final analysis, 95% CIs and 
nominal P values will be provided for other between-group comparisons (unless otherwise 
specified). If the one-sided P value ≤ 0.025, the difference between groups can be considered 
statistically significant. 
Unless otherwise specified, quantitative data will be descriptively summarized using mean ± 
standard deviation or median (maximum, minimum), while count data will be descriptively 
summarized using frequency (percentage). 
All statistical analyses, unless otherwise specified, will include treatment and randomization 
stratification factors in the analysis model. 


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9.4.2 Efficacy analysis 
9.4.2.1 Analysis of primary study endpoint 
 
PFS: time from randomization to the first objective tumor progression or death of the 
subject. Subjects who do not have PD or die will be censored on the date of their last 
imaging evaluation. Subjects who do not receive any imaging evaluation after baseline 
or have no death record will be censored on the date of randomization. 
The stratified log-rank test will be used to compare the PFS between groups. The between-group 
HR and corresponding 95% CI will be estimated with a stratified COX proportional hazards 
model, with the randomization stratification factor as the stratification factor. The COX 
proportional hazards model will also be used to assess the effects of various covariates possibly 
related to prognosis and efficacy prediction on the estimated HR. The covariates may include 
randomization stratification factor, ECOG PS (0 vs. 1), age (> 60 vs. ≤ 60), sex (male vs. 
female), smoking history (previous/present vs. never), and liver metastases (yes vs. no). Before 
much more complicated models are adopted, an initial model only containing treatment and 
randomization stratification factors will be constructed to ensure that the conclusion obtained 
from the COX model is consistent with that obtained from the stratified log-rank test. 
Furthermore, the median PFS and corresponding 95% CI will be estimated by using the 
Kaplan-Meier method, and the survival curves will be plotted. 
Considering the possible influence of tumor evaluation interval on PFS analysis, the 
interval-censored non-parametric method will also be used to estimate the median PFS and 
corresponding 95% CI. 
9.4.2.2 Analysis of secondary study endpoints 
 
OS: the time from randomization to the death of the subject. If the subject is still alive at 
the end of the study, the known "last date of subject survival" will be used as the 
censoring date. 
A stratified log-rank test will be used to compare the OS between groups. The between-group 
HR and corresponding 95% CI will be estimated with a stratified COX proportional hazards 
model, with the randomization stratification factor as the stratification factor. The COX 
proportional hazards model will also be used to assess the effects of various covariates possibly 
related to prognosis and efficacy prediction on the estimated HR. The covariates may include 
randomization stratification factor, ECOG PS (0 vs. 1), age (> 60 vs. ≤ 60), sex (male vs. 
female), smoking history (previous/present vs. never), and liver metastases (yes vs. no). Before 
much more complicated models are adopted, an initial model only containing treatment and 
randomization stratification factors will be constructed to ensure that the conclusion obtained 


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from the COX model is consistent with that obtained from the stratified log-rank test. 
Furthermore, the median OS and corresponding 95% CI will be estimated by using the 
Kaplan-Meier method, and the survival curves will be plotted. 
Given the fact that patients receiving standard chemotherapy may be crossed over to receive 
treatment with IBI308 after PD, a recognized statistical method will be used to adjust the effect 
of crossover treatment on OS. For example, the two-stage method or the rank-preserving 
structural failure time (RPSFT) model proposed by Robin and Tsiatis is adopted after checking 
method assumptions/applicability based on the obtained data. 
 
ORR: the proportion of subjects achieving complete response (CR) or partial response (PR) 
as per RECIST V1.1 in the analysis population (the formula is as follows). 
%
100
*
subjects
 
all
 
of
Number 
PR
 
achieving
 
subjects
 
of
Number 

CR
ORR
 
The ORRs and corresponding 95% CIs of treatment group and control group as well as the 
between-group difference and corresponding 95% CI will be estimated by using binomial 
distribution. 
 
DCR: the proportion of subjects achieving CR, PR or stable disease (SD) as per RECIST 
V1.1 in the analysis population (the formula is as follows). 
%
100
*
subjects
 
all
 
of
Number 
SD
 
achieving
 
subjects
 
of
Number 



PR
CR
DCR
 
The ORRs and corresponding 95% CIs of treatment group and control group as well as the 
between-group difference and corresponding 95% CI will be estimated by using binomial 
distribution. 
 
TTR: time from randomization to the first objective tumor response (CR or PR) of the 
subject. Subjects achieving neither CR nor PR will be censored on the date of their last 
imaging evaluation. 
The median TTR will be estimated via the Kaplan-Meier method and survival curves will be 
plotted. 
 
DOR: the time from the first documented objective tumor response (CR or PR) to objective 
PD or death for subjects achieving CR or PR. Subjects who do not have PD or die will be 
censored on the date of their last imaging evaluation. 
The median DOR will be estimated via the Kaplan-Meier method and survival curves will be 
plotted. 


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9.4.3 Safety analysis 
The safety analysis will be performed based on SS. Safety parameters include AEs, laboratory 
tests, vital signs, ECG, and immunogenicity. Data will be summarized by group, and AEs will be 
aggregated and summarized. For patients receiving placebo in combination with chemotherapy 
followed by crossover treatment with IBI308, the primary safety analysis will only be performed 
on the data obtained before crossover treatment (e.g., for the placebo in combination with 
chemotherapy group, AEs during treatment with IBI308 will not be analyzed). Exploratory 
analyses will be performed on the safety data obtained since the first crossover treatment with 
IBI308. 
9.4.3.1 Drug exposure 
The drug exposure, duration of treatment (number of treatment cycles), dose adjustments during 
treatment, and accumulative number of dose adjustments during treatment will be summarized. 
9.4.3.2 Adverse events 
All adverse events (AEs) will be coded and categorized according to MedDRA, and graded by 
severity level according to CTCAE V4.03. 
The distributions of incidences (frequency) and severity levels of AEs, adverse drug reactions 
(ADRs), immune related adverse events (irAEs), AEs leading to treatment discontinuation, AEs 
leading to study termination, AEs leading to death, grade 3 or greater AEs, serious adverse events 
(SAEs), etc. will be summarized respectively according to SOC and PT in MedDRA. 
Subjects who discontinue the treatment due to AEs, develop SAE, or die will be listed (include at 
least the followings: start and end date of the AEs, severity levels, relationship with study drugs, 
measures taken, and outcomes). 
9.4.3.3 Pharmacokinetic and immunogenicity analyses 
The immunogenicity and PK data are collected in this study, and the number and percentage of 
subjects who develop ADAs and NAbs during the study will be summarized by group. The PK 
analysis will include, but is not limited to, descriptive statistical analysis of IBI308 trough 
concentrations in cycles 1/3/11. 
9.4.3.4 Laboratory test 
Measured values and changes from baseline of laboratory tests will be analyzed using descriptive 
statistics. Baseline results and worst results during the study will be presented in cross tabulation. 


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9.4.3.5 ECG 
Descriptive statistics will be performed on the changes of ECG parameters from baseline. A 
cross-classification table will be used to describe normal and abnormal changes after treatment 
and data lists will be provided. 
9.4.3.6 Vital signs, physical examination, and other safety-related examinations 
Measured values and changes from baseline of vital signs, physical examination, and other 
safety-related examinations will be analyzed using descriptive statistics. Baseline results and 
worst results during the study will be presented in cross tabulation. 
9.4.4 Compliance analysis 
The proportion and frequency of subjects who violate the expected administration regimen, the 
proportion of subjects receiving drugs at 80–120% of the dose prescribed in the protocol, the 
proportion of subjects who complete the study, and the proportion of subjects who complete 
different treatment cycles will be summarized by group. 
9.4.5 Subjects' baseline characteristics 
Subjects' demographic characteristics (sex and age), diagnosis and treatment information of 
indication (tumor types, pathological diagnosis, clinical staging, and previous therapy), baseline 
tumor evaluation (target lesion, number of non-target lesions, sites, total diameter, etc.), and 
other baseline information (height and weight (BMI, BSA), vital signs, ECOG PS scores, 
laboratory tests, past/concomitant/new combined medications) will be analyzed using descriptive 
statistics. 
9.4.6 Interim Analysis 
The primary endpoint PFS is analyzed at approximately 23 months after the start of the trial (i.e., 
at the end of the study, expected to be at approximately 8 months after randomization of the last 
subject). Besides, an interim analysis will be carried out during the study.  
Time of interim analysis: The analysis will be performed when 70% of PFS events (185 cases) 
occur (at approximately 16 months after the start of the trial). 
Objective of interim analysis: to demonstrate that IBI308 in combination with chemotherapy is 
superior to placebo in combination with chemotherapy regarding the primary study endpoint PFS 
In the interim analysis, with one-sided α = 0.0074, if HR ≤ 0.698 is observed for the test group of 
IBI308 in combination with gemcitabine and cisplatin or carboplatin chemotherapy vs. the 
control group of placebo in combination with gemcitabine and cisplatin or carboplatin 
chemotherapy, it is demonstrated that the superiority has been concluded in the interim analysis. 


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The analysis results and reports will be submitted to the IDMC, which will judge whether the 
trial is valid according to the estimated valid cut-off value and give advice to the sponsor on 
whether the study data can be submitted in advance. The IDMC charter will be finalized and 
approved by IDMC and sponsor prior to the interim analysis. If the study proceeds, the IDMC 
will continue performing regular evaluation and monitoring on safety data until the final 
analysis. 
If the IDMC suggests the sponsor to submit the trial data in advance based on the estimated valid 
cut-off value and the sponsor decides to follow the advice, the investigator, subjects, the 
independent imaging evaluation, and the sponsor staff who directly participate in the study 
implementation should remain blinded. Some sponsor staff not directly involved in the study 
implementation will be unblinded for the submission based on interim analysis data. 
9.4.7 Subgroup analysis 
In order to confirm the consistency of efficacy in various subgroup populations, subgroup 
analyses will be performed regarding randomization stratification factors, ECOG PS (0 vs. 1), 
age (> 60 vs. ≤ 60), sex (male vs. female), smoking history (previous/present vs. never), liver 
metastases (yes vs. no), etc., and the HRs and corresponding 95% CIs of efficacy endpoints 
(PFS, OS, and ORR) of different subgroups will be estimated, and forest plots will be 
constructed. 
9.4.8 Multiple comparisons and adjustments 
The only primary endpoint of this study is PFS (assessed by blinded independent central review). 
The interim analysis will be performed when 70% of PFS events occur. In order to strictly 
control the overall type I error rate of this study at the one-sided level of 0.025, the interim test of 
PFS will be carried out at the one-sided level of 0.0074 (corresponding HR cut-off value is 
0.698). If the interim analysis result is not significant, PFS will be tested at the one-sided level of 
0.0228 at the end of the study. 
Final PFS analysis is expected to be performed about 8 months after enrollment of the last 
subject. If the interim analysis results fail to reach statistical significance, and the PFS events at 
the final analysis are significantly more than the estimated, the P value of the final analysis will 
be recalculated using the Flexible spending function according to the α value actually spent in 
the interim analysis, so as to ensure that the overall type I error is controlled at a one-sided level 
of 0.025. 
For other analyses, 95% CIs and nominal P values will be provided unless otherwise specified. If 
the one-sided P value ≤ 0.025, the difference between groups can be considered statistically 
significant. 


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9.4.9 Eligible subject data lists 
In addition to subjects' data list, tumor evaluation (date of evaluation, lesion status, evaluation 
results) and efficacy endpoints of subjects who have achieved CR and PR will be listed 
separately. 
9.4.10 Exploratory analyses 
Descriptive statistics will be given for baseline PD-L1 expression (< 1%, 1–49%, > 49%) and 
dynamic changes in TCR and ctDNA of overall subjects, as well as proportion of subjects with 
different expression or distribution levels and corresponding ORR and DOR. 
Scores based on LCSS and EORTC QLQ-C30 (V3.0 Chinese version) will be converted from 
raw scores into standardized scores ranging between 0–100. The results will be subjected to 
descriptive statistics and Wilcoxon test to analyze the quality of life of patients in the two groups. 
Besides, the ECOG PS will also be analyzed using descriptive statistics and Wilcoxon test. 
The PFS (time from the first dose of IBI308 to objective PD or death from any cause) of the 
subjects in the control group receiving crossover treatment with IBI308 should be investigated 
based on the RECIST V1.1. 
The PK analysis will include but is not limited to descriptive statistical analysis of IBI308 trough 
concentrations in cycles 1/3/11. 
10 Quality assurance and quality control 
According to the GCP guidelines, the sponsor was responsible for implementing and maintaining 
quality assurance and quality control systems in accordance with the corresponding standard 
operation procedures to ensure that the implementation of the clinical trial and the collection, 
recording, and reporting of clinical trial data comply with the requirements in the protocol, GCP, 
and corresponding regulations. 
10.1 Clinical monitoring 
The sponsor or its authorized contract research organization (CRO) will conduct clinical 
monitoring of this study. The CRA shall perform the monitoring in accordance with the standard 
operation procedures provided by the sponsor or CRO, and has the same rights and 
responsibilities as the sponsor's medical monitor. The CRA should maintain regular 
communication with the investigator and the sponsor. 
Before the start of the study, the CRA assesses the qualifications of each study site, and reports 
issues related to facilities, technical equipment, or medical staff to the sponsor. During the course 
of the study, the CRA is responsible for the monitoring of whether the written ICF from all 


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subjects has been obtained and whether the data records are correct and complete. Also, the CRA 
will compare the data entered into the eCRF with the source data, and inform the investigator of 
any errors or omissions. Besides, the CRA will also monitor the protocol compliance of the study 
site, arrange for the supply of the study drugs, and ensure that the drugs are kept under proper 
conditions. 
The monitoring visit will be conducted in accordance with applicable statutes and regulations. 
Each site receives regular monitoring visits from the time the subjects are enrolled. After each 
visit to the investigator, the CRA should submit a written report to the sponsor. 
10.2 Data Management/Coding 
This study will use an electronic data collection (EDC) system, and the research data will be 
recorded in the eCRFs by the investigators or its authorized personnel. Before the initial of the 
study site or data entry, the investigators and authorized personnel should be properly trained and 
appropriate security measures should be taken for the computer and other equipment. 
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 developments of the 
subjects. To avoid the differences in evaluations by different evaluators, it is recommended that 
the baseline and all the subsequent efficacy and safety evaluations of a given subject shall be 
performed by the same individual. The investigators are required to review the data to ensure the 
accuracy and correctness of all the data entered into the eCRFs. During the study, the investigator 
should document any evaluations that are not conducted, or any information that is not available, 
applicable, or known. The investigator needs to sign all verified data electronically. 
The CRA will review the eCRF, and assess the completeness and consistency. The CRA will also 
compare the eCRF with the source documents to ensure the consistency of critical data. Data 
entry, corrections, and modifications should be performed by the investigator or his/her 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 modification. 
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 manager will submit data queries in the electronic 
data capture (EDC) system, and study personnel should respond to the queries. The EDC system 
will record the audit trail of each query, including the name of the investigator, as well as the 
time and date. 
Unless otherwise specified, the eCRF should be considered simply as a form for data collection 
and not a source document. The source documents are used by the investigators or hospital, 
including all records related to the subjects, which are able to demonstrate the presence, 


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inclusion criteria, and participation of subjects (laboratory records, ECGs, pharmaceutical 
records, and subject folders etc.). 
The investigators are required to maintain all source documents and to 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 privacy information 
(including the subjects' names) should be deleted or made illegible to protect the privacy of the 
subjects. The investigators verify that the record has been reviewed and that the data are accurate 
with an electronic signature. The electronic signature is completed with the investigator's user ID 
and password. The system automatically attaches the date and time of the signature. The 
investigator could not share the user ID and password with other personnel. If data in the eCRF 
need to be modified, the procedures defined by the EDC system have to be followed. All 
modifications and reasons for the changes are recorded in the audit trail. 
AEs, and concurrent diseases/medical history will be coded. The medical dictionary used for 
coding will be described in the Clinical Study Report (CSR). 
10.3 Quality Control Audit 
During the course of the study, the sponsor or the representative authorized by the sponsor may 
perform quality control audit on the study sites, database, and relevant study documents. At the 
same time, the corresponding regulatory authorities may also audit the study sites, database, and 
relevant study documents at their own discretion. The investigator must inform the sponsor 
promptly upon receipt of the inspection notice from the regulatory authorities. 
The quality control department of the sponsor may also conduct an audit on the clinical study 
sites. which includes the supply of drugs, required trial documents, records of informed consent 
process, as well as the consistency of medical report forms with the source documents. The 
content and scope of the audits can also be increased as the circumstance may require. After 
receiving the notice, the investigator should allow auditors commissioned by the sponsor to 
conduct trial-related audits and audits conducted by the regulatory authorities. The main 
objective of an audit is to ensure that the rights and health of the subjects are protected, the ICF 
is signed, the trial procedures are implemented correctly, and all data processing and reporting 
related to the evaluation of the study drugs are in line with the requirements of the plan, protocol, 
implementation, ethical standard operation procedures, GCP, and applicable regulations. The 
investigator should provide all trial files, source records, and source data. 


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11 Ethics 
11.1 Ethics committee 
The sponsor or the representative authorized by the sponsor will provide relevant documents to 
the corresponding ethics committee (EC) of the study site for approval, including the trial 
protocol, ICF, Investigator's Brochure, subject recruitment materials or advertising, and other 
documents required by regulations. Prior to the start of the study, the investigator must obtain 
written approval from the EC and submit it to the sponsor. The written approval from the EC 
must specify the title, number, and version number of the study protocol, as well as the version 
number of other documents (such as ICF) and the approval date. The investigator is required to 
notify the sponsor of the EC's written comments regarding delay, interruption, and re-approval of 
the study. 
The study site must follow the requirements of the EC in the study site. The modified study 
protocol, ICF, and subject recruitment materials should be submitted to the EC for approval. 
Report and update regularly, and submit the final report according to the safety reporting 
requirements stipulated by EC. All the above documents and EC approvals must be provided to 
the sponsor or designee. 
11.2 Ethics 
The process of study and informed consent are subject to the Declaration of Helsinki, relevant 
GCP requirements, as well as laws and regulations related to the protection of drug and data in 
China. 
The GCP is an international ethical and scientific specification for designing, conducting, 
recording and reporting clinical trials that involve the participation of 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 must not 
change the procedures without consent from the sponsor. Any protocol deviations must be 
reported to the EC, the sponsor, or regulatory authorities. 
11.3 Informed Consent of Subjects 
Before the start of any study procedure, the ICF should be used to explain the possible risks and 
benefits of this study to potential participants, and the expression used in the ICF should be 
straightforward. The ICF statement should clarify that the ICF is voluntarily signed and the risks 
and benefits of participating in this study should be clearly outlined. The subject can withdraw 


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from the study at any time. Can a subject be enrolled to the clinical trial only when the 
investigator has fully explained the details of this study, the subject's questions have been 
satisfactorily answered, the subject has been given sufficient time for consideration, and the 
written consent from the subject or his/her legal representative has been obtained. All signed 
ICFs must be kept in the investigator's files or in the subject's folder. 
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF 
signed and dated by the subject or his/her legal representative prior to starting the study. The 
investigator should provide the subject with a copy of the signed ICF. The investigator must 
document the informed consent process in the source document of the trial. 
11.4 Data Protection of Subjects 
Information about data and privacy protection will be included in the ICF. Precautions should be 
taken to ensure the confidentiality of the documents and prevent the disclosure of information on 
the identity of the subject. However, under special circumstances, some personnel may be 
permitted to see the genetic data and personal identification number of a subject. For example, in 
the event of a medical emergency, the sponsor, designated physician, or investigator will have 
access to the identification code and the genetic data of the subject. In addition, relevant 
regulatory authorities may also request access to relevant documents. 
12 STUDY MANAGEMENT 
12.1 Data Processing and Record Keeping 
Records from the clinical trial (such as protocol and protocol revision, completed eCRFs, and 
signed ICFs) are to be kept and managed in accordance with the GCP. The study sites should 
keep these documents for 5 years after the end of the study. 
Study documents should be retained properly for future access or data traceability. Safety and 
environmental risks should be considered when retaining documents. 
The documents associated with the study may only be destroyed with the written consent of the 
sponsor and the investigator. Can the investigator/study site transfer the study documents to other 
parties that comply with the record-keeping requirements or to another locations that meet 
record-keeping requirements only after notifying the sponsor and obtaining the written consent. 
12.2 Source Data/File Access 
The investigator agrees that the sponsor, CRO, and relevant authorized regulatory agencies shall 
have direct access to all the study-related documents, including medical records of the subjects. 


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12.3 Protocol Revisions 
All protocol revisions during the course of the study period must be communicated between and 
agreed by the sponsor and the investigator. The sponsor shall ensure that the protocol revision is 
submitted to the regulatory authority in a timely manner. 
All revisions to the protocol shall be kept as supplements to the protocol. Any changes to the 
protocol must be submitted to the EC for approval or filing in accordance with the EC's 
regulations. If necessary, it should also be submitted to the regulatory authorities for approval 
and only implemented after being approved by the EC and regulatory authorities (if applicable) 
(with the exception of changes to the protocol that eliminate direct hazards to the trial subjects). 
12.4 Responsibilities of the Investigator 
The investigator will conduct this study in accordance with the protocol, ethical principles of the 
Declaration of Helsinki, Chinese GCP, and applicable regulations. 
The detailed responsibilities of the relevant investigators are listed in Chapter 5 (Investigator's 
Responsibilities) of the Chinese GCP (Order No. 3). 
12.5 Publishing Policy 
All the data generated in this study are confidential information owned by the sponsor. The 
sponsor has the right to publish the study results. Information on the publishing policies of the 
sponsor and investigator will be described in the clinical trial agreement. 
All the information on this trial (not limited to the protocol and Investigator's Brochure) must be 
kept strictly confidential. The investigator must recognize that the scientific or medical 
conclusion derived from this trial may be of commercial value to the sponsor. The investigator 
should keep the information and data related to this study confidential. The sponsor must be 
consulted in advance and written consent must be obtained prior to publishing of any 
study-related data or conclusions. In order to protect the rights and interests, the sponsor may 
request the investigator not to publish relevant trial data before the investigational drug is 
approved for marketing. 
The sponsor has the right to announce or publish information or data related to the trial or to report 
it to the drug administration. The sponsor must obtain consent of the investigator if the name of the 
investigator will be included in the content of the announcement, publication, or advertising. 
12.6 Financing and Insurance 
The sponsor shall purchase insurance for participants in the study in accordance with local 
regulations and minimum requirements. Insurance related terms shall be saved in the study folder. 


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13 REFERENCES 
1. 
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J Clin. 2017; 
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Boyd, J. A. et al. Timing of local and distant failure in resected lung cancer: Implications 
for reported rates of local failure. J. Thorac. Oncol. 2010; 5: 211–214. 
3. 
Paz-Ares, L. et al. Maintenance therapy with pemetrexed plus best supportive care versus 
placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin 
for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): A double-blind, 
phase 3, random. Lancet Oncol. 2012; 13: 247–255. 
4. 
Sandler, A. et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell 
Lung Cancer. N. Engl. J. Med. 2006; 355: 2542–2550. 
5. 
Solomon, B. J. et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung 
Cancer. N. Engl. J. Med. 2014; 371: 2167–2177. 
6. 
Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with 
advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, 
CTONG-0802): a multicentre, open-label, randomized, phase 3 study. Lancet Oncol. 
2011; 12: 735–742. 
7. 
Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced 
non-small-cell lung cancer. N. Engl. J. Med. 2002; 346: 92–8. 
8. 
Scagliotti, G. V. et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin 
plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung 
cancer. J. Clin. Oncol. 2008; 26, 3543–51. 
9. 
Herzberg, B., Campo, M. J. & Gainor, J. F. Immune Checkpoint Inhibitors in Non-Small 
Cell Lung Cancer. Oncologist. 2017; 22: 81–88. 
10. 
Brahmer, J. et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell 
Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015; 373: 123–135. 
11. 
Borghaei, H. et al. Nivolumab versus Docetaxel in Advanced Nonsquamous 
Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015; 373: 1627–39. 
12. 
Reck, M. et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell 
Lung Cancer. N. Engl. J. Med. 2016; 375: 1823–1833. 


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13. 
Carbone, D. P. et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung 
Cancer. N. Engl. J. Med. 2017; 376: 2415–2426. 
14. 
Hellmann, M. D. et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor 
Mutational Burden. N. Engl. J. Med. 2018; NEJMoa1801946. 
doi:10.1056/NEJMoa1801946 
15. 
Brown, J. S., Sundar, R. & Lopez, J. Combining DNA damaging therapeutics with 
immunotherapy: More haste, less speed. Br. J. Cancer. 2018; 118: 312–324. 
16. 
Gandhi, L. et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung 
Cancer. N. Engl. J. Med. 2018; NEJMoa1801005. doi:10.1056/NEJMoa1801005 
17. 
Nowak, A., Robinson, B. & Lake, R. Gemcitabine Exerts a Selective Effect on the 
Humoral Immune Response. Cancer Res. 2002; 62: 2353–2358. 
18. 
Hato, S. V., Khong, A., De Vries, I. J. M. & Lesterhuis, W. J. Molecular pathways: The 
immunogenic effects of platinum-based chemotherapeutics. Clin. Cancer Res. 2014; 20: 
2831–2837. 
19. 
Chen, L. & Han, X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. 
J. Clin. Invest. 2015; 125: 3384–91. 
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Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 
(80-. ). 2018; 359: 1350–1355. 
 


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14 APPENDIX 
Appendix 1: Signature Page for Investigator 
Protocol Title: 
A Randomized, Double-Blind, Phase III Study to Compare the Efficacy and Safety of 
IBI308 in Combination with Gemcitabine and Platinum-Based Chemotherapy Vs. Placebo 
in Combination with Gemcitabine and Platinum-Based Chemotherapy in the First-Line 
Treatment for Patients with Advanced or Metastatic Squamous Non-Small Cell Lung 
Cancer (ORIENT-12) 
 
Protocol No.: CIBI308C303  
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and 
fully understood this protocol, and agree to conduct this study in accordance with the 
requirements found in this protocol and the GCP, and in compliance with relevant laws and 
regulations and the Declaration of Helsinki. Also, I promise not to reveal any confidential 
information to a third-party without the written consent from Innovent Biologics (Suzhou) Co., 
Ltd. 
Instructions for the Investigator: Please sign and date this signature page, type the 
investigator's name and job title, as well as the name of the study site, and return this 
document to Innovent Biologics (Suzhou) Co., Ltd. 
 
I have read the entire contents of this study protocol and shall perform the study as required: 
Investigator's signature:  
____________ Date: __________ 
Name (Print):  
___________________________ 
Job Title:  
___________________________ 
Name and Address of Study Site: ___________________________ 
 
___________________________ 
 
___________________________ 


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Appendix 2: Performance Status Scoring Criteria (ECOG PS) 
Activity score 
Description 
0 
Asymptomatic, fully active, able to carry on all performance without restrictions. 
1 
Symptomatic, restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work. 
2 
Symptomatic, ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours (confined to bed < 50% during the day). 
3 
Symptomatic, capable of only limited selfcare. Confined to bed or chair > 50% of waking hours, 
while not bedridden yet. 
4 
Completely disabled, cannot carry out any selfcare. Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 


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Appendix 3: Calculation of Clearance of Creatinine and Body Surface Area 
Clearance of creatinine (CCr) is calculated based on Cockcroft-Gault formula 
 
Calculation of serum creatinine (SCr) concentration (mg/dL): 
Male CCr (mL/min) = 
(140 – age) × (body weight)a 
72 × SCr 
 
Female CCr (mL/min) = 
0.85 × (140 – age) × (body weight)a 
72 × SCr 
 
Calculation of serum creatinine (SCr) (mol/L): 
Male CCr (mL/min) = 
(140 – age) × (body weight)a 
0.81 × SCr 
 
Female CCr (mL/min) = 
0.85 × (140 – age) × (body weight)a 
0.81 × SCr 
 
a: The unit of age is year and the unit of body weight is kg. 
 
 
Calculation of body surface area 
Body surface area (m2) = 0.00616 × height (cm) + 0.01286 × body weight (kg) – 0.1529 
 


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Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST), V1.1 (Excerpts) 
 
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 greater than 5 mm) 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
1.1.2 Non-measurable lesion 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions with previous local therapy require particular comment: 
Bone lesions: 
1) 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions; 


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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 patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
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 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations regarding the size of tumor lesions should be performed as close as possible 
to the treatment start. In this study, the baseline evaluations must be completed within 28 days 
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 evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 


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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. However, 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 or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm 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 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 to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 


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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. In other words, if the lymph node is a target 
lesion, even if the criteria for CR are reached, a CR cannot be determined due to the definition of 
< 10 mm of the minimum diameter of a normal lymph node. Case report forms (CRF) 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 are too small to be measured: In clinical studies, all lesions (nodules or 
non-nodules) recorded at baseline should be recorded again in subsequent evaluations, even if 
these lesions are very small (as small as 2 mm, for example). However, in some cases, the lesion 
may be too small so that the CT scan image is very blurry, and it is difficult for the radiologist to 
define the measurement value. Therefore, such lesion may be reported as "too small to be 
measured". In this case, it is very important to record a value on the eCRF. If it is the opinion of 
the radiologist that the lesion has probably disappeared, the measurement value should be 
recorded as 0 mm. If the lesion does exist but with a blurry image so that an exact measurement 
value cannot be obtained, the default recording should be 5 mm. (Note: This is unlikely to occur 
in lymph nodes, because a lymph node normally has a measurable size, or it is often surrounded 
by fat tissues as in the retroperitoneal cavity; but if the measurement value of such node cannot 
be obtained, the default recording should also be 5 mm). The default value of 5 mm is 
determined by the cutting thickness of the CT scan (which will not change due to different 
cutting thickness values of CTs). Since the same measurement value is hardly possible to occur 
twice, providing the aforesaid default value can reduce the risk of erroneous assessment. But it 
needs to be reiterated that if the radiologist can provide the exact measured size of the lesion, the 
actual value must be recorded, even if the diameter of the lesion is less than 5 mm. 
Separated or combined lesions: When a non-nodular lesion is presented in parts, the maximum 
diameter of each separated part is added to calculate the sum of the lesion diameters. Similarly, 
for combined lesions, they can be distinguished by the plane between the combined parts, and 
then calculate the maximum diameter of each. However, if the combination is inseparable, the 
maximum diameter should be taken as the longest diameter of the entire combined lesion. 


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2.3 Evaluation of Non-Target Lesions 
This section defines the response criteria for 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): All non-target lesions are disappeared and the levels of tumor markers 
are recovered to normal. All lymph nodes must be non-pathological in size (with the minimum 
diameter of < 10 mm). 
Incomplete response/non-PD: At least 1 non-target lesion is found with/without persistent tumor 
marker levels that exceed normal levels. 
Progressive disease (PD): Definitive progression of existing non-target lesions. Note: A PD will 
be considered if at least 1 new lesion is found. 
2.4 Special Notes on the Assessment of Progression of Non-Target Lesions 
The concept of progression of disease requires additional explanation as follows: When the 
patient also has measurable non-target 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. However, the 
general increase in the size of one or more non-target lesions is often insufficient to meet the 
criteria for PDs. Therefore, when the target lesion is stable or partially resolved, it is very rare 
that the change of non-target lesions alone can define the overall tumor progression. 
When the patient has only non-measurable non-target disease: This circumstance arises in some 
phase III trials when it is not a criterion of study entry to have measurable disease. However, the 
overall evaluation is also based on the aforesaid requirements since no measurement value can be 
obtained for the lesion. The assessment of the exacerbation of non-target lesions is a major 
challenge (by definition: all non-target lesions must not be measurable), and thus when the 
changes in non-target lesions lead to an increase in the overall disease load equivalent to the PD 
of target lesions, an effective test method should be established for evaluation according to the 
definitive progressions of non-target lesions. For example, the lesion can be described as an 
increase in tumor burden equivalent to an additional 73% increase in volume (equivalent to a 
20% increase in the diameter of a measurable lesion); or a peritoneal effusion from "minor" to 
"major"; or a lymphatic lesion from "local" to "extensive"; or in the protocol as "sufficient to 
cause changes in the therapy". Other examples include a pleural effusion from "trace" to "major", 
lymphatic involvement spreading from the primary site to a distant site, or lesions described in 
the protocol as "requiring changes in the treatment". If 'unequivocal progression' is seen, the 


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patient should be considered to have had overall PD at that point. It is best to have objective 
criteria applicable to the assessment of non-measurable lesions. Notably, the additional criteria 
must be reliable. 
2.5 New Lesions 
The appearance of new malignant lesions can be an indication for the progression of the disease. 
Therefore, it is critical to perform a certain assessment for such new lesions. Currently, there is 
no specific criteria for imaging tests of these lesions, while the findings for new lesions should 
be definitive. For example, the progression cannot be attributed to differences in imaging 
technologies, changes in imaging morphology, or other lesions except tumors (such as some 
"new bone lesions" that are simply the cure or the recurrence of the underlying lesions). This is 
of great importance when the patient is partially or completely responded to the treatment for 
his/her lesions at baseline. Specifically, a necrosis of a liver lesion may be defined as a new 
cystic lesion in the CT report, but it is not. 
Lesions that have been detected during follow-up but not found at baseline will be considered as 
new lesions, and will be an indication for a PD. An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases. The patient's brain metastases are considered to be evidence of PD even if he/she did 
not have brain imaging at baseline. 
If a new lesion is not definitive due to its size or other reasons, further treatment and follow-up 
evaluation are required to confirm whether it is a new lesion. If the lesion is confirmed to be a 
new one by repeated examinations, the time of the initial finding should be counted as the start of 
the PD. 
Generally, the FDG-PET assessment of lesions requires additional tests for supplemental 
confirmation, and it is reasonable to combine the results from FDG-PET tests and those from CT 
tests (especially for new suspicious diseases). New lesions can be identified by FDG-PET tests 
based on the following procedures: 
In case of negative FDG-PET test results at baseline in combination with positive results from 
subsequent follow-up FDG-PET tests, a PD is indicated. 
In case of no FDG-PET tests at baseline in combination with positive results from subsequent 
FDG-PET tests: 
A PD can be proved if new lesions determined by the subsequent FDG-PET test results which 
are positive are consistent with those determined by CT test results; 


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Otherwise, the CT tests should be performed again for confirmation (if confirmed, the time of 
abnormality found by previous FDG-PET tests should be counted as the start of the PD); 
And no progression should be determined in case of consistency between the subsequent 
FDG-PET test results which are positive and those of existing lesions determined by CT tests. 
2.6 Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at a particular time point, the patient is not evaluable 
(NE) at that time point. If only part of the lesions of a subject can be evaluated in an evaluation, 
the case should then be determined as non-evaluable at that time point, unless there is evidence 
to prove that the missing lesions will not affect the efficacy evaluation at the specified time point. 
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. In order to avoid 
overestimating the condition indicated by the increase in nodule size, the measurement result will 
still be recorded even if the size is normal. As mentioned above, this suggests that the 
measurement results from subjects who are evaluated with CR will not be recorded as 0 on the 
eCRF. 
If the efficacy confirmation is required during the study, the optimal overall efficacy will be 
more difficult to be evaluated at the repeated "non-measurable" time points. For these missing 
data/evaluations, it must be stated in the analysis plan of the study that they can be explained 
clearly when determining efficacy. In most studies, for example, the response from a subject in 
PR-NE-PR can be considered as the efficacy confirmation. 
When a subject experiences a global exacerbation of the health status requiring discontinuation 
of the treatment, but no objective evidences are obtained, it should be reported as a symptomatic 
progression. In addition, the cases with objective progression should be possibly assessed even 
after the treatment is terminated. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Attached 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). 
Sometimes, it may be difficult to distinguish local lesions from normal tissues. When such 
definition is the basis for the assessment of CRs, we recommend a biopsy before evaluating the 


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efficacy by CR of local lesions. When the abnormal imaging results of the local lesions in some 
subjects are considered as indications for lesion fibrosis or scarring, the FDG-PET should be 
taken as criteria similar to biopsy, in order to confirm the efficacy by CR. In this case, the 
application of FDG-PET should be prospectively described in the protocol, and supported by the 
report of the specialty medical literature. However, it must be realized that false positive results 
can be obtained in the CR assessment due to the limitations of FDG-PET and biopsy themselves 
(including the resolution and sensitivity). 
Attached Table 1. Time point response: patients with target (+/– non-target) disease 
Target lesion 
Non-target lesion 
New lesion 
Overall response 
CR 
CR 
Absent 
CR 
CR 
Non-CR/non-PD 
Absent 
PR 
CR 
NE 
Absent 
PR 
PR 
Non-progressive or not completely evaluable 
Absent 
PR 
SD 
Non-progressive or not completely evaluable 
Absent 
SD 
Not completely evaluable 
Non-progressive 
Absent 
NE 
PD 
Any 
Any 
Any 
PD 
Any 
Yes or No 
Yes or No 
Yes 
PD 
PD 
PD 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable. 
Attached Table 2. Time point response: patients with non-target disease only 
Non-target lesion 
New lesion 
Overall response 
CR 
Absent 
CR 
Non-CR/non-PD 
Absent 
Non-CR/non-PD 
Not completely evaluable 
Absent 
NE 
PD that cannot be determined 
Yes or No 
PD 
Any 
Yes 
PD 
Note: 'Non-CR/non-PD' is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.  
For indefinite progression findings (such as very small and uncertain new lesions; and cystic or 
necrotic changes in the underlying lesions), the treatment can be continued until the next 
assessment. If a PD is confirmed in the next assessment, the date when a suspected progression is 
found previously will be taken as the date of the progression. 


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Attached Table 3. Best overall response when confirmation of CR and PR required 
Overall response at 
the first time point 
Overall response at the 
subsequent time points 
Optimal overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
If SD meets the minimum time requirement, it should be 
the result otherwise PD 
CR 
PD 
If SD meets the minimum time requirement, it should be 
the result otherwise PD 
CR 
NE 
If SD meets the minimum time requirement, it should be 
the result otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
If SD meets the minimum time requirement, it should be 
the result otherwise PD 
PR 
NE 
If SD meets the minimum time requirement, it should be 
the result otherwise NE 
NE 
NE 
NE 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, NE = not evaluable. a: If a CR is truly met at first time point, then any disease seen at a 
subsequent time point, even disease meeting PR criteria relative to baseline, makes the disease 
PD at that point (since disease must have reappeared after CR). The optimal response will be 
determined by whether SD is observed at the minimum treatment interval. The first evaluation 
result may be CR in some cases, while small lesions are indicated by scanning at the subsequent 
time points. Consequently, the efficacy in the subjects at the first time point should actually be 
PR rather than CR. In this case, the initial CR result should be changed to PR, for which the 
optimal response will be 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 studies where 
SD or PD 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.  


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2.8.2 Duration of overall response 
The overall response period refers to the time from the first measurement consistent with the 
criteria for CR or PR (whichever is obtained first) to the time when the recurrence or progression 
of the disease is firstly recorded (the minimum measurement recorded in the study is used as a 
reference for determination of PD). The overall response duration refers to the time from the first 
measurement consistent with the criteria for CR to the time when the recurrence or progression 
of the disease is firstly recorded. 
2.8.3 Duration of stable disease 
SD 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 relativity of 
SD period varies with different studies and diseases. For a specific trial using the proportion of 
patients with SD for a minimum period of time as an endpoint, it should be specified in the 
protocol that the minimal time interval between two measurements defined by SD. 
Note: The DOR and SD as well as the progression free survival (PFS) are influenced by the 
frequency of the follow-up after baseline evaluation. It is not in the scope of the guidelines to 
define a standard follow-up frequency. A number of factors should be considered for the 
follow-up frequency, such as the type and staging of the disease, treatment cycles, criteria, and 
specifications. When a comparison across studies is required, the accuracy limitations of the 
corresponding measurement endpoints should also be considered. 
 
 


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Appendix 5: EORTC QLQ-C30 V3.0 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers, 
so please circle whichever best applies to you. The information you provide will remain strictly 
confidential. 
 
Please fill in your name: ____________________ 
Your birthdate:  
MM/DD/YYYY 
Today's date:  
MM/DD/YYYY 
 
 
Not at all 
A little 
Quite a 
bit 
Very 
much 
1. Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside of the 
house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing yourself or 
using the toilet? 
1 
2 
3 
4 
During the last week 
Not at all 
A little 
Quite a 
bit 
Very 
much 
6. Were you limited to doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other leisure time 
activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 


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15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, such as 
reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel nervous? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment interfered 
with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment interfered 
with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment caused you 
financial difficulties? 
1 
2 
3 
4 
For the following questions, please circle the number between 1 
and 7 that best applies to you 
29. How would you rate your overall health during the past week? 
1       2       3       4       5       6       7 
Very poor                                        Excellent 
30. How would you rate your overall quality of life during the past week? 
1       2       3       4       5       6       7 
Very poor                                        Excellent 
 
1. Description of quality of life scoring: 
The EORTC QLQ-C30 (V3.0) is a core questionnaire for patients with cancer consisting of 30 
items. Items 29 and 30 are divided into 7 grades and are scored 1 to 7 points based on the exact 
answers; other items are divided into 4 grades (not at all, a little, quite a bit, and very much) and 
are directly scored 1 to 4 points. 
2. Calculation of scores (raw scores) of EORTC QLQ-C30 domain (dimension): 
For the convenience of statistical analysis and application, the scale is often divided into certain 
domains, each of which composed of an aspect of the quality of life component, also known as a 


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dimension, and serves as an independent variable in analyses. The EORTC QLQ-C30 (V3.0) are 
composed of 30 items which are divided into 15 domains: 5 functional domains (physical, role, 
cognitive, emotional, and social functions), 3 symptom domains (fatigue, pain, nausea and 
vomiting), 1 domain of global health status/quality of life, and 6 single items (each item serves as 
one domain). The classification is shown in the table below. 
The score of the domain (raw score, RS) is obtained by adding up the score of each item in the 
domain and divided by the number of items included, that is, RS = (Q1 + Q2 + ... + Qn)/n. 
Classification of domains of EORTC QLQ-C30 
 
Item 
Item no. 
Physical functioning  
5 
1~5 
Role functioning 
2 
6~7 
Emotional functioning 
4 
21~24 
Cognitive functioning 
2 
20~25 
Social functioning 
2 
26~27 
Global health status 
2 
29~30 
Fatigue 
3 
10、12、18 
Nausea and vomiting 
2 
14~15 
Pain 
2 
9、19 
Dyspnoea 
1 
8 
Insomnia 
1 
11 
Appetite loss 
1 
13 
Constipation 
1 
16 
Diarrhea 
1 
17 
Financial difficulties 
1 
28 
3. Calculation of standardized scores of EORTC QLQ-C30 
In order to make the scores of all domains comparable, linear transformation is performed by 
using the range method to transform the raw scores into standardized scores within the range 
from 0 to 100. Besides, another purpose of the transformation is to change the direction of the 
score. In the QLQ-C30 questionnaire, all items other than items 29 and 30 are reverse scoring 
(the higher scores suggesting the worse quality of life). Scoring rules specify: for functional and 
global health status domains, the higher scores indicate better functional status and quality of 
life; however, for symptom domain, the higher scores indicate the more symptoms and healthy 
issues (the worse quality of life). Therefore, the standardized scores of the functional domain 
needs to change the direction, and more specifically, are calculated by the following formula 
(where R is the score range for each domain or item). 


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Functional domain: SS = [1 – (RS – 1)/R] × 100 
Symptom and global health status domains: SS = [(RS – 1)/R] × 100 

SAP_001.pdf: 
 
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Sponsor 
: Innovent Biologics (SuZhou) Co., Ltd. 
Document type 
: Statistical Analysis Plan (SAP) 
 
Title 
: Statistical Analysis Plan - A Randomized, Double-Blind, Phase 
III Study to Compare the Efficacy and Safety of IBI308 in 
Combination with Gemcitabine and Platinum-Based 
Chemotherapy vs. Placebo in Combination with Gemcitabine 
and Platinum-Based Chemotherapy in the First-Line Treatment 
for Patients with Advanced or Metastatic Squamous Non-Small 
Cell Lung Cancer (ORIENT-12) 
Product name 
: Sintilimab (IBI308) 
Protocol number 
: CIBI308C303 
Effective date / Version 
: 17Nov2020, Version 2.0 
 
Author: 
Xiuping Zhang 
2020-11-17 
dMed Biopharmaceutical Co., Ltd. 
 
Approver: 
Name and Title 
Signature 
Date (yyyy-mm-dd) 
Jie Li 
 
 
dMed Biopharmaceutical Co., Ltd. 
 
Name and Title 
Signature 
Date (yyyy-mm-dd) 
Xing Sun, Senior Director Biostatistics 
 
 
Innovent Biologics (SuZhou) Co., Ltd. 
 
Name and Title 
Signature 
Date (yyyy-mm-dd) 
Hui Zhou, VP Medical Science Oncology 
 
 
Innovent Biologics (SuZhou) Co., Ltd. 


 
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Version History:  
Version Date 
Summary of Changes 
0.1 
2019-02-11 
Draft 
1.0 
2019-11-21 
Version 1.0 
2.0 
2020-4-24 
1. Correct the name of dMed Biopharmaceutical Co., 
Ltd. on cover page 
2. Modify the calculation formula of dose intensity in 
6.5, as Days of Exposure can better reflect Dose 
delays. The original formula is as follow: Dose 
intensity = Cumulative dose / Number of cycles 
3. Add two-stage method in 8.1.1 to adjust the effect of 
crossover on OS.  
4. Correct the definition of TEAE in 8.2.1.1. The cut-off 
day is defined as 90 days after the last dose of study 
treatment or starting of crossover treatment. 
 
 


 
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TABLE OF CONTENT 
PAGE 
1. 
INTRODUCTION ................................................................................................................... 6 
2. 
SUMMARY OF STUDY PLAN ............................................................................................. 6 
2.1. 
Modifications to the Statistical Section of the Protocol .............................................. 6 
2.2. 
Study Objectives and Endpoints ................................................................................. 6 
2.3. 
Study Design ............................................................................................................... 8 
2.4. 
Statistical Hypothesis ................................................................................................ 20 
2.5. 
Sample Size ............................................................................................................... 20 
2.6. 
Randomization .......................................................................................................... 20 
3. 
PLANNED ANALYSES ....................................................................................................... 21 
3.1. 
Interim Analyses ....................................................................................................... 21 
3.2. 
Final Analyses ........................................................................................................... 22 
4. 
ANALYSIS POPULATIONS ................................................................................................ 22 
5. 
GENERAL RULES AND DATA HANDLING CONVENTIONS ...................................... 23 
5.1. 
General Rules ............................................................................................................ 23 
5.2. 
Missing Data Handling ............................................................................................. 24 
5.3. 
Other Data Handling Rules ....................................................................................... 24 
5.4. 
General Definition ..................................................................................................... 25 
6. 
SUBJECT DISPOSITION ..................................................................................................... 25 
6.1. 
Subject Disposition ................................................................................................... 25 
6.2. 
Protocol Deviation and Code Broken ....................................................................... 26 
6.3. 
Demographics and Disease Characteristics .............................................................. 26 
6.4. 
Concomitant Medication ........................................................................................... 27 
6.5. 
Drug Exposure .......................................................................................................... 28 
7. 
STATISTICAL ANAYSIS METHOD .................................................................................. 29 
7.1. 
Primary Efficacy Analysis ........................................................................................ 29 
7.1.1. 
Definition of PFS ..................................................................................... 29 
7.1.2. 
Primary Analysis Methods ....................................................................... 30 
7.1.3. 
Covariate Adjustment/Subgroup Analyses .............................................. 30 


 
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8. 
SECONDARY ENDPOINT ANALYSES ............................................................................ 31 
8.1. 
Analyses for Secondary Endpoints ........................................................................... 31 
8.1.1. 
Overall Survival (OS) .............................................................................. 31 
8.1.2. 
Objective Response Rate (ORR) .............................................................. 32 
8.1.3. 
Disease Control Rate (DCR) .................................................................... 32 
8.1.4. 
Time to Response (TTR) .......................................................................... 32 
8.1.5. 
Duration of Response (DOR) ................................................................... 32 
8.2. 
Safety Analyses ......................................................................................................... 33 
8.2.1. 
Adverse Events ........................................................................................ 33 
8.2.2. 
PK and Immunogenicity Analyses ........................................................... 35 
8.2.3. 
Clinical Laboratory Test .......................................................................... 35 
8.2.4. 
ECG .......................................................................................................... 36 
8.2.5. 
Vital Sign, Physical Exam and other Safety Exams ................................. 36 
9. 
EXPLOATORY ANALYSES ............................................................................................... 37 
9.1. 
Biomarkers in tumor tissue and peripheral blood ..................................................... 37 
9.2. 
Quality of Life Analysis ............................................................................................ 37 
9.2.1. 
Lung Cancer Symptom Scale (LCSS) ...................................................... 37 
9.2.2. 
EORTC QLQ-C30 ................................................................................... 37 
9.3. 
Efficacy Analyses after PD ....................................................................................... 39 
10. REFERENCES ....................................................................................................................... 39 
11. APPENDICES ....................................................................................................................... 40 
11.1. 
Acronym.................................................................................................................... 40 
 
 
 
 
 


 
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LIST OF TABLES 
Table 1. Changes from Protocol ...................................................................................................... 6 
Table 2. Study Obejectives and Definition of Study Endpoint ........................................................ 6 
Table 3. Schedule of study visits ................................................................................................... 11 
Table 4. Schedule of visits during crossover treatment with IBI308 ............................................. 17 
Table 5. Definition of Analysis Population ................................................................................... 22 
Table 6. Censoring Rules for Primary and Sensitivity Analyses of PFS ....................................... 29 
Table 7. Category of Chemistry Laboratory Parameters ............................................................... 35 
Table 8. PCSA Criteria .................................................................................................................. 36 
Table 9. QLQ-30 Scoring Methods................................................................................................ 38 
 
LIST OF FIGURES 
Figure 1. Study Design .................................................................................................................... 9 
 
 
 


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical methodology to be used to implement the analysis of data based on protocol “A 
Randomized, Double-Blind, Phase III Study to Compare the Efficacy and Safety of IBI308 in 
Combination with Gemcitabine and Platinum-Based Chemotherapy vs. Placebo in Combination 
with Gemcitabine and Platinum-Based Chemotherapy in the First-Line Treatment for Patients with 
Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (ORIENT-12)” (CIBI308C303, 
version 2.1 dated 24Jan2019). The purpose of the SAP is to ensure the credibility of the study 
findings by pre-specifying the statistical approaches to the analysis of study data prior to database 
lock and will be approved before database lock. This SAP does not include analysis plan for 
population PK which will be described in a separate document.  
2. 
SUMMARY OF STUDY PLAN 
2.1. 
Modifications to the Statistical Section of the Protocol 
The changes made in this SAP from protocol version 3.0 are summarized in Table 1.  
Table 1. Changes from Protocol 
Protocol 
Changes made in SAP 
Reasons 
Definition of TTR: from the 
date of randomization to the 
date of the first confirmed 
response (CR or PR). Subjects 
who do not meet CR or PR, 
will be censored at the last 
date of imaging assessment. 
Time to response (TTR): Defined as 
from the date of randomization to the 
date of the first confirmed response 
(CR or PR). 
To keep the consistency of the 
analysis of the same study drug 
 
2.2. 
Study Objectives and Endpoints 
Table 2. Study Obejectives and Definition of Study Endpoint 
Study objective 
Study endpoint 
Primary objective 
Primary endpoint 


 
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Study objective 
Study endpoint 
• 
To compare the progression-free survival (PFS) 
per RECIST v1.1 in the first-line treatment of 
advanced or metastatic squamous non-small cell 
lung cancer (NSCLC) treated with sintilimab in 
combination with gemcitabine and platinum-
based chemotherapy versus placebo in 
combination with gemcitabine and platinum-
based chemotherapy 
• 
Progression free survival (PFS) per RECIST 
v1.1 assessed by independent radiographic 
review committee (IRRC) 
Secondary objective 
Secondary endpoint 
• 
To compare the overall survival (OS) between 
the two treatment arms 
• 
Overall survival (OS) 
• 
To compare the objective response rate (ORR) 
per RECIST v1.1 between two treatment arms 
• 
Objective response rate (ORR) per RECIST 
v1.1 
• 
To compare the disease control rate (DCR) per 
RECIST v1.1 between the two treatment arms 
• 
Disease control rate (DCR) per RECIST v1.1 
• 
To compare the time to objective response 
(TTR) per RECIST v1.1 between the two 
treatment arms 
• 
Time to response (TTR) per RECIST v1.1 
• 
To compare the duration of response (DOR) per 
RECIST v1.1 between the two treatment arms 
• 
Duration of response (DOR) per RECIST v1.1 
• 
To evaluate the safety and tolerability of 
sintilimab in combination with gemcitabine and 
platinum-based chemotherapy 
• 
Adverse Events 
• 
Clinical laboratory test 
• 
Vital Sign 
• 
Electrocardiogram 
• 
Immunogenicity 
• 
 
Exploratory objective 
Exploratory endpoint 
• 
To explore the biomarkers in tumor tissue that 
can potentially predict the efficacy of sintilimab 
• 
PD-L1 expression 


 
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Study objective 
Study endpoint 
arm including but not limited to PD-L1 
expression 
• 
To explore the biomarker in peripheral blood 
that can potentially predict the efficacy of 
sintilimab arm including but not limited to T 
cell receptor (TCR) and circulating tumor DNA 
(ctDNA) 
• 
TCR 
• 
ctDNA 
• 
To compare the quality of life of subjects treated 
with sintilimab in combination with 
chemotherapy and placebo in combination 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) 
• 
Lung cancer symptom scale (LCSS) 
• 
EORTC QLQ-C30 
• 
To compare PFS in sintilimab arm receiving 
subsequent anti-cancer therapy after disease 
progression versus placebo arm crossing over to 
receive sintilimab 
• 
PFS 2 after initiation of new anti-cancer therapy 
• 
ORR with new anti-cancer therapy after PD 
• 
TTR with new anti-cancer therapy after PD 
• 
DoR with new anti-cancer therapy after PD 
• 
To explore the population pharmacokinetic (PK) 
characteristics of sintilimab 
• 
(See separate population PK analysis plan) 
2.3. 
Study Design 
This study is a multicenter, randomized, double-blind, phase III study to compare the efficacy and 
safety of IBI308 in combination with gemcitabine and platinum-based (cisplatin/carboplatin) 
chemotherapy 
vs. 
placebo 
in 
combination 
with 
gemcitabine 
and 
platinum-based 
(cisplatin/carboplatin) chemotherapy in first-line treatment of previously untreated Chinese 
subjects with advanced or metastatic squamous NSCLC. 
In this study, a total of 348 previously untreated subjects with advanced or metastatic squamous 
cell NSCLC will be randomized in a 1:1 ratio to the test group and the control group, 174 cases in 
the test group and 174 cases in the control group (in the actual study, if the actual number of 
enrolled subjects is different from the number of planned enrollment due to unforeseen reasons, 
such as the enrollment speed is faster than the requirements of the protocol, the end date of 


 
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screening should be determined in advance to ensure that the number of actually enrolled subjects 
does not exceed the number of planned enrollment by 10%, i.e., a maximum of 382 subjects shall 
be enrolled, 191 in each group). Randomization stratification factors include staging (stage 
IIIB/IIIC vs. stage IV), platinum-based medications (cisplatin vs. carboplatin), and PD-L1 
expression level (< 1% vs. ≥ 1%). In this study, the parallel control is placebo in combination with 
gemcitabine and platinum-based (cisplatin/carboplatin) chemotherapy and the test group will 
receive IBI308 in combination with gemcitabine and platinum-based (cisplatin/carboplatin) 
treatment. Both groups will receive the corresponding treatment for 4 or 6 cycles, followed by 
IBI308 or placebo maintenance therapy, respectively (see Figure 1). 
 
Figure 1. Study Design 
Note: In the actual study, if the actual number of enrolled subjects is different from the number of planned enrollment due to 
unforeseen reasons, such as the enrollment speed is faster than the requirements of the protocol, the end date of screening should 
be determined in advance to ensure that the number of actually enrolled subjects does not exceed the number of planned enrollment 
by 10%, i.e., a maximum of 382 subjects shall be enrolled, 191 in each group. 
Tumor imaging evaluation will be performed at week 6 (± 7 days) and week 12 (± 7 days) since 
randomization, every 9 weeks (± 7 days) thereafter until week 48, and every 12 weeks (± 7 days) 
after week 48. 
After the first assessment of imaging PD by the investigator based on RECIST V1.1, if the subject 
has SD clinically, the current treatment can be continued and the imaging evaluation should be 
performed again 4–6 weeks later for confirmation (based on RECIST V1.1). If PD is confirmed, 
unblinding should be performed and subjects of IBI308 in combination with chemotherapy group 
(test group) should end the study treatment, while subjects of placebo in combination with 
chemotherapy group (control group) can be conditionally crossed to monotherapy of IBI308 based 


 
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on the judgment of the investigator and the willingness of the subjects, until PD, toxicity 
intolerability, receiving new anti-tumor therapy, withdrawal of ICF, loss of follow-up or death, or 
other reasons requiring termination of study treatment, whichever occurs first; if PD is not 
confirmed, the study treatment will be continued until imaging-confirmed PD followed by 
unblinding and other subsequent processing same as above.  
If the subject has clinically unstable disease after the first assessment of imaging PD, the 
confirmation 4–6 weeks later is not required and unblinding can be directly performed followed 
by processing same as above. During the study, the treatment should be discontinued if one of the 
following occurs: clinically unstable disease, intolerable toxicity, receipt of new anti-tumor 
therapy, withdrawal of ICF, loss to follow-up, death, or other conditions requiring treatment 
discontinuation as judged by the investigator, whichever occurs first. The maximum duration of 
treatment with IBI308 is 24 months in both groups. For patients who discontinue the treatment for 
reasons other than PD, an imaging evaluation should be performed at the end of treatment, and 
during follow-up the imaging evaluation should be performed according to imaging examination 
scheduled time points specified in the protocol until one of the following events occurs: start of 
new anti-tumor therapy, objective PD, loss of follow-up or death, withdrawal of ICF by the 
subjects, whichever occurs first. 
Table 3 and Table 4 below show the schedule of study visits. 
 
 


 
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Table 3. Schedule of study visits 
 


 
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Note:  
1. The ICF should be signed by subjects prior to any procedures outlined in the protocol. 
2. Previous therapies for lung cancer: all treatments for lung cancer, including chemotherapy, radiotherapy, and surgery. 
3. Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. 
4. Height is measured during screening period only. Body weight is measured prior to each dose. If the body weight of a subject fluctuates by less than 10% from the baseline (the 
day when the first dose of study drugs is given), the baseline body weight will be used to calculate the chemotherapeutic dose. Otherwise, the actual dose will be calculated based on 
the weight of scheduled dosing days. 
5. Time of 12-lead ECG examinations: within 7 days before the first dose of study drugs during screening, within 3 days before each administration of study drugs from cycle 2 
onwards, and during safety follow-up. 
6. Routine blood test: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell (WBC), platelet (PLT), and WBC differential [lymphocyte, neutrophil, monocyte, 
eosinophil, and basophil]. Blood chemistry: hepatic function [TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, and CK], renal function (UREA or BUN, and Cr), blood 
electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Urinalysis: pH, UWBC, UPRO, URBC, UGLU, and specific gravity. Subjects with ≥ 2+ urine 
protein in urinalysis during screening should undergo a 24-h urine protein quantitation test. The tests will be conducted within 7 days before the first dose of study drugs during 
screening, within 3 days before each administration of study drugs from cycle 2 onwards, and during safety follow-up. Tests will be conducted at each study site. 
7. Coagulation function test: PT and INR. The test will be conducted within 7 days before the first dose of study drugs during screening and during the safety follow-up. Tests will 
be conducted at each study site. 


 
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8. Women of childbearing age will undergo urine or serum pregnancy test within 3 days before the first dose during screening and during the safety follow-up. If the urine pregnancy 
test is not conclusive, then blood pregnancy test should be performed. The conclusion should be based on the blood pregnancy test. Tests will be conducted at each study site. 
9. The thyroid function test will be conducted within 28 days before the first dose, within 3 days before each administration of study drugs from cycle 2 onwards, and during the 
safety follow-up. T3/FT3, FT4, and TSH are examined during screening, and only TSH is examined from cycle 2 onwards. In case of any abnormalities, the examination of other 
thyroid function parameters should be considered. During study treatment, the study drugs can be administered before the test results are accessible. Tests will be conducted at each 
study site. 
10. This item involves the testing of HIV and HCV antibodies as well as hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), and should be completed within 28 days 
before the first dose. The test will be conducted at the study site during screening. 
11. Anti-HCV antibodies will be tested at the screening visit. For subjects tested positive for HCV antibodies, HCV-RNA load should be determined during screening, within 3 days 
before each administration of study drugs from cycle 2 onwards, or at an earlier time if clinically indicated. During study treatment, the study drugs can be administered before the 
test results are accessible. 
12. Hepatitis B panel will be tested at the screening visit. For subjects tested positive for HBsAg and/or HBcAb, HBV-DNA load should be determined during screening, within 3 
days before each administration of study drugs from cycle 2 onwards, or at an earlier time if clinically indicated. During study treatment, for patients previously tested negative for 
HBsAg, the study drugs can be administered before the HBV-DNA load test results are accessible. 
13. The blood myocardial enzyme and troponin tests should at least include: creatine phosphokinase (CK), creatine phosphokinase isoenzyme (CK-MB), and troponin (troponin T 
or troponin I). The tests will be conducted within 7 days before the first dose of study drugs during screening and within 3 days before each administration of study drugs from cycles 
2 and 3 onwards. The conduct or not of subsequent tests will be decided by the investigator. 
14. AEs and laboratory safety assessments will be performed based on CTCAE V4.03. Refer to Section 8 for definitions, recording, causality determination, severity level, reporting 
deadlines, and treatment of AEs and SAEs. 
15. Quality-of-life questionnaires include LCSS and EORTC QLQ-C30 (V3.0 Chinese version), which will be completed on the day of the first dose (predose), at each imaging 
evaluation (during the visit), and at the safety follow-up (during the visit). If an unscheduled imaging evaluation is performed, the quality-of-life questionnaires should also be 
completed. 
16. Tumor assessment includes the assessment based on RECIST V1.1. Tumor imaging examinations usually include contrast-enhanced CT or MRI of chest, abdomen, and pelvic 
cavity. Contrast-enhanced MRI of head should also be performed at baseline for subjects with signs or symptoms of suspected CNS metastasis. The same subject should receive the 
same type of imaging examination during the study. The baseline evaluation will be performed within 28 days before randomization. Tumor imaging evaluation will be performed 
at week 6 (± 7 days) and week 12 (± 7 days) since randomization, every 9 weeks (± 7 days) thereafter until week 48, and every 12 weeks (± 7 days) after week 48. After the first 
assessment of imaging PD (PD) by the investigator based on RECIST V1.1, if the subject has SD clinically, the current treatment can be continued and the imaging evaluation should 
be performed again 4–6 weeks later for confirmation (based on RECIST V1.1). If PD is not confirmed, the study treatment should be continued and imaging evaluations should be 
performed at the protocol-specified time points until imaging-confirmed PD. If a subject discontinues study treatment for a reason other than objective PD, the imaging evaluation 
should be performed at the end of treatment and then at the protocol-specified time points thereafter until one of the following events occurs: initiation of new anti-tumor therapy, 
objective PD, loss to follow-up, death, or withdrawal of ICF, whichever occurs first. Unscheduled imaging evaluations can be performed at any time during the study if the patient 
develops clinically unstable disease. If the subject has clinically unstable disease after the first assessment of imaging PD, the confirmation 4–6 weeks later is not required and the 
study treatment should be discontinued. 


 
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17. Immunogenicity assays will be performed within 1 h prior to IBI308/placebo infusion in cycles 1/2/4/8/12/16, then every 8 cycles (cycle 24, 32, and so on) thereafter, and during 
the safety visit. If an infusion-related reaction occurs during IBI308 or placebo administration, blood samples should be taken near the start and end of this event and around 30 days 
after the reaction, for comparative analysis of immunogenicity. Tests will be conducted in the central laboratory. 
18. PK samples will be collected at the following time points: within 1 h before and immediately (+ 5 min) after IBI308 or placebo infusion in cycle 1, and within 1 h before IBI308 
or placebo infusion in cycles 2/4/12. Tests will be conducted in the central laboratory. 
19. Subjects will receive treatment with either IBI308 in combination with gemcitabine and platinum (cisplatin or carboplatin) or placebo in combination with gemcitabine and 
platinum (cisplatin or carboplatin) for 4 or 6 cycles, followed by maintenance therapy with IBI308 or placebo, respectively. After the first assessment of imaging PD by the investigator 
based on RECIST V1.1, if the subject has SD clinically, the current treatment can be continued and the imaging evaluation should be performed again 4–6 weeks later for confirmation 
(based on RECIST V1.1). If PD is confirmed, unblinding should be performed and subjects of IBI308 in combination with chemotherapy group (test group) should end the study 
treatment, while subjects of placebo in combination with chemotherapy group (control group) can be conditionally crossed over to receive monotherapy of IBI308 based on the 
judgment of the investigator and the willingness of the subjects; if PD is not confirmed, the study treatment will be continued until imaging-confirmed PD followed by unblinding 
and other subsequent processing same as above. If the subject has clinically unstable disease after the first assessment of imaging PD, the confirmation 4–6 weeks later is not required 
and unblinding can be directly performed followed by processing same as above. During the study, the treatment should be discontinued if one of the following occurs: clinically 
unstable disease, intolerable toxicity, receipt of new anti-tumor therapy, withdrawal of ICF, loss to follow-up, death, or other conditions requiring treatment discontinuation as judged 
by the investigator, whichever occurs first. The maximum duration of treatment with IBI308 is 24 months in both groups. 
20. Each subject is required to provide at least 10 sections of archived or fresh tumor tissue samples meeting test requirements during screening. 
21. Each subject is also required to provide 10 mL of whole blood samples for tumor biomarker testing at the following time points: prior to the first dose, every time when imaging 
evaluation is performed but before the next treatment is started in the treatment period, the time when PD is confirmed, and during safety visit. Tests will be conducted in the central 
laboratory. 
22. A safety follow-up visit will be carried out on day 30 (± 3 days) after the last dose or before initiation of new anti-tumor therapy, whichever occurs first. All AEs that occur prior 
to the safety follow-up visit should be documented until the events recover to grade 0–1 or the baseline level, or until the investigator believes that no further follow-up is required 
for reasonable reasons (e.g., the event cannot be resolved or has already been improved), whichever occurs first. All SAEs that occur within 90 days after the last dose or before 
initiation of new anti-tumor therapy (whichever occurs first) should be followed up and documented. 
23. Survival follow-ups: once every 90 days (± 7 days) after the safety follow-up. Telephone follow-ups are allowed. 


 
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Table 4. Schedule of visits during crossover treatment with IBI308 
 


 
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Note:  
1. Only after all patients in the control group have been assessed for overall status by the investigator and confirmed to have PD by the IRRC and meet the requirements for 
administration of IBI308, can they be crossed over to receive treatment with IBI308. The imaging results obtained at the end of the last dose can be used for the evaluation before 
crossover treatment. Regardless of the confirmation date of PD, subjects must start the administration of IBI308 at least 21 days after the last chemotherapy. 
2. Vital signs include: body temperature, pulse, respiratory rate, and blood pressure. 
3. Body height is measured only before the first dose. 
4. Time of 12-lead ECG examinations: within 7 days before the first dose of IBI308, within 3 days before each administration from cycle 2 onwards, and during safety follow-up. 
5. Routine blood test: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell (WBC), platelet (PLT), and WBC differential [lymphocyte, neutrophil, monocyte, 
eosinophil, and basophil]. Blood chemistry: hepatic function [TBIL, DBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, and CK], renal function (UREA or BUN, and Cr), blood 
electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Urinalysis: pH, UWBC, UPRO, URBC, UGLU, and specific gravity. Subjects with ≥ 2+ urine 
protein in urinalysis during screening should undergo a 24-h urine protein quantitation test. The tests will be conducted within 7 days before the first dose of IBI308, within 3 days 
before each administration of study drugs from cycle 2 onwards, and during safety follow-up. Tests will be conducted at each study site. 
6. Coagulation function test: PT and INR. The test is conducted within 7 days before the first dose of IBI308 and during safety follow-up. Tests will be conducted at each study site. 
7. Women of childbearing age will undergo urine or serum pregnancy test within 3 days before the first dose of IBI308 and during the safety follow-up. If the urine pregnancy test 
is not conclusive, then blood pregnancy test should be performed. The conclusion should be based on the blood pregnancy test. Tests will be conducted at each study site. 


 
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8. The thyroid function test will be conducted within 21 days before the first dose, within 3 days before each administration from cycle 2 onwards, and during the safety follow-up. 
During study treatment, the study drugs can be administered before the test results are accessible. Tests will be conducted at each study site. 
9. This item involves the testing of HCV antibodies and hepatitis B panel (HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb), and should be completed within 21 days before the first 
dose. Tests will be conducted at each study site. 
10. For subjects tested positive for HCV antibodies, HCV-RNA load should be determined within 3 days before administration of study drugs in each cycle, or at an earlier time if 
clinically indicated. During study treatment, the study drugs can be administered before the test results are accessible. 
11. For subjects tested positive for HBsAg and/or HBcAb, HBV-DNA load should be determined within 3 days before administration of study drugs in each cycle, or at an earlier 
time if clinically indicated. During study treatment, for patients previously tested negative for HBsAg, the study drugs can be administered before the HBV-DNA load test results 
are accessible. 
12. The blood myocardial enzyme and troponin tests should at least include: creatine phosphokinase (CK), creatine phosphokinase isoenzyme (CK-MB), and troponin (troponin T 
or troponin I). The tests are performed within 7 days before the first dose of IBI308 during crossover treatment and within 3 days before each administration of study drugs from 
cycles 2 and 3 onwards. The conduct or not of subsequent tests will be decided by the investigator. 
13. AEs and laboratory safety assessments will be performed based on CTCAE V4.03. Refer to Section 8 for definitions, recording, causality determination, severity level, reporting 
deadlines, and treatment of AEs and SAEs. 
14. Quality-of-life questionnaires include LCSS and EORTC QLQ-C30 (V3.0 Chinese version), which will be completed on the day of the first dose (predose), at each imaging 
evaluation (during the visit), and at the safety follow-up (during the visit). 
15. Tumor assessment includes the assessment based on RECIST V1.1. Tumor imaging examinations usually include contrast-enhanced CT or MRI of chest, abdomen, and pelvic 
cavity. Contrast-enhanced MRI of head should also be performed at baseline for subjects with signs or symptoms of suspected CNS metastasis. The same subject should receive the 
same type of imaging examination during the study. Subjects in the stage of crossover treatment with IBI308 will be assessed every 9 weeks (± 7 days) since the first dose until the 
occurrence of imaging PD (based on RECIST V1.1). For patients who discontinue the treatment for reasons other than objective PD, an imaging evaluation should be performed at 
the end of treatment and then at the protocol-specified time points thereafter until one of the following events occurs: initiation of new anti-tumor therapy, PD, loss to follow-up, 
death, or withdrawal of ICF, whichever occurs first. Unscheduled imaging evaluations can be performed at any time during the study if the patient develops clinically unstable 
disease. 
16. If an infusion-related reaction occurs during IBI308 infusion, blood samples should be taken near the start and end of this event and around 30 days after the reaction and used 
for comparative analysis of immunogenicity. Tests will be conducted in the central laboratory. 
17. A safety follow-up visit will be carried out on day 30 (± 3 days) after the last dose or before initiation of new anti-tumor therapy, whichever occurs first. 
18. Survival follow-ups: once every 90 days (± 7 days) after the safety follow-up. Telephone follow-ups are allowed. 


 
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2.4. 
Statistical Hypothesis 
This study mainly aims to confirm that IBI308 in combination with chemotherapy can prolong the 
progression free survival (PFS) of treatment-naive patients with advanced or metastatic squamous 
NSCLC compared with chemotherapy alone. The following statistical hypothesis tests will be 
performed in this study for the primary endpoint PFS: 
Null hypothesis H0: PFS (test group) ≠ PFS (control group)  
Alternative hypothesis H1: PFS (test group) > PFS (control group) 
2.5. 
Sample Size 
This study mainly aims to confirm that IBI308 in combination with chemotherapy can prolong the 
progression free survival (PFS) of treatment-naive patients with advanced or metastatic squamous 
NSCLC compared with chemotherapy alone. 
IBI308 is expected to prolong PFS of subjects from 5.5 months to 7.9 months (HR = 0.7). 
Calculated with the enrollment time of 15 months and the total study time of 23 months, power = 
82% and one-sided α = 0.025. Besides, an interim analysis (Lan-deMets spending function 
combined with O'Brien-Fleming) will be performed when 70% of PFS events are observed. 
Considering a monthly dropout rate of 0.5%, a total of 348 subjects (174 in the test group and 174 
in the control group) are needed to be randomized to achieve the 264 PFS events required in the 
trial. In the actual study, if the actual number of enrolled subjects is different from the number of 
planned enrollment due to unforeseen reasons, such as the enrollment speed faster than the 
requirements of the protocol, the end date of screening should be determined in advance to ensure 
that the number of actually enrolled subjects does not exceed the number of planned enrollment 
by 10%, i.e., a maximum of 382 subjects should be enrolled, 191 in each group. 
2.6. 
Randomization 
The randomization method of this study is as follows: Subjects are randomized in a 1:1 ratio to the 
test group and the control group, receiving IBI308 in combination with chemotherapy and placebo 
in combination with chemotherapy, respectively. The stratification factors of randomization are as 
follow: 
• staging (stage IIIB/IIIC vs. stage IV) 
• platinum-based medications (cisplatin vs. carboplatin) 
• PD-L1 expression level (< 1% vs. ≥ 1%). Subjects with unevaluable PD-L1 expression level 
will be classified as < 1%. 


 
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The central randomization method is adopted with competitive enrollment for each center. The 
central randomization procedure will use an interactive web response system (IWRS), which can 
generate and dispense a random number to subjects who have completed all of the screening 
assessment items of the study and meet the inclusion criteria. The random number will connect the 
subjects into a designed treatment group (IBI308 in combination with chemotherapy group or 
placebo in combination with chemotherapy group) and can assign investigational drugs to subjects 
as per required quantity. For subjects withdrew from the study, whatever the reason of withdrawal, 
their random numbers will be retained. IWRS staff will only write randomized table and will not 
be involved in any specific trial operation. The assigned study drug must be administered within 
48 hours of randomization. 
IBI308 and placebo will be in the same packages to ensure blindness. The subjects, investigators, 
and sponsor staff or designee participating in the treatment or clinical evaluation of the subjects 
should be unknown about the grouping. 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The primary endpoint PFS will be analyzed at approximately 23 months after the start of the trial 
(i.e., at the end of the study, expected to be at approximately 8 months after randomization of the 
last subject). Besides, an interim analysis will be carried out during the study. 
Time of interim analysis: The analysis will be performed when 70% of PFS events (185 cases) 
occur (at approximately 16 months after the start of the trial). 
The α boundary for the efficacy stopping at the interim analysis is based on O’Brien-Fleming 
spending function, where 1-sided nominal α=0.0074 (corresponding HR≈0.698). The overall 1-
sided type I error is therefore controlled at level of 0.025. If at the interim analysis the actual 
number of PFS events differs from planned 185, the α boundary will be adjusted based on the 
actual number of PFS events observed according to O’Brien-Fleming spending function. 
Objective of interim analysis: to demonstrate that IBI308 in combination with chemotherapy is 
superior to placebo in combination with chemotherapy regarding the primary study endpoint PFS. 
In the interim analysis, with one-sided α = 0.0074, if HR ≤ 0.698 is observed for the test group of 
IBI308 in combination with gemcitabine and cisplatin or carboplatin chemotherapy vs. the control 
group of placebo in combination with gemcitabine and cisplatin or carboplatin chemotherapy, it is 
demonstrated that the superiority has been concluded in the interim analysis. 
The analysis results and reports will be submitted to the IDMC, which will judge whether the trial 
is valid according to the estimated valid cut-off value and give advice to the sponsor on whether 


 
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the study data can be submitted in advance. The IDMC charter will be finalized and approved by 
IDMC and sponsor prior to the interim analysis. If the study proceeds, the IDMC will continue 
performing regular evaluation and monitoring on safety data until the final analysis. 
3.2. 
Final Analyses 
The final analysis for PFS of this study is expected to occur after approximately 23 months after 
first subject randomized (which is expected to be approximately 8 months after last subject 
randomized). However, please note the time might be different than planned as the final analysis 
time of this study is event driven. 
After approximately 263 PFS events occur, the following steps will be completed before 
performing the final analysis: 
1. All subject will complete study or the study is discontinued at the interim analysis. 
2. All data are cleaned and database are locked for final analysis. 
3. All pre-requisite steps before unblinding are completed, and formal randomization code 
release for final analysis is performed. 
4. 
ANALYSIS POPULATIONS 
Table 5. Definition of Analysis Population 
Analysis 
population 
Definition 
Scope 
Full Analysis Set 
(FAS) 
• 
Randomized subjects who received at least 1 
administration of study medication. 
• 
Analysed based on randomization assignment 
• 
 
• 
Analysis of medical 
history, prior and 
concomitant medication, 
demographics and baseline 
characteristics 
• 
Efficacy analysis 
Safety Set (SS) 
• 
Randomized subjects who received at least 1 
administration of study medication 
• 
According to actual study drug received. If a 
subject receives incorrect treatment during the 
study, this subject’s data will be summarized 
according to the first study drug actually 
received. 
• 
Safety analysis 
• 
Drug exposure analysis 


 
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Analysis 
population 
Definition 
Scope 
Per-protocol Set 
(PPS) 
• 
Subset of FAS 
• 
Randomized subjects who do not have major 
protocol deviations affecting efficacy 
evaluation and have completed at least 1 cycle 
of administration with available imaging 
evaluation results (or have failed to completed 
at least 1 cycle of administration due to PD 
and have clear evidence of imaging PD). 
• 
 
• 
Sensitivity analyses for 
primary and key secondary 
efficacy endpoints 
Intent To Treat 
(ITT) 
• 
All randomized subjects 
• 
Analysed based on randomization assignment 
• 
Sensitivity analyses for 
primary and key secondary 
efficacy endpoints 
ITT, FAS and SS set will be determined by programming. PP set will be determined by blind 
clinical review committee before database locking. 
5. 
GENERAL RULES AND DATA HANDLING CONVENTIONS 
5.1. 
General Rules 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
Except for the superiority hypothesis test of the primary efficacy endpoint PFS (one-sided α = 
0.0074) in interim analysis and PFS (one-sided α = 0.0228) in final analysis, 95% CIs and nominal 
P values will be provided for other between-group comparisons (unless otherwise specified). If the 
one-sided P value ≤ 0.025, the difference between groups can be considered statistically significant. 
Unless otherwise specified, all data collected will be summarized and listed. Categorical variables 
will be summarized with number and percentage of subjects for each category. Unless otherwise 
specified, number of subjects per each treatment group in the corresponding analysis population 
will be the default denominator in percentage calculation. For percentage, 1 decimal point will be 
displayed.  
Descriptive summary with n, mean, standard deviation (SD), median, min and max will be 
provided for continuous variables. Mean and median will be displayed with 1 additional decimal 
points than the raw values. SD will be displayed with 2 additional decimal points than the raw 
values. Min and Max will be displayed with the same decimal points as the raw values. Hazard 


 
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ratio will be displayed with 3 decimal points and p-value will be displayed with 5 decimal points 
(or >0.99999, or <0.00001). 
5.2. 
Missing Data Handling  
The following approaches are default methods for missing data handling. Imputation is only 
conducted for summary, and the imputed data will not be presented in listings. 
• 
Missing date for AE and CM will be imputed following rules below: 
o 
If start date is partial missing, without conflicts with other data (such as end date), 
Jan will be used to impute missing month and 01 will used to impute missing day. 
However, if the year or year-month for the partial missing start date is the same as 
the year or year-month of the first dose date, the event will be considered as starting 
during treatment period and first dose date will be used to impute the partial missing 
start date. If the end date is determined to be earlier than the first dose date, 
aforementioned imputation with Jan/01 is applicable to the partial missing end dates.  
o 
If start date is completely missing, without conflicts with other data (such as end 
date), first dose date will be used to impute the missing start date. If the end date is 
determined to be earlier than the first dose date, then start date will be imputed with 
end date-1.  
o 
Partial missing end date will be imputed with Dec (for missing month) and or last 
date of the month (for missing day). If the result from such imputation gives dates 
after death date, data cut-off date, end of study date, the earliest date in the above 
mentioned dates will be used to impute the missing end date.  
o 
Actual missing value will be displayed in AE or CM listing 
• 
AE with missing CTCAE grade will be counted as grade 3 or above.  
• 
If AE assessment of the relationship with the investigational drug is missing, it will be 
counted as “related”. 
• 
Other missing values will not be imputed and only non-missing data will be included in 
the analysis.  
5.3. 
Other Data Handling Rules  
If raw value from laboratory tests cannot be included in the calculation directly (e.g. coded with 
characters), coded values will be converted first as appropriate. Generally, upper and lower limit, 
such as “<10” or “≤5” will be converted to “10” or “5”, “<100” will be converted to “100” in the 
summary tables. Original values will be kept in subject listings. BQL data in PK and PD analysis 
will be imputed with BQL/2 for post baseline samples and 0 for baseline samples. 


 
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5.4. 
General Definition 
Age 
Age is calculated based on years between informed consent date and birthday: 
[integer part of (informed consent date - birthday + 1) / 365.25]. 
Baseline 
Unless otherwise specified, baseline values will be the last non-missing value before first 
study drug administered. 
In analyses for the crossover phase, new baseline will be defined as last non-missing value 
before crossover if applicable. If appropriate, starting of new anti-cancer therapy will be 
considered as new baseline for crossover phase. 
Change from baseline 
Change from baseline at any specific time point is defined as values at this time point - 
corresponding baseline values. 
Relative days in study 
Days lapsed since first study drug taken: 
If a date is missing, relative days is missing. 
If the date is earlier than the date of first study drug taken, relative days = date - date of first 
study drug taken. 
If the date is not earlier than the date of first study drug taken, relative days = date -date of 
first study drug taken+1. 
6. 
SUBJECT DISPOSITION 
6.1. 
Subject Disposition 
Following information will be provided for subject disposition: 
• 
Number and percentage of screened subjects, including screen failure subjects and reason 
for screen failure 
• 
Number and percentage of subjects randomized by study centres 
• 
Number and percentage of subjects randomized, receiving treatment during double blind 
phase of the study, completing double blind phase of the study, prematurely discontinuing 
study treatment during double blind phase of the study and discontinuing study early 


 
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• 
Number of percentage of subjects unblinded during the study, number and percentage of 
subjects receiving crossover treatment after unblinding, and number and percentage of 
subjects discontinuing study during crossover phase of the study 
• 
Listing of subjects prematurely discontinuing study and reason for discontinuing during 
double blind phase and crossover phase according to the e-CRF record 
• 
Number and percentage for each analysis population (FAS population, ITT population, 
SS population and PPS population) 
• 
Listing of reasons for subjects excluded in each of the analysis population 
• 
Listing of randomization assignment and actual treatment received for each subject 
6.2. 
Protocol Deviation and Code Broken 
All critical/major deviations potentially impacting efficacy analyses and other important 
deviations will be summarized in tables giving numbers and percentages of deviations by treatment 
group. Listing will also be provided.  
Protocol deviation will be monitored, classified and recorded during the study before database lock. 
Protocol deviation data will be reviewed. Analysis population will be finalized if applicable based 
on protocol deviation classifications before database lock.  
Number and percentage of subjects and the reasons that these subjects have code broken during 
the study conduct will be summarized. A listing will also be provided. 
6.3. 
Demographics and Disease Characteristics 
In general, baseline is defined as the last non-missing evaluable assessment prior to initiation of 
any of the study treatment unless specified otherwise. Demographic variables as listed below will 
be summarized by treatment arm: 
• 
Gender 
• 
Age and Age group (≤60 years vs >60 years) 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
BMI 
• 
BSA  
• 
Stratification factors 
• 
Smoking history 
• 
ECOG PS 


 
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• 
Duration of disease 
Baseline disease characteristics as listed below will be summarized by treatment arm: 
• 
Lung cancer diagnosis (Histological diagnosis, diagnosis method, TNM staging, clinical 
staging, EGFR status, ALK status, Metastasis status, CNS involvement) 
• 
Baseline target lesion and non-target lesion 
• 
Prior anti-cancer surgery for lung cancer  
• 
Prior anti-cancer medication for lung cancer 
• 
Prior anti-cancer radiation therapy for lung cancer 
• 
Prior surgery other than anti-cancer therapies 
• 
Medical history related to other type of cancer 
• 
Non-oncology related medical history 
Medical history data will be coded based on latest Medical Dictionary of Regulatory Activities 
(MedDRA) version available at the time of analysis. Summary by SOC and PT by treatment group 
will be provided. Each subject will only be counted once for the same SOC or PT. 
Listings will also be provided for demographics and baseline characteristic data. 
Other baseline characteristics such as vital sign and etc. are presented along with the post baseline 
values in corresponding summary tables. 
6.4. 
Concomitant Medication 
Prior medications are those the subject used prior to first study treatment intake and discontinued 
before first dosing. 
Concomitant medications are any treatments received by the subject concomitantly to study 
treatment, from first study treatment intake to the last study treatment + 90 days. 
Treatment emergent concomitant medications are any treatments received by the subject 
concomitantly to study treatment, from first study treatment intake to the last study treatment + 90 
days, which are not received before first study treatment intake. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using version currently in effect at the time of analysis. Summary of concomitant medication will 
be provided by ATC 3 and ATC 4. Each subject will be only counted once for each ATC 3/ATC 
4 classification. 
In addition, radiation therapy during the treatment period and post treatment discontinuation, 
new anti-cancer therapy or surgery will also be summarized by treatment group. 


 
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6.5. 
Drug Exposure 
Duration of drug exposure in days 
• 
last dose date - first dose date + 21 days (except for gemcitabine).  
• 
For gemcitabine, if the last dose date is at D1, duration of drug exposure in days = last 
dose date – first dose date + 10.5; else duration of drug exposure in days = last dose date 
– first dose date + 14. 
Duration of drug exposure in weeks 
• 
Duration of drug exposure in weeks = duration of drug exposure in days / 7, with 1 
decimal point. 
Number of cycles administered 
• 
Actual number of cycles during which non-zero dose drug are administered. Cycles with 
discontinuing or missing of treatment will not be counted. 
Number of administered 
• 
Actual number of drug administered. If a planned dose is discontinued or missing, it will 
not be counted. 
Cumulative dose 
• 
the sum of all actual doses. The dosage unit for sintilimab/placebo is mg; the dosage unit 
for carboplatin is AUC (min•mg/mL); the dosage units for cisplatin and gemcitabine are 
mg/m2. 
Dose intensity  
• 
Dose intensity = (Cumulative dose / Drug exposure in days) * 21 
• 
Relative dose intensity = 100 * (Actual dose intensity / Planned dose intensity)  
Planned dose is calculated according to Table 4 in the study protocol. Extent of exposure will be 
assessed within the safety population for sintilimab / placebo and chemotherapy. Number of 
administered, duration of drug exposure (in days and in weeks), and percentage of subjects 
completing different number of cycles will be summarized for combination treatment period, 
maintenance period and overall treatment period. The cumulative dose, dose intensity, relative 
dose intensity, and percentage of subjects in different categories of the relative dose intensity 
(<80%, 80% - 120%, >120%), dose reduction (occur or not, number of dose reduction during 
treatment period), dose delay (occur or not, number of dose delay during treatment period) will 
also be summarized. 
Study drug exposure in subjects receiving crossover treatment of sintilimab will also be 
summarized for their treatment received during the crossover period. 


 
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7. 
STATISTICAL ANAYSIS METHOD 
Unless otherwise stated, primary analyses will be conducted in FAS and sensitivity analyses in 
ITT, PPS will also be provided. 
For efficacy endpoints based on tumor assessment according to RECIST v1.1, primary analysis 
will be based on the assessment result by independent radiographic review committee (IRRC). 
Assessment result by investigator will be used in sensitivity analysis, unless otherwise specified. 
7.1. 
Primary Efficacy Analysis 
7.1.1. 
Definition of PFS 
Progression-free survival (PFS) is defined as 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 
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. Detailed PFS censor 
rule is described in Table 6. 
Table 6. Censoring Rules for Primary and Sensitivity Analyses of PFS 
Scenarios 
Primary analysis 
Sensitivity analysis 1 
Sensitivity analysis 2 
No post-baseline 
evaluation nor 
death 
Censored at 
randomization 
Censored at 
randomization 
Censored at 
randomization 
No PD, no death, 
new anti-cancer 
therapy not 
initiated 
Censored at last 
valid tumor 
assessment 
Censored at last valid 
tumor assessment 
Censored at last valid 
tumor assessment if 
treatment continues, 
otherwise PD at the time 
of treatment 
discontinuation 
No PD, no death, 
anti-cancer 
therapy is 
initiated 
Censored at last 
valid tumor 
assessment before 
starting of the new 
anti-cancer therapy 
Censored at last valid 
tumor assessment 
before starting of the 
new anti-cancer 
therapy 
PD at starting of the new 
anti-cancer therapy 


 
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PD or death after 
1 missing 
assessment 
Event at the time of 
PD or death 
Event at the time of 
PD or death 
Event at the time of PD 
or death 
PD or death after 
≥2 missing 
assessments 
Event at the time of 
PD or death 
Censored at last non-
missing assessment 
before 2 missing 
assessments 
Event at the time of PD 
or death 
 
7.1.2. 
Primary Analysis Methods 
To comparing PFS between treatment arm, A p-value by stratified log-rank test will be provided, 
stratified by randomization stratification factors. 
The hazard ratio and its 95% confidence interval (CI) will be estimated using the stratified Cox 
proportional hazards regression model (stratified by randomization stratification factors) with 
treatment covariate only.  
Kaplan-Meier estimates of the median progression-free survival time and the associated 95% CIs 
will be provided for each treatment group, ignoring the impact of stratification factors. Kaplan-
Meier curve will be plotted. The Non-parametric maximum likelihood estimation (NPMLE) 
method based on EMICM algorithm will also be applied to estimate median PFS and 95% CI.  
7.1.3. 
Covariate Adjustment / Subgroup Analyses 
In order to evaluate the effect of other co-variates, study site (fixed or random effect) will also be 
added to the Cox model to explore whether the effect of study site is significant. 
The consistency of the treatment effect on PFS between subgroups will be evaluated with respect 
to stratification factors, ECOG PS (0 vs 1), age (>60, ≤60), sex (male vs female), smoking status 
(previous/current use vs never), and hepatic metastasis (Yes vs No) by adding each subgroup factor 
as interactive covariate into Cox model. Forest plot of HR and 95% CI will also be provided. If 
the covariate for subgroup analyses is one of the stratification factors, corresponding stratification 
factor will be excluded from the statistical model. 


 
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8. 
SECONDARY ENDPOINT ANALYSES 
8.1. 
Analyses for Secondary Endpoints 
Unless otherwise stated, analyses for secondary endpoints will be conducted in FAS, and 
sensitivity analyses in ITT, PPS will also be provided. 
Analyses based on IRRC assessed ORR, DCR, TTR, DOR will be the primary analyses. Such 
analyses based on investigator’s assessment will also be provided as sensitivity analyses unless 
otherwise specified. 
Summarize the baseline sum of longest diameters of target lesions and the change from baseline 
(absolute change and relative change) by visit. Waterfall plot will also be provided for best 
percentage change in sum of longest diameters of target lesions. 
8.1.1. 
Overall Survival (OS) 
OS: Defined as the 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 was known to be alive or at the study cut-off date, whichever is earlier. 
The determination of a subject’s last survival date will be based on all data collected in the database 
which can verify a subject’s last known alive date.  
If the test for PFS is significant, a confirmatory test for OS will be conducted. 
Same analysis approaches as those for PFS analyses will be applied to OS analyses, including 
stratified log-rank test, stratified Cox model, estimates of HR and 95% CI, subgroup analysis, 
estimate of median survival time and 95% CI.  
Considering that subject may receive new anti-cancer treatment, and subject in placebo group may 
crossover to sintilimab monotherapy after PD, widely used methods such as rank preserving 
structural failure time (RPSFT, Robins & Tsiatis, 1991), and two-stage method (Latimer et al., 
2014) will be applied to adjust for crossover effect in OS analysis. The adjusted OS and 95% CI 
will be provided. This method is an extension of rank preserved accelerated failure time model, 
which is proposed to adjust the bias caused by noncompliance of protocol treatment. Since the 
above RPSFT model does not include the effect of disease progression, analysis using RPSFT 
model considering the effect of PD proposed by Li et al. will also be conducted, according to the 
actual proportion of crossover after PD. Estimate of survival rate at different time points (e.g. 6 
months, when PD and crossover are most likely to occur) will also be provided to evaluate the 
effect of crossover. Besides, the following sensitivity analysis will be conducted: 


 
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• Same approach as specified in primary analysis of OS, except that subjects who crossover to 
sintilimab monotherapy after PD (for placebo group) or start new anti-cancer therapy will be 
censored at the first time of starting new anti-cancer therapy or sintilimab monotherapy. 
8.1.2. 
Objective Response Rate (ORR) 
ORR: Defined as the proportion of subjects who have achieved confirmed CR or PR per RECIST 
1.1 in the analysis population. 
ORR = 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑎𝑎𝑎𝑎ℎ𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝐶𝐶𝐶𝐶 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
× 100% 
The ORRs and 95% CIs will be provided for each group as well as for the difference in ORRs and 
95% CI of the difference between sintilimab and placebo group. CIs per treatment group will be 
calculated using Clopper-Pearson method, ignoring the effect of stratification factors. Treatment 
group difference and associated 95% CI will be calculated based on Miettinen-Nurminen methods 
for stratified data. 
Subgroup analysis will also be performed to estimate ORR and 95% CI within each treatment 
group and between treatment groups for each subgroup. Forest plot will also be provided. 
8.1.3. 
Disease Control Rate (DCR) 
DCR: the proportion of subjects who have achieved confirmed CR or PR or stable disease (SD) 
per RECIST 1.1. 
DCR = 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑎𝑎𝑎𝑎ℎ𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝐶𝐶𝐶𝐶 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
× 100% 
Same analysis approach as those used for ORR analyses will be applied to DCR except for 
subgroup analyses. 
8.1.4. 
Time to Response (TTR) 
Time to response (TTR): Defined as from the date of randomization to the date of the first 
confirmed response (CR or PR). 
The descriptive statistics including number of subjects, mean, variance, median, minimum and 
maximum will be provided for TTR by treatment groups for the objective responders only. 
8.1.5. 
Duration of Response (DOR) 
Duration of response (DoR): Defined as the time from the date of the first confirmed response (CR 
or PR) to the date of subsequent PD or death, whichever is earlier. DoR is calculated only for 
subjects who have had a response. In the absence of subsequent disease progression or death before 


 
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the study cut-off date, DoR will be censored at the date of the last valid assessment performed 
before the cut-off date. 
The descriptive statistics such as min and max, and Kaplan-Meier curves will be provided for DoR 
by treatment groups for the objective responders only. 
8.2. 
Safety Analyses 
Safety analysis will be based on the SS population. The primary analysis of safety will be based 
on the “treatment-emergent” principle defined as from the first dose to last dose of study drug + 
90 days. Analysis of safety will include:  
• 
AEs 
• 
Clinical laboratory variables 
• 
Vital signs 
• 
ECG 
• 
Immunogenicity 
• 
Other safety variables, including physical examinations and ECOG performance status 
Unscheduled visit will be included in any post-baseline summaries but will not be included in the 
by-visit summaries. All unscheduled visits will be displayed in the listing. 
Separate analyses will be provided for subjects in placebo arm who receives crossover treatment 
by period before crossover and after crossover. The safety analyses based on safety data before 
crossover will be the primary safety analyses (i.e. safety data after crossover will not be included 
in the primary safety analysis for subjects in placebo arm). Safety data after crossover will be 
summarized separately as exploratory analyses. 
8.2.1. 
Adverse Events  
8.2.1.1. 
Definition 
Treatment emergent adverse events are AEs first occurring or worsened in severity from baseline 
within the time a subject receiving first dose of study treatment to 90 days after the last dose of 
study treatment or starting of crossover treatment. 
8.2.1.2. 
Analysis of TEAE 
Before the clinical database lock, all AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) (last version available). Each AE is also graded according to NCI CTCAE 


 
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4.03 for its severity. Summary will be provided for double-blind phase, crossover phase, and 
overall phase. 
An overall summary of TEAEs will be provided. The number and percentage of subjects who 
experienced any:  
• 
TEAE 
• 
Treatment-related TEAE 
• 
Immune-related AE (irAE) 
• 
Infusion reaction 
• 
Serious TEAE 
• 
Treatment-related serious TEAE (TESAE) 
• 
Fatal TEAE leading to death 
• 
TEAE leading to permanent treatment discontinuation 
• 
TEAE leading to study discontinuation 
Number and percentage of subjects with AE will also be summarized by SOC, PT and/or CTCAE 
grade according to the following categories by treatment group: 
• 
TEAE 
• 
Treatment-related TEAE 
• 
irAE 
• 
Infusion reaction 
• 
TESAE 
• 
Treatment-related TESAE 
• 
TEAE leading to permanent treatment discontinuation 
• 
TEAE leading to study discontinuation 
• 
TEAE with CTCAE grade 3 or above 
• 
Treatment-related TEAE with CTCAE grade 3 or above 
• 
Fatal TEAE leading to death 
• 
Important TEAE: refers to any adverse event and obvious abnormality in haematology or 
other laboratory tests that results in targeted medical measures (such as drug withdrawal, 
dose reduction and symptomatic treatment) except for serious adverse events. It will be 
determined in the blind clinical evaluation committee meeting before database locking. 


 
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A subject will only be counted once for each unique PT according to the highest grade occurred 
and most conservative relationship to the study drug determined by the investigators. An AE with 
CTCAE grade missing will be counted as grade 3 or above. An AE with missing relationship to 
study drug will be counted as related. 
Listings will be provided for all AEs, irAE, infusion reaction, SAE, AE leading to permanent 
treatment discontinuation, and AE leading to study discontinuation including information on AE 
start date, end date, CTCAE grade, relationship to study drug, action taken and AE outcomes.  
8.2.2. 
PK and Immunogenicity Analyses 
Immunogenicity and pharmacokinetic (PK) data will be collected. The number and percentage of 
subjects with positive anti-drug antibody (ADA) and neutralizing antibody (NAB) will be 
summarized by treatment group. 
The trough concentration of sintilimab in cycle 1 / 3 / 11 will be summarized descriptively. 
8.2.3. 
Clinical Laboratory Test  
Summary of clinical laboratory data will include Haematology, chemistry, urine examination and 
other laboratory examination including coagulation. Chemistry laboratory test will be further 
categorized as following table (renal function, liver function, electrolyte and other). In addition, 
subjects in placebo group receiving crossover treatment will be analysed separately according to 
different study phases (before or after the crossover) the laboratory tests are taken. 
Table 7. Category of Chemistry Laboratory Parameters 
Renal function 
creatinine, CrCl, BUN/UREA 
Liver function 
ALT, AST, ALP, direct bilirubin, total bilirubin, albumin, TP, γ-GGT 
Electrolyte 
Ca, Cl, Mg, P, K, Na 
Other 
glucose, amylases 
Descriptive statistics will be provided for each continuous parameter result and for change from 
baseline by treatment group, and cycle. 
For CTCAE 4.03 gradable laboratory parameters, a shift summary by treatment group of baseline 
grade versus maximum severity post-baseline grade will be presented. 


 
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8.2.4. 
ECG 
Summary statistics with changes from baseline will be provide for ECG. Shift tables on 
abnormality of ECG test at baseline and post-baseline will also be provided. ECG data will also 
be listed. 
8.2.5. 
Vital Sign, Physical Exam and other Safety Exams 
Vital signs, including systolic and diastolic blood pressure, pulse rate, respiratory rate, body 
temperature, and weight as well as change from baseline for these measurements, will be 
summarized by treatment group and cycle for the safety population. Shift table by treatment group 
of baseline status versus worst post-baseline status will be provided according to the potentially 
clinically significant abnormality (PCSA) criteria (Table 8). It should be noted that the analysis of 
increase in diastolic blood pressure from baseline > 20 mmHg is only for subjects with both 
baseline and post-baseline measurements. 
Table 8. PCSA Criteria 
Parameters 
Criteria 
Reference 
SBP (mmHg) 
Increase from baseline > 20 mmHg* 
CTCAE Version 4.03 Grade 2 
DBP (mmHg) 
≥ 140 mmHg 
CTCAE Version 4.03 Grade 2 
HR slow 
< 60 beats/min 
The definition of “Sinus bradycardia” in 
CTCAE Version 4.03 
HR fast 
> 120 beats/min 
The definition of “Sinus tachycardia”, 
“Supraventricular tachycardia”, and “Ventricular 
tachycardia” in CTCAE Version 4.03 
 
Number and percentage of abnormal physical exam will also be provided. Listing of abnormal 
physical exam will also be provided. 
Shift table will be provided to summarize changes in ECOG PS. 
Listing will be provided for all other safety exams. 


 
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9. 
EXPLOATORY ANALYSES 
9.1. 
Biomarkers in tumor tissue and peripheral blood 
Summarize the number and percentage of subjects, as well as the corresponding ORR, DOR, 
PFS in different subgroup based on the baseline level of PD-L1 expression (<1%, 
1~49%, >49%), and dynamic change in TCR, and ctDNA.   
9.2. 
Quality of Life Analysis 
9.2.1. 
Lung Cancer Symptom Scale (LCSS) 
The Lung Cancer Symptom Scale (LCSS) consists of nine graphical subscales.  Additional scores 
are derived based on methods described below. 
• All symptom score: Average of question 1 to 6 
• Respiratory symptom score: Average of question 3 to 5 
• Global health score: Average of question 1 to 2 
In the above score derivation, no imputation will be used for missing questions. 
Descriptive statistics will be provided for each item, derived scores and their corresponding 
changes from baseline at each visit by treatment groups. Baseline values are defined as last non-
missing LCSS measurements before first administer of study drug. The descriptive statistics 
include mean, standard deviation, min, max, quartiles (q1, q3), median and range. 
Stratified Wilcoxon test will be performed to compare between group differences at each post-
baseline LCSS assessment visit. 
In addition, constrained longitudinal data analysis by Liang-Zeger (2000) will be performed to 
compare between group differences at each LCSS assessment visit and overall study period. Least 
square estimate (LSE) with 95% CI for each treatment group and between group differences will 
be provided and plotted. 
9.2.2. 
EORTC QLQ-C30 
The EORTC 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. The scoring method is summarized in Table 9. 


 
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Table 9. QLQ-30 Scoring Methods 
Dimensions 
Code 
Category 
# of 
Items 
Score range (R) 
Scoring method 
Physical 
PF 
Functional 5 
3 
(Q1+Q2+Q3+Q4+Q5)/5 
Role 
RF 
Functional 2 
3 
(Q6+Q7)/2 
Emotion 
EF 
Functional 4 
3 
(Q21+Q22+Q23+Q24)/4 
Cognition 
CF 
Functional 2 
3 
(Q20+Q25)/2 
Sociability 
SF 
Functional 2 
3 
(Q26+Q27)/2 
Global health status 
QL 
 
2 
6 
(Q29+Q30)/2 
Fatigue 
FA 
Symptom 
3 
3 
(Q10+Q12+Q18)/3 
Nausea and vomiting 
NV 
Symptom 
2 
3 
(Q14+Q15)/2 
Pain 
PA 
Symptom 
2 
3 
(Q9+Q19)/2 
Dyspnoea 
DY 
Symptom 
1 
3 
Q8 
Sleepless 
SL 
Symptom 
1 
3 
Q11 
Appetite loss 
AP 
Symptom 
1 
3 
Q13 
Constipation 
CO 
Symptom 
1 
3 
Q16 
Diarrhoea 
DI 
Symptom 
1 
3 
Q17 
Financial difficulty 
FI 
Symptom 
1 
3 
Q28 
Data collected from questionnaires are considered as raw scores. Analysis variables are derived 
from raw scores using the formulas below. Missing value will not be included in the calculation. 
For functional items, analysis variable is defined as ቀ1 −
raw score−1
𝑅𝑅
ቁ× 100; 
For symptom variables and global health score, analysis variables are defined as 
raw score−1
𝑅𝑅
×
100. 
All analyses variables take value between 0-100 after normalization. 


 
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Descriptively summarize the analysis variables and provide the p value (Wilcoxon rank test) for 
group comparison by each assessment visit. 
Same approaches as those used for LCSS will be applied for missing data handling, weighted 
averaging, summary and statistical inference on QLQ-30 data. 
9.3. 
Efficacy Analyses after PD 
Placebo subjects after PD confirmation and unblinding may crossover to receive sintilimab 
monotherapy as agreed by sponsor per protocol allowance. Only investigator assessment per 
RECIST 1.1 will be available during crossover phase. PFS 2 is defined as time from start of new 
anti-cancer therapy until subsequent PD based on RECIST 1.1 or death due to any cause, 
whichever is earlier. In the absence of disease progression or death at the last tumor assessment, 
PFS will be censored at this time point. 
If subject in IBI308 group receive new anti-cancer treatment after disease progression, subsequent 
information of new treatment and treatment effect should be collected. 
PFS 2 analyses are only applied to subjects receiving crossover treatment in FAS set. The analysis 
methods are the same as those for PFS analysis. 
Post disease progression ORR, TTR, and DOR will also be analyzed for subjects receiving 
sintilimab crossover treatment in FAS set. Analysis methods are similar to those descripted in 8.1.2, 
8.1.4 and 8.1.5, but without between-group comparison. 
10. 
REFERENCES 
[1] Protocol: A Randomized, Double-Blind, Phase III Study to Compare the Efficacy and Safety 
of IBI308 in Combination with Gemcitabine and Platinum-Based Chemotherapy vs. Placebo 
in Combination with Gemcitabine and Platinum-Based Chemotherapy in the First-Line 
Treatment for Patients with Advanced or Metastatic Squamous Non-Small Cell Lung Cancer 
(ORIENT-12). Protocol number CIBI308C303, version 2.1 dated 2019-01-24. 
[2] CFDA, Biostatistics guidance for clinical trials 2016. 
[3] ICH E9: Statistical Principles for Clinical Trials, 1998. 
[4] Robins, Tsiatis, Correcting for non-compliance in randomized trials using rank preserving 
structural failure time models. Communications in Statistics - Theory & Methods 20 (8): 2609-
2631, 1991. 
[5] Latimer. et. al. (2014) Adjusting for treatment switching in randomised controlled trials – A 
simulation study and a simplified two-stage method. Statistical Methods in Medical Research, 
26(2), 724-751 


 
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[6] Latimer. et. al. (2019) Two-stage estimation to adjust for treatment switching in randomised 
trials: a simulation study investigating the use of inverse probability weighting instead of re-
censoring. BMC Medical Research Methodology, 19(1), 69 
[7] Li. et. al. (2017) On an enhanced rank‐preserving structural failure time model to handle 
treatment switch, crossover, and dropout. Statistics in Medicine. 36(10), 1532-1547 
[8] Liang & Zeger (2000) Longitudinal data analysis of continuous and discrete response for pre-
post designs. Sankhya, 62(1), 134-148 
[9] Turnbull B.W., The empirical distribution function with arbitrarily grouped, censored, and 
truncated Data. Journal of the Royal Statistical Society Series B (38): 290-295, 1976. 
[10] Wellner J. A., Zhan Y., A hybrid algorithm for computation of the nonparametric maximum 
likelihood estimator from censored Data. Journal of the American Statistical Association 92: 
945-959, 1997. 
11. 
APPENDICES 
11.1. 
Acronym 
Abbreviation 
Description 
ADA 
Anti-drug antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
ALT 
Alanine transaminase 
ALK 
Anaplastic lymphoma kinase 
ALK 
Anaplastic lymphoma kinase 
AST 
Aspartate amino transferase 
BOR 
Best overall response 
CFDA 
China Food and Drug Administration 
CR  
Complete Response           
Cr 
Creatinine 


 
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Abbreviation 
Description 
CRF 
Case Report Form 
CTLA-4 
Cytotoxic T Lymphocyte Antigen 4 
DCR 
Disease control rate 
DOR 
Duration of response 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EORTC QLQ 
European organization for research and treatment of cancer quality of life 
questionnaire 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
irAE 
Immune-related Adverse Event 
IRRC 
Independent radiographic review committee 
LCSS 
The Lung Cancer Symptom Scale 
MTD 
Maximal tolerated dose 
Nab 
Neutralizing antibody 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall response rate 


 
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Abbreviation 
Description 
OS 
Overall Survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
PD-1 
Programmed cell death 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR   
Partial Response  
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D  
Recommended Phase II dose  
SAE 
Severe Adverse Event 
SD 
Stable Disease 
TBIL 
Total bilirubin 
TCR 
T-Cell Receptor 
ctDNA 
circulating tumor DNA 
TMB 
Tumor Mutation Burden 
TTR 
Time to response 
UADR 
Unexpected adverse drug reaction 
ULN 
Upper limits of normal