Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 550
Healthy volunteers: no

Brief summary:
The purpose of study is to compare the efficacy and safety of ONO-4538 in combination with carboplatin, paclitaxel, and bevacizumab (ONO-4538 group) to placebo in combination with carboplatin, paclitaxel, and bevacizumab (placebo group) in chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation in a multicenter, randomized, double-blind study.

Detailed description:

Arms:
arm 1: ONO-4538: 360 mg solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.

Chemotherapy: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. arm 2: Placebo: Placebo solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.

Chemotherapy: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.

Interventions: intervention 1: ONO-4538 intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Bevacizumab intervention 5: Placebo
Intervention descriptions: intervention 1: 360 mg solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. intervention 2: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. intervention 3: Carboplatin at AUC 6 and Paclitaxel at 200 mg/m2 intravenously in every 3 weeks for up to 4 cycles and if deemed safe, Carboplatin and Paclitaxel may continue for up to a maximum of 6 cycles until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. intervention 4: Bevacizumab at 15 mg/kg intravenously in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. intervention 5: Placebo solution intravenously for 30 min in every 3 weeks until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent.

Protocol document:
Prot_000.pdf: 
 
 
 
 
1 
 
 
 
 
 
 
ONO-4538 Phase 3 Study 
 
 
A Multicenter, Randomized, Double-Blind Trial in Subjects 
with Non-Squamous Non-Small Cell Lung Cancer 
 
 
Clinical Protocol 
 
 
 
 
 
 
ONO PHARMACEUTICAL CO., LTD. 
 
 
 
 
Protocol Number: ONO-4538-52 
Version Number: 5.0 
Prepared Date: October 17, 2019 
 


Clinical Protocol 
 
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nivolumab 
 
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CONFIDENTIALITY STATEMENT 
This document is the confidential and proprietary information of the Sponsor and its global 
affiliates. By reviewing this document, you agree to keep it confidential and to use and disclose it 
solely for the purpose of assessing whether your organization will participate in and/or the 
performance of the proposed study requested by the Sponsor. Any permitted disclosures will be 
made only on a confidential “need to know” basis within your organization or to your 
independent ethics committee(s). 
Any other use, copying, disclosure or dissemination of this information is strictly prohibited 
unless expressly authorized in writing by the Sponsor. Any supplemental information (eg, 
amendments) that may be added to this document is also confidential and proprietary to the 
Sponsor and must be kept in confidence in the same manner as the contents of this document. 
Any person who receives this document without due authorization from the Sponsor is requested 
to return it to the Sponsor or promptly destroy it. All other rights reserved. References to the 
Sponsor in this protocol may apply to partners to which the Sponsor has transferred obligations, 
eg, a Contract Research Organization (CRO). 
 


Clinical Protocol 
 
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SYNOPSIS 
1 
Study Objective 
To compare the efficacy and safety of ONO-4538 in combination with carboplatin, paclitaxel, 
and bevacizumab (treatment administered to ONO-4538 group) to placebo in combination with 
carboplatin, paclitaxel, and bevacizumab (treatment administered to placebo group) in 
chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation in a multicenter, randomized, double-blind study. 
 
2 
Study Design 
A multicenter, randomized, double-blind study 
 
2.1 
Overview of Study Design 
This study is a multicenter, randomized, double-blind, placebo controlled phase 3 study in 
chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation. The study is intended to evaluate the superiority of the 
ONO-4538 group over the placebo group, with progression-free survival (PFS), based on the 
Independent Radiology Review Committee (IRRC) assessment, as the primary endpoint. 
The study will consist of the screening period, treatment period, and follow-up period. In a 
double-blind fashion, subjects will be randomized in a 1:1 ratio into either the ONO-4538 group 
or the placebo group and stratified by PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or 
indeterminate), ECOG Performance Status (0 vs 1), and gender (male vs female). 
In the ONO-4538 group, ONO-4538, carboplatin, paclitaxel, and bevacizumab will be 
administered every 3 weeks. In the placebo group, placebo, carboplatin, paclitaxel, and 
bevacizumab will be administered every 3 weeks. Subjects will receive ONO-4538 360 mg or 
placebo in combination with carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab 
(15 mg/kg). In both groups, carboplatin and paclitaxel will be administered for up to 4 cycles and 
if deemed safe, treatment may continue for up to a maximum of 6 cycles. Even after the 
completion of treatment with carboplatin and paclitaxel, the investigational product (ONO-4538 
or placebo) and bevacizumab will be administered intravenously on Day 1 of each cycle in both 
treatment groups until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. 
Upon completion of the investigational product and chemotherapy, subjects will enter the 
follow-up period. 
In this study, one interim analysis of PFS among randomized subjects is planned for early 
stopping in case of superior efficacy, at the time when approximately 82.4% of the target number 
of events are observed. 
An overview of the study design is shown in Figure 2-1. 


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Figure 2-1: 
Study Design 
 
3 
Study Population 
3.1 
Study Subjects 
Chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation 
 
3.2 
Inclusion Criteria 
After subjects provide written informed consent before participating in the study, subjects must 
meet all of following inclusion criteria at the time of randomization. When it has been confirmed 
that the subject does not meet any of the following criteria from randomization to the first dose 
of the investigational product, the subject will be withdrawn from the study without receiving 
any investigational products. 
 
1. Males and females 
2. ≥ 20 years of age (at the time of informed consent) 
3. Subjects with histologically- or cytologically-confirmed non-squamous non-small cell lung 
cancer 
4. Subjects who received a diagnosis of stage IIIB/IV or recurrent non-squamous non-small cell 
lung cancer unsuitable for radical radiation according to the UICC-TNM Classification (7th 
edition) with no prior systemic anticancer therapy (including EGFR, ALK and ROS1 
ONO-4538 group
(up to a maximum of 6 cycles)
ONO-4538: 360 mg flat dose
Carboplatin: AUC 6
Paclitaxel: 200 mg/m2
Bevacizumab: 15 mg/kg, q3w
Placebo group
(up to a maximum of 6 cycles)
Placebo
Carboplatin: AUC 6
Paclitaxel: 200 mg/m2
Bevacizumab: 15 mg/kg, q3w
Treatment will be repeated until PD, unacceptable toxicity, or 
withdrawal of consent.
* Treatment with ONO-4538 plus bevacizumab or placebo plus 
bevacizumab will continue in subjects achieving SD or better.
*
*
ONO-4538: 360 mg flat dose
Bevacizumab: 15 mg/kg, q3w
Placebo
Bevacizumab: 15 mg/kg, q3w
Follow-up/outcome survey
Screening Period
Randomization
Treatment Period
Follow-
up Period
• Stage IIIB/IV or recurrent 
non-squamous NSCLC 
unsuitable for radical 
radiotherapy
• No prior use of systemic 
antineoplastic dugs for the 
treatment of advanced or 
metastatic NSCLC
• Without EGFR mutations
• Without ALK/ROS1 
translocations or unknown 
or indeterminate 
ALK/ROS1 status
• ECOG PS 0 to 1
Randomization
Stratified by:
• PD-L1
• ECOG PS
• Gender


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inhibitors) given as primary therapy for advanced or metastatic disease. 
Prior adjuvant or neoadjuvant chemotherapy is permitted provided the last administration of 
the prior regimen occurred at least 6 months prior to enrollment. 
5. Subjects with at least one measurable lesion by radiographic tumor assessments per RECIST 
1.1 criteria; radiographic tumor assessments performed within 28 days of randomization 
(target lesions may be located in a previously irradiated field if there is documented disease 
progression after the completion of radiation therapy.) 
6. Subjects who are able to provide tumor tissue specimens. If no fresh specimens are available, 
these will be allowed as archival samples, but they must contain a minimum of 100 evaluable 
tumor cells. Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained 
tumor tissue sections must be submitted for investigational product assignment and 
biomarker evaluation. The tumor tissue sample may be fresh or archival if obtained within 6 
months prior to enrollment, and there was no systemic therapy (eg, adjuvant or neoadjuvant 
chemotherapy) given after the sample was obtained. 
Tissue must be from a core needle biopsy, excisional biopsy, incisional biopsy, or forceps 
biopsy. EBUS-TBNA is acceptable if no tissue can be obtained through the above biopsy 
methods and tumor tissues may be collected by EBUS-TBNA. Fine needle biopsies, biopsies 
of bone lesions that do not have a soft tissue component, or decalcified bone tumor samples 
are not acceptable. In addition, cell block is not acceptable. 
7. ECOG Performance Status of 0 or 1 
8. Life expectancy ≥ 90 days by investigator assessment 
9. Women of childbearing potential (including those who have no menses for medical reasons, 
such as chemotherapy-induced menopause)#1 must agree to follow instructions for method(s) 
of contraception#2 or maintain complete abstinence from the time of informed consent 
through at least 5 months after the last administration of the investigational product (ONO-
4538 or placebo) or at least 6 months after the last administration of bevacizumab, whichever 
is longer. Women of childbearing potential must agree to discontinue breastfeeding from the 
time of informed consent through at least 5 months after the last administration of the 
investigational product or at least 6 months after the last administration of bevacizumab, 
whichever is longer. 
10. Male subjects who have agreed to follow instructions for method(s) of contraception#2 from 
the start of administration of the investigational product through at least 7 months after the 
last administration of the investigational product or at least 6 months after the last 
administration of bevacizumab, whichever is longer 
11. Subjects with percutaneous oxygen saturation of ≥ 94% by pulse oximetry at rest, without 
oxygen supplementation, within 7 days prior to randomization 
12. Latest laboratory values obtained within 7 days prior to randomization must meet the criteria 
listed below. These values should not reflect granulocyte-colony stimulating factor (G-CSF) 
or blood transfusion given within 14 days before the test day. 
∙ WBC ≥ 2000/mm3 
∙ Neutrophils ≥ 1500/mm3 
∙ Platelets ≥ 100000/mm3 
∙ Hemoglobin ≥ 9.0 g/dL 
∙ AST (GOT) and ALT (GPT) ≤ 3.0 × upper limit of normal (ULN) 
∙ LDH ≤ 2.0 × ULN 
∙ Total bilirubin ≤ 1.5 × ULN 


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∙ Creatinine ≤ 1.5 mg/dL or creatinine clearance (observed values or estimates calculated 
by the Cockcroft-Gault formula) > 50 mL/min 
13. Subjects who have been fully informed of the nature of the study through the informed 
consent form by the investigator and gave their consent for voluntary participation in the 
study 
 
#1: Women of childbearing potential are defined as all premenopausal women who have 
reached menarche and who have not undergone sterilization (including hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). Menopause is defined as amenorrhea 
for at least 12 successive months in the absence of significant causes. Women who use 
oral contraceptives or mechanical contraception such as intrauterine devices or barrier 
methods are regarded as having childbearing potential. 
#2: Subjects must agree to dual contraception using any 2 of the following methods: 
vasectomy or condoms in male subjects or male partners, or tubal ligation, 
contraception pessaries, intrauterine devices, or oral contraceptives in female subjects or 
female partners. 
 
3.3 
Exclusion Criteria 
The investigator cannot enroll subjects meeting any of the following criteria at the time of 
randomization. When subjects meet any of the following criteria between randomization to the 
first dose of the investigational product, subjects will be withdrawn from the study without 
receiving any investigational products. 
 
1. Subjects with known EGFR mutations, including deletions in exon 19 and exon 21 (L858R) 
substitution mutations. All subjects must have been tested for EGFR mutation status. Non-
squamous non-small cell lung cancer subjects with unknown or indeterminate EGFR status 
are excluded. 
2. Subjects with known ALK or ROS1 translocations. Subjects with unknown or indeterminate 
ALK or ROS1 status will be eligible for randomization. 
3. Complication or history of severe hypersensitivity reactions to antibody products or 
platinum-containing compounds 
4. Subjects with current or prior ≥ Grade 2 peripheral neuropathy 
5. Subjects with residual effects of adverse drug reactions associated with prior treatment or 
surgery that may have an impact on the safety assessment of the investigational product 
and/or chemotherapy at the investigator’s discretion. 
6. Subjects with autoimmune disease or known chronic or recurrent autoimmune disease. 
Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement 
or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are 
acceptable for enrollment. 
7. Subjects with contraindications to carboplatin, paclitaxel, or bevacizumab 
8. Subjects with current or prior interstitial lung disease or pulmonary fibrosis diagnosed based 
on radiographic tumor assessments or clinical findings. Subjects with radiation pneumonitis 


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with fibrosis, which is considered to be stable, and without recurrence are acceptable for 
enrollment. 
9. Subjects with active diverticulitis or symptomatic gastrointestinal ulceration 
10. Subjects with multiple cancers (those with completely resected basal cell carcinoma, stage I 
squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder 
cancer or with a history of other forms of cancer that has not recurred for at least 5 years are 
acceptable for enrollment.) 
11. Subjects with brain or meningeal metastasis. Subjects with metastatic lesions can be enrolled 
if the metastases are adequately treated with radiotherapy and/or surgery and subjects are 
neurologically returned to baseline (except for residual signs or symptoms related to the CNS 
treatment) at least 14 days prior to randomization and subjects have no documented evidence 
of progression confirmed by CT/MRI. 
12. Subjects with pericardial, pleural, or peritoneal effusion requiring treatment. In subjects who 
have recently undergone aspiration, the date of the procedure (or, in the case of drainage, the 
date of removal of the drain) must be at least 14 days prior to randomization, and there must 
not be any finding of aggravation of pericardial, pleural, or peritoneal effusion. 
13. Subjects with uncontrollable cancer pain 
14. Subjects who have a history of transient ischemic attack, cerebrovascular accident, 
thrombosis, or thromboembolism (pulmonary thromboembolism or deep venous thrombosis) 
within 180 days prior to randomization 
15. Subjects with any of the following uncontrollable or significant cardiovascular disease: 
∙ Myocardial infarction occurring within 180 days prior to randomization; 
∙ Uncontrollable angina occurring within 180 days prior to randomization; 
∙ Congestive heart failure, defined as New York Heart Association (NYHA) functional 
Class III or IV; 
∙ Uncontrollable hypertension even if adequately treated (systolic blood pressure 
≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting for 24 hours or longer); or 
∙ Arrhythmia requiring treatment. 
16. Subjects who are receiving anticoagulants (except antiplatelet therapy including low-dose 
aspirin) or have a disease for which anticoagulant therapy is required 
17. Subjects with uncontrollable diabetes 
18. Subjects who have received systemic adrenocorticosteroids equivalent to prednisone > 10 
mg/day (except for temporary use for examination, prophylaxis, or a similar purpose) or 
immunosuppressants within 28 days prior to randomization 
19. Subjects who have received pleurodesis or pericardial adhesion within 28 days prior to 
randomization 
20. Subjects who have had surgery under general anesthesia within 28 days prior to 
randomization 
21. Subjects who have had surgery under local or surface anesthesia within 14 days prior to 
randomization 
22. Subjects who have received radiotherapy within 28 days prior to randomization, who have 
received stereotactic irradiation for brain metastasis within 14 days prior to randomization or 
who have received chest radiotherapy or radiopharmaceuticals (except for use of 
radiopharmaceuticals for examination and diagnosis) within 56 days prior to randomization 


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23. Subjects who have received radiotherapy for pain relief within 14 days prior to randomization. 
Subjects who may require palliative radiotherapy within 4 weeks of randomization are 
strongly encouraged to receive palliative radiotherapy before randomization. 
24. Subjects who have received any other unapproved drugs (including investigational 
treatments, unapproved combination drugs, and drugs with new dosage forms) within 28 
days prior to randomization 
25. Subjects with systemic infection requiring treatment 
26. Prior treatment with ONO-4538 (MDX-1106 or BMS-936558), anti-PD-1 antibody, anti-PD-
L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or any 
other antibody therapy for regulation of T cells or drug therapies including cancer vaccines 
27. Any positive test for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or 
HCV antibody 
28. Subjects who test positive for HBs antibody or HBc antibody and have detectable HBV-DNA 
levels despite testing negative for HBs antigen 
29. Subjects who are pregnant, breastfeeding, or may be pregnant 
30. Subjects who are judged to lack the ability to provide consent for reasons such as dementia 
31. Subjects disqualified from participation in the study at the investigator’s discretion 
32. Subjects who have received a live/attenuated vaccine within 28 days prior to randomization 
 
4 
Investigational Product (ONO-4538 or Placebo) and Chemotherapy 
4.1 
Dose and Mode of Administration and Duration of Treatment 
Subjects will be randomized in a 1:1 ratio into either the ONO-4538 group or the placebo group 
and then receive all drugs on the same day every 3 weeks. The subjects will be given the 
investigational product first and start to receive chemotherapy at least 30 minutes after 
completion of the investigational product infusion. 
The dose and mode of administration and duration of treatment with the investigational product 
and chemotherapy are as follows. 
 
4.1.1 
Dose and Mode of Administration and Duration of Treatment with Investigational 
Product 
The investigational product (ONO-4538 360 mg or placebo) will be administered intravenously 
over 30 minutes every 3 weeks. The investigational product will continue until the subject meets 
any of 7.1.4.1 Investigational Product Discontinuation Criteria. 
No escalations or reductions in the dose of the investigational product will be allowed. Please 
refer to the current version of the Investigator’s Brochure and pharmacy reference sheets for 
proper storage, handling, preparation, and administration of the investigational product. 
 
4.1.2 
Dose and Mode of Administration and Duration of Treatment with Chemotherapy 
Subjects will receive carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg 
every 3 weeks. When calculating doses, in principle, the dose (mg) will be rounded to one 
decimal place. 


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It is permissible for the initial dose of paclitaxel and bevacizumab to be calculated based on the 
body weight measured at the time of randomization, instead of that measured on the day of first 
dosing (predose). The dose will be adjusted in each cycle if the subject’s weight changes by ≥ 
10% compared to the weight used to calculate the initial dose. If the subject’s weight changes by 
≥ 10% compared to the weight used to calculate the initial dose on the day of dosing, dose 
adjustment is acceptable for future infusions. Thereafter, similar action will be taken for any 
further changes in the subject’s weight (≥ 10% compared to the weight used to calculate the dose 
adjusted).  
Carboplatin dose will be calculated using the Calvert formula as follows: 
Carboplatin dose (mg) = Target AUC × [(Creatinine clearance (mL/min) + 25] 
Creatinine clearance calculation is based on the Cockcroft/Gault formula and should include the 
most recent serum creatinine and most recent weight. If calculation of the creatinine clearance by 
the Cockcroft/Gault formula yields a result of > 125 mL/min, then a creatinine clearance should 
be calculated by an alternative formula per institutional standards or capped at 125 mL/min. The 
dose of carboplatin may be capped as per local standards.  
The mode of administration should be based on the procedures specified by the study site and 
recommended procedures are described below. 
Subjects will receive paclitaxel as a 180-minute IV infusion on Day 1 of each cycle (3 weeks). 
On Day 1 of each cycle, subjects will receive carboplatin as a 30-minute IV infusion at least 30 
minutes after paclitaxel treatment completion. On Day 1 of each cycle, subjects will receive 
bevacizumab as an IV infusion at least 30 minutes after carboplatin treatment completion. The 
initial administration of bevacizumab will be given intravenously over 90 minutes, and if well 
tolerated, the duration of the second administration will be reduced to 60 minutes and to 30 
minutes in subsequent cycles. 
Carboplatin and paclitaxel will be administered for up to 4 cycles and if deemed safe, treatment 
may continue for up to a maximum of 6 cycles. Even after the completion of treatment with 
carboplatin and paclitaxel, bevacizumab will be administered intravenously on Day 1 of each 
cycle until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Even where 
carboplatin and paclitaxel have been discontinued for reasons such as adverse events, 
bevacizumab may be continued if deemed safe. 
 
5 
Concomitant Treatments 
5.1 
Treatments Prohibited during the Study 
The following treatments are prohibited during the study (from the time of informed consent 
through completion of protocol-specified final examination [except outcome survey]); except 
when the final examination at the completion of treatment period (the discontinuation) is 
completed and the treatment is medically unavoidable. For any drugs other than those mentioned 
below, please refer to the current version of the package inserts for chemotherapy administrated 
concomitantly in the study: 
 
1. Immunosuppressive drugs 


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2. Adrenocorticosteroids equivalent to prednisone > 10 mg/dayNote 1) 
3. Antineoplastic drugs except chemotherapy assigned in the study (such as chemotherapy, 
molecular targeted therapy, and immunotherapyNote 2]) 
4. Surgery for malignant tumor 
5. Radiotherapy (including chemoradiation)Note 3) 
6. RadiopharmaceuticalsNote 4) 
7. Bisphosphonates and anti-RANKL antibodiesNote 5) 
8. Transplantation therapy 
9. Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment with the investigational product and until 
100 days after the last dose of the investigational product 
10. Any other unapproved drugs (including investigational treatments, unapproved combination 
drugs, and drugs with new dosage forms) 
 
Note 1): Subjects are permitted the local use of topical, intra-articular, intranasal, ocular, or 
inhalational adrenocorticosteroids or the temporary use of adrenocorticosteroids for 
the treatment or prophylaxis of contrast media allergy or adverse events. The 
Sponsor’s Medical Monitor must be consulted for continued treatment with the 
investigational product or chemotherapy in subjects requiring systemic 
adrenocorticosteroids for treating drug-related adverse events and if necessary, the 
investigator will determine whether or not to continue treatment with the 
investigational product or chemotherapy after consultation with the Sponsor’s Medical 
Monitor. 
Note 2): Including local therapy with Picibanil. 
Note 3): Radiotherapy to brain or meningeal metastasis in the screening period is permitted 
unless subjects meet 3.3 Exclusion Criteria 22. As for palliative radiotherapy, only 
procedures specified in 5.2.1 Palliative Radiotherapy are permitted. 
Note 4): Use of radiopharmaceuticals for examination and diagnosis is permitted. 
Note 5): Use of bisphosphonates and anti-RANKL antibodies is acceptable only when their 
administration is started prior to randomization and the same dosage and 
administration are maintained. 
 
5.2 
Permitted Therapy 
5.2.1 
Palliative Radiotherapy 
Palliative radiotherapy for non-target lesions, except the chest lesion, is permitted only if 
clinically indicated. Radiographic tumor assessments should be performed wherever possible 
before starting palliative radiotherapy. 
The potential for overlapping toxicities of radiotherapy and ONO-4538 is not currently known. 
As concurrent radiotherapy and ONO-4538 have not been formally evaluated, in cases where 
palliative radiotherapy is required for a tumor lesion, then the investigational product and 
chemotherapy should be withheld for at least 1 week before, during, and 1 week after radiation. 


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Subjects should be closely monitored for any potential toxicity during and after receiving 
radiotherapy, and adverse events related to radiotherapy should resolve to Grade 1 or less prior to 
resuming administration of the investigational product and chemotherapy. 
 
5.2.2 
Prophylactic Administration 
Prophylactic medications for administration of the investigational product or chemotherapy 
should follow the procedures specified by the study site. Recommended medications and 
procedures for administration of the investigational product are described below. 
 
5.2.2.1 Prophylactic Medications for Administration of Investigational Product 
Prior prophylactic use of acetaminophen or diphenhydramine is recommended for subjects who 
are at risk of infusion-related reaction after administration of the investigational product. 
 
6 
Time and Events Schedule and Observations 
6.1 
Screening Period 
Following the subject’s written consent to participate in the study, examination and assessment 
will start in the screening period. After obtaining informed consent, the investigator will proceed 
to enrollment and select subjects eligible for the study who have satisfied all of 3.2 Inclusion 
Criteria and do not meet any of 3.3 Exclusion Criteria in the randomization process. Table 6-1 
(Synopsis) shows assessments and tests in the screening period and the time and events schedule. 
 
6.2 
Treatment Period 
6.2.1 
Investigational Product (ONO-4538 or placebo) 
ONO-4538 360 mg or placebo will be administered intravenously over 30 minutes every 3 
weeks. The investigational product will continue until the subject meets any of 7.1.4.1 
Investigational Product Discontinuation Criteria. In the protocol synopsis, Table 6-1 shows 
assessments and tests in the treatment period and the time and events schedule. 
 
6.2.2 
Chemotherapy 
Subjects will receive carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg 
every 3 weeks. Carboplatin and paclitaxel will be administered for up to 4 cycles and if deemed 
safe, treatment may continue for up to a maximum of 6 cycles. Even after the completion of 
treatment with carboplatin and paclitaxel, bevacizumab will be administered intravenously on 
Day 1 of each cycle until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of 
consent. In the protocol synopsis, Table 6-1 shows the assessments and tests in the treatment 
period and the time and events schedule. 
 


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6.3 
Follow-up Period 
Subjects meeting any of 7.1.4 Treatment Discontinuation Criteria will be evaluated at the 
completion of the treatment period (at discontinuation) and enter the follow-up period. In the 
protocol synopsis, Table 6-1 shows the assessments and tests in the follow-up period and the 
time and events schedule. 




 
 
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1. Recent test results obtained within 1 year, 28 days, and 28 days prior to randomization will be used, respectively, for viral test, radiographic tumor assessments 
(except chest X-ray), and immunological/hormonal examinations. Images obtained within 28 days prior to randomization will be used for radiographic tumor 
assessments performed to determine the presence or absence of brain metastases and bone metastases. 
2. If the last examination is within the time window for completion of the treatment period (at discontinuation) or 28 days after completion of the treatment 
period, previous test results may be used except when medically indicated. However, an examination must be performed if at least 2 days (vital signs), 15 days 
(radiographic tumor assessments except chest X-ray), and 8 days (other tests) have elapsed since the last examination. An examination will be performed as 
needed if medically indicated. 
3. If subsequent anticancer therapy for non-squamous non-small cell lung cancer is started out of clinical necessity by 28 days after completion of the treatment 
period, the assessment scheduled for 28 days after completion of the treatment period will be performed before start of subsequent anticancer therapy. 
4. An initial dose should be administered within 60 days after informed consent. The re-enrollment of a subject who failed to proceed to randomization is 
permitted. If re-enrolled, the subject needs to be re-consented in writing. 
5. Subjects will be randomized through the IWRS. An initial dose should be administered within 3 days after randomization. 
6. Subjects will receive the investigational product and chemotherapy at least 18 days after the previous dose, namely on or after Day 19. 
7. Data obtained on Day 22 in the previous cycle may be used for ECOG Performance Status, vital signs, body weight, hematology, serum chemistry, and 
urinalysis, except when medically indicated. However, an examination must be performed if at least 2 days (vital signs) and 8 days (other tests) have elapsed 
since the last examination. An examination will be performed as needed if medically indicated. 
8. Women of childbearing potential will undergo a serum or urine pregnancy test. The same procedures should be used as much as possible throughout the study. 
In Cycle 2 and subsequent cycles, a pregnancy test will be performed within 7 days prior to administration of the investigational product. 
9. An examination will be performed before administration of the investigational product. A pregnancy test will be performed only in odd cycles. 
10. Height will be measured only during the screening period. 
11. No weight determination is required. 
12. For any symptoms/signs or laboratory data indicative of respiratory disease, chest X-ray may be performed as needed in addition to scheduled examinations 
during the study (from the time of informed consent through completion of the protocol-specified final examination [except outcome survey]). 
13. Only applicable to Cycles 2, 6, and 8. 
14. SP-D and KL-6 measurement is optional. 
15. An examination will be performed only in even cycles. 
16. Measurement will continue up to Cycle 16, but not be required for the subject who discontinued the investigational product but remained in the treatment 
period. 
17. Samples will be collected immediately before the end of infusion of the investigational product. 
18. Only applicable to Cycle 7. Samples will be collected immediately before the end of infusion of the investigational product. 
19. Applicable to Cycles 2, 6, 8, 12, and 16. 
20. Measurement will be performed only in subjects who entered the follow-up period by Cycle 16. 
21. Measurement will also be performed, wherever possible, 6 to 12 weeks after the last administration of the investigational product. For the subject who 
discontinued only the investigational product, the measurement may be performed during the treatment period. 
 
 
24. Tumor markers must be measured continuously wherever possible in subjects who have tumor marker levels exceeding the upper limit of normal. Tumor 
markers will be measured as needed. 
25. Tissue samples will be submitted for PD-L1 IHC testing performed by the central laboratory during the screening period. Either a formalin-fixed, paraffin-
embedded (FFPE) tissue block or unstained tumor tissue sections must be submitted for investigational product assignment and biomarker evaluation prior to 


 
 
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randomization. The tumor tissue sample may be fresh or archival if obtained within 6 months prior to enrollment, and there was no systemic therapy (eg, 
adjuvant or neoadjuvant chemotherapy) given after the sample was obtained. The PD-L1 status will be determined before randomization and used for IWRS-
based assignment. 
26. After the end of efficacy assessment, tumor tissues will be collected. 
27. A chest, abdominal, and pelvic CT scan will be performed to determine antitumor activity. The same procedures will be used for antitumor activity 
assessment throughout the study. The antitumor activity is assessed according to the RECIST 1.1 criteria. 
28. Subjects will be examined for brain metastases by head CT/MRI scan (images obtained within 28 days prior to randomization will be used). According to 
clinical symptoms, FDG-PET (or bone scintigraphy) must be performed to determine the presence or absence of bone metastases. 
29. The first tumor assessment will take place 6 weeks after the first day of treatment (+ 7 days). Subsequent tumor assessments will be performed every 6 weeks 
(± 7 days) for the first 12 months (until Week 48) and after Week 48, assessments will be conducted every 12 weeks (± 7 days) until PD. According to clinical 
symptoms, radiographic tumor assessment results will be used to determine the presence or absence of brain metastases and bone metastases. 
30. For subjects whose overall response is a CR, PR, or SD per RECIST 1.1 criteria and who terminated the treatment period for safety reasons or disease 
progression, radiographic tumor assessments should be continued wherever possible until start of subsequent anticancer therapy for non-squamous non-small 
cell lung cancer or the outcome is assessed as PD or recurrence. Subjects whose PD is not confirmed by the IRRC will be required to continue radiographic 
tumor assessments according to the protocol-specified schedule, and their subsequent tumor images must be submitted to the IRRC (if clinically feasible). If 
thoracentesis, pericardiocentesis, or abdominal paracentesis is considered, for example due to clinical symptoms, a CT scan should be performed wherever 
possible before these treatments. 
31. All adverse events and concomitant treatments will be investigated for up to 100 days after the last administration of the investigational product or 
chemotherapy, whichever comes later. When drug-related adverse events or adverse events leading to discontinuation are reported at the start of follow-up, 
concomitant treatments administered for these events should be investigated at appropriate intervals until no further follow-up is required because the events 
have resolved or are resolving, or the symptoms become stable. The presence or absence of subsequent anticancer therapy for non-squamous non-small cell 
lung cancer, the date of starting such therapy, and details of the therapy should also be investigated wherever possible during the follow-up. 
32. Outcome survey (date and cause of death will be investigated if the subject has died) can be conducted by phone or letter, which will be performed 
approximately every 3 months or as needed depending on the incidence of events. Any new information on survival status should be entered on the eCRF 
accordingly. The presence or absence of subsequent anticancer therapy for non-squamous non-small cell lung cancer, the date of starting such therapy, and 
details of the therapy should also be investigated wherever possible. 
33. QoL and healthcare resource utilization assessments will be performed every 6 weeks (± 7 days) for the period from the first day of Cycle 1 through 
completion of the treatment period. To minimize potential bias, QoL assessments should be, in principle, conducted prior to any study procedures in each study 
visit. QoL assessments will also be performed before administration of the investigational product. In follow-up study visits, EQ-5D will be collected every 3 
months for the first year of the follow-up period, and every 6 months thereafter. 
 


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7 
Endpoints 
7.1 
Efficacy Endpoint - Primary Endpoint 
Progression-free survival (as assessed by the Independent Radiology Review Committee 
[IRRC]) 
 
7.2 
Efficacy Endpoint - Secondary Endpoints 
1. Overall survival 
2. Progression-free survival (as assessed by the study site’s investigator) 
3. Objective response rate (as assessed by the IRRC and study site’s investigator) 
4. Disease control rate (as assessed by the IRRC and study site’s investigator) 
5. Duration of response (as assessed by the IRRC) 
6. Time to response (as assessed by the IRRC) 
7. Best overall response (as assessed by the IRRC and study site’s investigator) 
8. Maximum percentage of change in the sum of diameters of target lesions (as assessed by the 
IRRC) 
 
7.3 
Safety Endpoints 
1. Adverse events 
2. Laboratory tests 
3. Vital signs 
4. Chest X-ray 
5. 12-lead ECG 
6. ECOG Performance Status 
 
7.4 
Patient Reported Outcomes 
1. QoL questionnaire (EQ-5D) 
2. Questionnaire to assess disease-related symptoms (LCSS) 
 
7.5 
Other Tests 
Healthcare resource utilization 
 
7.6 
Biomarkers 
 
 
3. Tumor markers (as needed) 
 
5. Tumor tissues 
 


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7.7 
Pharmacokinetic Assessment 
Serum ONO-4538 concentration 
 
7.8 
Immunogenicity Assessment 
Anti-ONO-4538 antibody 
 
8 
Interim Analysis 
One interim analysis for PFS per IRRC will be performed in the ITT population to determine 
whether to stop the study early for superiority based on the stratified log-rank test with allocation 
factors (PD-L1 expression level, ECOG PS, and gender) as stratification factors when 
approximately 82.4% (n = 280) of the target number of PFS events over the entire study 
(n = 340) have occurred. To control the overall type I error rate at no more than 5% (two-sided), 
the significance levels used in the interim and final analyses will be calculated by the Lan-
DeMets α spending function (O’Brien-Fleming type) based on the actual number of events. 
When the planned interim analysis is performed when exactly 280 PFS events have been 
reported, the nominal two-sided significance levels for the interim and final analyses are 
calculated as shown in Table 8-1. 
Whether the study is to be stopped for superiority based on the interim analysis will be decided 
by the IDMC. The details of the interim analysis are separately specified in the IDMC procedural 
manual and the interim analysis plan. 
 
Table 8-1: 
Criteria for Success at Interim and Final Analyses 
Analysis 
Timing 
Nominal two-sided significance level 
Interim analysis 
280 events 
2.70% 
Final analysis 
340 events 
4.22%a) 
a): In the final analysis using the ITT and the PD-L1 1% Positive Set, Hochberg’s method will also be used to adjust 
multiplicity. 
 
9 
Planned Sample Size 
The target sample size is approximately 265 subjects per group, and approximately 530 subjects 
in total for the entire study. 
 
10 
Planned Study Period 
Mar-2017 to Jul-2022 
 


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TABLE OF CONTENTS 
1 
PRODUCT DEVELOPMENT BACKGROUND ......................................................28 
1.1 
Introduction ..............................................................................................................28 
1.2 
Summary of Major Findings from Nonclinical and Clinical Studies ......................29 
1.2.1 
Nonclinical Overview ............................................................................................29 
1.2.2 
Clinical Overview and Summary of Known and Potential Risks and 
Benefits ..................................................................................................................31 
2 
STUDY ADMINISTRATIVE STRUCTURE AND RESPONSIBILITIES 
(IF APPLICABLE) .....................................................................................................32 
3 
STUDY OBJECTIVES ..............................................................................................32 
3.1 
Primary Objectives of the Study ..............................................................................32 
3.2 
Secondary Objective of the Study ............................................................................32 
4 
STUDY POPULATION .............................................................................................32 
4.1 
Study Subjects ..........................................................................................................32 
4.2 
Inclusion Criteria ......................................................................................................33 
4.2.1 
Rationale ................................................................................................................34 
4.3 
Exclusion Criteria ....................................................................................................35 
4.3.1 
Rationale ................................................................................................................37 
5 
STUDY PROCEDURES ............................................................................................37 
5.1 
Study Design ............................................................................................................37 
5.1.1 
Study Design .........................................................................................................37 
5.1.1.1 
Rationale for study design ..................................................................................38 
5.1.2 
Planned Sample Size .............................................................................................39 
5.1.2.1 
Rationale .............................................................................................................39 
5.1.3 
Planned Study Period ............................................................................................40 
5.2 
Enrollment of Subjects .............................................................................................41 
5.3 
Method of Assigning Subjects .................................................................................42 
5.4 
Blinding/Unblinding ................................................................................................42 
5.4.1 
Maintenance of Blinding .......................................................................................42 
5.4.2 
Unblinding .............................................................................................................42 
5.5 
Endpoints .................................................................................................................43 
5.5.1 
Efficacy Endpoints ................................................................................................43 
5.5.1.1 
Primary Endpoint ................................................................................................43 


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5.5.1.2 
Secondary Endpoints ..........................................................................................43 
5.5.2 
Safety Endpoints ....................................................................................................43 
5.5.2.1 
Rationale .............................................................................................................44 
5.5.3 
Patient Reported Outcomes ...................................................................................44 
5.5.4 
Other Tests ............................................................................................................44 
5.5.5 
Biomarkers ............................................................................................................44 
5.5.6 
Pharmacokinetic Assessment ................................................................................44 
5.5.7 
Immunogenicity Assessment .................................................................................44 
6 
INVESTIGATIONAL PRODUCT ............................................................................44 
6.1 
Handling and Dispensing of Investigational Product ..............................................45 
6.2 
Investigational Product Management and Return of Unused Investigational 
Product .....................................................................................................................45 
6.2.1 
Storage and Management of Investigational Product ............................................45 
6.2.2 
Destruction of Investigational Product ..................................................................46 
6.2.3 
Return of Investigational Product ..........................................................................47 
7 
STUDY TREATMENT ..............................................................................................47 
7.1 
Investigational Product and Chemotherapy .............................................................47 
7.1.1 
Dose and Mode of Administration and Duration of Treatment ............................47 
7.1.1.1 
Dose and Mode of Administration and Duration of Treatment with 
Investigational Product .......................................................................................47 
7.1.1.2 
Dose and Mode of Administration and Duration of Treatment with 
Chemotherapy .....................................................................................................48 
7.1.2 
Dosing Criteria ......................................................................................................49 
7.1.2.1 
Dosing Criteria for Investigational Product ........................................................50 
7.1.2.2 
Dosing Criteria for Chemotherapy .....................................................................50 
7.1.3 
Dose Reduction Criteria ........................................................................................51 
7.1.3.1 
Dose Reduction Criteria for Investigational Product ..........................................51 
7.1.3.2 
Dose Reduction Criteria for Chemotherapy .......................................................51 
7.1.4 
Treatment Discontinuation Criteria .......................................................................52 
7.1.4.1 
Investigational Product Discontinuation Criteria ...............................................52 
7.1.4.2 
Chemotherapy Discontinuation Criteria .............................................................53 
7.2 
Concomitant Treatments ..........................................................................................54 
7.2.1 
Treatments Prohibited During the Study ...............................................................54 


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7.2.1.1 
Rationale .............................................................................................................55 
7.2.2 
Permitted Therapy .................................................................................................56 
7.2.2.1 
Palliative Radiotherapy .......................................................................................56 
7.2.2.2 
Prophylactic Administration ...............................................................................56 
7.3 
Discontinuation for Supply of Investigational Product ............................................56 
7.4 
Post-Study Access to Therapy .................................................................................57 
8 
TIME AND EVENTS SCHEDULE AND OBSERVATIONS..................................57 
8.1 
Time and Events Schedule .......................................................................................57 
8.1.1 
Screening Period ....................................................................................................57 
8.1.2 
Treatment Period ...................................................................................................57 
8.1.2.1 
Investigational Product .......................................................................................57 
8.1.2.2 
Chemotherapy .....................................................................................................57 
8.1.3 
Follow-up Period ...................................................................................................58 
8.2 
Observations .............................................................................................................58 
8.2.1 
Demographics ........................................................................................................58 
8.2.2 
Drug Administration and Provision of Concomitant Treatments .........................58 
8.2.2.1 
Administration of Investigational Product and Chemotherapy ..........................58 
8.2.2.2 
Administration of Other Drugs and Concomitant Treatments............................59 
8.2.3 
Efficacy Endpoints ................................................................................................59 
8.2.3.1 
Radiographic Tumor Assessments (Measurement of Tumor Diameter 
and Evaluation of Antitumor Activity) ...............................................................59 
8.2.4 
Safety Items ...........................................................................................................61 
8.2.4.1 
Vital Signs, Body Weight, Height, 12-Lead Electrocardiogram ........................61 
8.2.4.2 
Chest X-Ray ........................................................................................................62 
8.2.4.3 
Laboratory Tests .................................................................................................63 
8.2.4.4 
Pregnancy Test (Women of Childbearing Potential Only) .................................64 
8.2.4.5 
Viral Test ............................................................................................................65 
8.2.4.6 
ECOG Performance Status .................................................................................66 
8.2.4.7 
Adverse Events ...................................................................................................66 
8.2.5 
Measurement of Serum Drug Concentration .........................................................67 
8.2.6 
Measurement of Anti-ONO-4538 Antibodies .......................................................67 
8.2.7 
Exploration of Biomarkers ....................................................................................68 
8.2.7.1 
............................................................................................................68 


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8.2.7.2 
 ........................................................................................69 
8.2.7.3 
Tumor Markers (As Needed) ..............................................................................69 
8.2.7.4 
 ............................................................69 
8.2.7.5 
Tumor Tissues.....................................................................................................70 
8.2.8 
Patient Reported Outcome .....................................................................................71 
8.2.9 
Other Examinations ...............................................................................................71 
8.2.9.1 
Healthcare Resource Utilization .........................................................................71 
8.2.10 
Follow-up ..............................................................................................................72 
8.2.11 
Lost to Follow-up ..................................................................................................72 
9 
ADVERSE EVENTS AND ITEMS TO ENSURE SUBJECT SAFETY ..................73 
9.1 
Definition of Adverse Events ...................................................................................73 
9.2 
Definition of Serious Adverse Events ......................................................................73 
9.3 
Grading .....................................................................................................................74 
9.4 
Causal Relationship with Investigational Product or Chemotherapy ......................75 
9.5 
Outcome ...................................................................................................................75 
9.6 
Continuation of Investigational Product or Chemotherapy .....................................76 
9.7 
Treatment .................................................................................................................76 
9.8 
Action taken for Serious Adverse Events (SAE) .....................................................76 
9.9 
Action taken for Pregnancy ......................................................................................78 
9.10 
Action taken for Overdose .......................................................................................78 
9.11 
Other Safety Considerations ....................................................................................78 
9.12 
Provision of New Information .................................................................................78 
10 
STATISTICAL ANALYSIS ......................................................................................79 
10.1 
Explanation of Statistical Methods including Timing of Planned Interim 
Analysis ....................................................................................................................79 
10.2 
Independent Data Monitoring Committee (IDMC) .................................................79 
10.3 
Significance Level Used ..........................................................................................80 
10.3.1 
Efficacy .................................................................................................................80 
10.3.2 
Safety .....................................................................................................................80 
10.4 
Selection of Subjects to Be Included in Analyses ....................................................80 
10.4.1 
Definition of Analysis Sets ....................................................................................80 
10.4.1.1 
Enrolled Set (ENR) .............................................................................................80 
10.4.1.2 
ITT/Randomized Set (RND) ...............................................................................80 


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10.4.1.3 
SAF .....................................................................................................................81 
10.4.1.4 
PDL1-PS .............................................................................................................81 
10.4.1.5 
Anti-Drug Antibody Set......................................................................................81 
10.4.2 
Criteria for Handling of Subjects ..........................................................................81 
10.4.2.1 
Non-randomized Subjects ...................................................................................81 
10.4.2.2 
Untreated Subjects ..............................................................................................81 
10.4.2.3 
Incomplete Anti-Drug Antibody Subjects ..........................................................81 
10.4.3 
Criteria for Handling of Time Points ....................................................................82 
10.5 
Analytical Methods ..................................................................................................82 
10.5.1 
Examinations on Reliability of Study ...................................................................82 
10.5.1.1 
Presence of Subjects Who Are Excluded ...........................................................82 
10.5.1.2 
Discontinuations from Study ..............................................................................82 
10.5.2 
Administration of Investigational Product and Chemotherapy .............................82 
10.5.3 
Distribution of Background Factors ......................................................................82 
10.5.3.1 
Demographic Variables ......................................................................................82 
10.5.3.2 
Patient Characteristics.........................................................................................82 
10.5.3.3 
Baseline Values during Observation Period .......................................................83 
10.5.4 
Efficacy Endpoints ................................................................................................83 
10.5.4.1 
Objectives ...........................................................................................................83 
10.5.4.2 
Hypothesis ..........................................................................................................83 
10.5.4.3 
Analysis Item and Handling of Data...................................................................83 
10.5.4.4 
Analytical Methods .............................................................................................84 
10.5.5 
Efficacy Secondary Endpoints ..............................................................................85 
10.5.5.1 
Objective .............................................................................................................85 
10.5.5.2 
Analysis Items and Handling of Data .................................................................85 
10.5.5.3 
Analytical Methods .............................................................................................87 
10.5.6 
Examination of Interactions ..................................................................................87 
10.5.7 
Adjusted Analysis ..................................................................................................88 
10.5.8 
Safety Analysis ......................................................................................................88 
10.5.8.1 
Objective .............................................................................................................88 
10.5.8.2 
Analysis Items.....................................................................................................88 
10.5.8.3 
Analytical Methods .............................................................................................88 
10.5.9 
Blinded Review .....................................................................................................88 


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10.5.10 
Other Items ............................................................................................................89 
11 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .............................89 
11.1 
Good Clinical Practice .............................................................................................89 
11.2 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ..................89 
11.3 
Protection of Subject’s Privacy ................................................................................90 
12 
SUBJECT INFORMED CONSENT ..........................................................................90 
12.1 
Informed Consent .....................................................................................................90 
12.2 
Withdrawal of Consent ............................................................................................91 
13 
STOPPING RULES OR DISCONTINUATION CRITERIA FOR 
INDIVIDUAL SUBJECTS ........................................................................................91 
14 
STUDY MANAGEMENT .........................................................................................92 
14.1 
Compliance with the Protocol and Protocol Revisions ............................................92 
15 
ENTRY OF DATA ON ELECTRONIC CASE REPORT FORM (ECRF)...............93 
15.1 
eCRF ........................................................................................................................93 
16 
MONITORING ...........................................................................................................93 
17 
PROCEDURES FOR CONFIRMING COMPLIANCE WITH 
ADMINISTRATION TO SUBJECTS AND OTHER AGREEMENTS ...................93 
18 
ARCHIVING OF ESSENTIAL DOCUMENTS ........................................................94 
18.1 
Archiving of Records ...............................................................................................94 
19 
PUBLICATION OF RESULTS .................................................................................94 
20 
REFERENCES ...........................................................................................................95 
 


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LIST OF TABLES 
Table 6-1: Time and Events Schedule ..........................................................................................13 
Table 8-1: Criteria for Success at Interim and Final Analyses ....................................................17 
Table 1: 
List of Abbreviations ..................................................................................................25 
Table 7.1.1-1: 
Predicted Steady-State Exposure of ONO-4538 .................................................48 
Table 7.1.3-1: 
Dose Reductions of Carboplatin and Paclitaxel .................................................52 
Table 7.1.3-2: 
Dose Reduction Criteria for Carboplatin and Paclitaxel ....................................52 
Table 9.8-1: 
Facsimile Number and Telephone Contact by Country ........................................77 
Table 10.1-1: 
Criteria for Success at Interim and Final Analyses.............................................79 
 
LIST OF FIGURES 
Figure 2-1: Study Design .................................................................................................................4 
 
LIST OF APPENDICES 
APPENDIX 1 
Criteria for Antitumor Activity Used in the Study...................................97 
APPENDIX 2 
Performance Status Scale/Scores ECOG ...............................................104 
APPENDIX 3 
List of Autoimmune Diseases (reference)..............................................105 
 


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Table 1: 
List of Abbreviations 
Term 
Definition 
ADCC 
antibody-dependent cell cytotoxicity 
ALP 
alkaline phosphatase 
ALT (GPT) 
alanine aminotransferase (glutamic pyruvic transaminase) 
ANA 
antinuclear antibody 
AST (GOT) 
aspartate aminotransferase (glutamic oxaloacetic transaminase) 
AUC 
area under the plasma concentration-time curve 
BOR 
best overall response 
BUN 
blood urea nitrogen 
CD 
cluster of differentiation (antigen) 
CDC 
complement-dependent cytotoxicity 
CHO 
Chinese hamster ovary 
CMV 
cytomegalovirus 
CR 
complete response 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
CTLA-4 
cytotoxic T lymphocyte-associated antigen 4 
CV 
coefficient of variation 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DNP-Ficoll 
2,4-dinitrophenyl-conjugated Ficoll 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
GAD 
glutamic acid decarboxylase 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HBc 
hepatitis B virus core protein 
HBs 
hepatitis B virus surface protein 
HBsAg 
hepatitis B virus surface antigen 


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Term 
Definition 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV-1 
human immunodeficiency virus type 1 
HIV-2 
human immunodeficiency virus type 2 
 
 
 
 
 
 
 
 
 
 
HTLV-1 
human T-cell leukemia virus type 1 
ICOS 
inducible costimulator 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
interferon-gamma 
IgA 
immunoglobulin A 
IRRC 
Independent Radiology Review Committee 
ITT 
Intention-to-Treat 
IWRS 
Interactive Web Response System 
KD 
dissociation constant 
KL-6 
sialylated carbohydrate antigen 
LAG-3 
lymphocyte activation gene 3 
LDH 
lactate dehydrogenase 
LKM 
liver kidney microsome 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MLR 
mixed lymphocyte reaction 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 


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Term 
Definition 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-ligand 1 
PD-L2 
programmed cell death-ligand 2 
Performance Status 
general performance status 
PK 
pharmacokinetics 
PFS 
progression-free survival 
PPK 
population pharmacokinetics 
PR 
partial response 
PT 
preferred term 
QoL 
quality of life 
RA 
rheumatoid factor 
RANKL 
receptor activator of NF-κB ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAF 
Safety Set 
SD 
stable disease 
SOC 
system organ class 
SP-D 
pulmonary surfactant protein D 
SpO2 
percutaneous oxygen saturation 
SSA 
Sjogren syndrome A 
SSB 
Sjogren syndrome B 
TSH 
thyroid-stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
Vss 
volume of distribution at steady state 
γ-GTP 
gamma-glutamyl transpeptidase 
 


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1 
PRODUCT DEVELOPMENT BACKGROUND 
1.1 
Introduction 
Lung cancer remains the leading cause of cancer-related deaths worldwide and approximately 
1,589,900 deaths in 2012 from lung cancer are reported.1 Non-small cell lung cancer is the major 
histological subtype of lung cancer accounting for 85% of all lung cancers. Of these, 
approximately 70% are non-squamous and approximately 30% are squamous.2 
Clinical practice guidelines recommend the use of platinum-based chemotherapy with a third- or 
later-generation anticancer drug as standard of care for chemotherapy-naïve subjects with stage 
IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation. 
The use of platinum-based chemotherapy with a third- or later-generation anticancer drug and 
bevacizumab combination therapy is also one of the therapies recommended.3  However, 
clinical benefit of the use of platinum-based chemotherapy with a third- or later-generation 
anticancer drug as standard of care has a median Progression Free Survival (PFS) of 4.5 to 6.2 
months, and a median Overall Survival (OS) of 10.3 to 12.3 months.4 5 Therefore, conventional 
therapies are not effective for treating stage IIIB/IV or recurrent non-small cell lung cancer 
unsuitable for radical radiation, and there is an urgent need for development of novel therapeutic 
drugs in these patient populations. 
ONO-4538 is a human monoclonal antibody to human programmed cell death-1 (PD-1, also 
known as cluster of differentiation 279 [CD279]) produced by ONO PHARMACEUTICAL CO., 
LTD. (ONO PHARMA) and Medarex, Inc. (current Bristol-Myers Squibb [BMS]). Programmed 
cell death-1 is a 55-kDa type I transmembrane protein and belongs to the CD28 subfamily 
known as a costimulatory receptor for T cells, including CD28, CTLA-4, ICOS, and BTLA, 
within the immunoglobulin superfamily. Programmed cell death-1 is primarily expressed on 
activated T cells and B cells. Programmed cell death-1 is also expressed on the memory T cell 
subset with varying levels of expression. Two specific ligands for PD-1 have been identified: 
programmed cell death-ligand 1 (PD-L1, also known as B7-H1 or CD274) and programmed cell 
death-ligand 2 (PD-L2, also known as B7-DC or CD273). Binding of PD-L1 and PD-L2 to PD-1 
in mice and humans results in the down-regulation of T cell activation.6 to 8 
ONO-4538 is approved in a number of countries including Japan (Jul-2014), the United States 
(US, Dec-2014), South Korea (Mar-2015), the European Union (EU, Jun-2015), and Taiwan 
(May-2016). 
In CA209017 (in subjects with stage IIIB/IV or recurrent squamous non-small cell lung cancer 
after failure of prior platinum-based chemotherapy), ONO-4538 demonstrated superior OS 
compared with docetaxel. The median overall survival (OS) was 9.2 months in the ONO-4538 
group and 6 months in the docetaxel group (hazard ratio [HR] = 0.59).9 In CA209057 (in 
subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer after failure of 
prior platinum-based chemotherapy), ONO-4538 also demonstrated superior OS compared with 
docetaxel. The median OS was 12.2 months in the ONO-4538 group and 9.4 months in the 
docetaxel group (HR = 0.73).10 In CA209026, a phase III study of ONO-4538 versus 
investigator's choice chemotherapy as first-line therapy for stage IV or recurrent PD-L1+ (≥ 1%) 
non-small cell lung cancer, the study did not meet the primary endpoint (PFS in PD-L1 strongly 


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positive [≥ 5%] subjects) with a median PFS of 4.2 months in the ONO-4538 group and 5.9 
months in the chemotherapy group (HR = 1.15).11 
Chemotherapy has been reported to not only directly inhibit tumor proliferation but also reinstate 
anticancer immunosurveillance.12 The immune response eliminating the tumor is made robust 
when chemotherapy results in tumor cell death with a resultant increase in tumor antigen 
delivery to antigen-presenting cells.13 14 Chemotherapy may also disrupt immune system 
regulatory networks to reinstate anticancer immunosurveillance by decreasing the number of T-
regulatory cells.12 15 Antiangiogenic agents have been shown to induce antitumor activity by 
impairing vascular endothelial growth factor (VEGF) signal-mediated immune evasion in cancer, 
in addition to angiogenesis.16 to 19 
Based on findings described above, the potential for synergistic antitumor activity to disturb 
cancer-immune evasion system via multiple mechanisms by combining an antiangiogenic agent-
based chemotherapy and immune checkpoint inhibitor in addition to chemotherapy induced 
cytotoxic antitumor activity could be offered. 
ONO-4538-04, a phase 1 study in subjects with untreated NSCLC in Japan, evaluated safety and 
tolerability of ONO-4538 plus platinum-based chemotherapy. The combination therapy showed 
a tolerable safety profile, in addition to some promising activity evaluated for exploratory 
endpoint in this study.20 
From the above, the study is to evaluate the efficacy and safety of ONO-4538 in combination 
with chemotherapy, including platinum-based drugs, in chemotherapy-naïve subjects with stage 
IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation. 
 
1.2 
Summary of Major Findings from Nonclinical and Clinical Studies 
1.2.1 
Nonclinical Overview 
ONO-4538 is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. 
The drug substance is ONO-4538 aqueous solution and is a clear to opalescent colorless to pale 
yellow liquid, light (few) particulates may be present. The drug product is an aqueous solution, 
containing 100 mg of ONO-4538 per vial, and must be stored at 2°C to 8°C and protected from 
light (for details, refer to the Investigator’s Brochure). 
ONO-4538 has been shown to bind specifically to PD-1 and bind with high affinity to human 
and monkey PD-1 with KD of 3.06 nmol/L and 3.92 nmol/L, respectively. ONO-4538 inhibits the 
binding of PD-1 to its ligands (PD-L1 and PD-L2), resulting in enhanced T-cell proliferation and 
interferon-gamma (IFN-γ) release in vitro in a mixed lymphocyte reaction (MLR). When ONO-
4538 was investigated by restimulating human peripheral blood mononuclear cells (PBMCs) 
from a cytomegalovirus (CMV)-exposed donor with CMV antigen, ONO-4538 augmented IFN-γ 
secretion by priming in a dose-dependent manner. In monkeys inoculated with HBsAg, SKMel, 
and DNP-Ficoll, ONO-4538 increased specific antibody titers to SKMel cells. 
In several syngeneic murine tumor models, an anti-mouse PD-1 antibody (4H2) delayed tumor 
growth and the results demonstrate that an anti-PD-1-antibody inhibiting PD-1 binding to its 
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Therefore, ONO-4538 inhibits the binding of PD-1 to its ligands and enhances antigen-specific 
T-cell activation, resulting in an augmented immune response to cancer and antitumor activity. 
Following single intravenous administration of ONO-4538 to conscious monkeys, ONO-4538 
did not affect clinical signs, body temperature, heart rate, blood pressure, and electrocardiogram 
at concentrations up to 50 mg/kg. No drug-related findings were observed in standard clinical 
evaluations of neurologic, cardiovascular, and respiratory functions conducted in monkeys as 
part of the repeated-dose toxicity studies for up to 13 weeks with ONO-4538. 
In monkeys receiving 1, 10, and 50 mg/kg IV single doses of ONO-4538, the AUC of serum 
ONO-4538 increased in an approximately dose-proportional manner. The Vss was similar to 
plasma volume, suggesting that ONO-4538 is mainly distributed in circulating blood. The serum 
ONO-4538 concentrations were lower in anti-ONO-4538-positive monkeys than in monkeys 
with no detectable anti-ONO-4538 antibodies. In a reproductive and developmental toxicity 
study in pregnant monkeys, ONO-4538 was detected in the serum of offspring, suggesting the 
placental transfer of maternal ONO-4538 to the fetus. 
In a single-dose intravenous toxicity study with monkeys, no deaths or ONO-4538-related 
adverse effects were noted at the maximum dose level, 10 mg/kg. 
In repeated-dose intravenous toxicity studies with monkeys, no adverse events associated with 
ONO-4538 were observed when administered by weekly IV injections at the maximum dose 
(50 mg/kg) for 4 weeks and by IV injections twice weekly for 13 weeks, and the no-observed-
adverse-effect level was determined to be 50 mg/kg. In these studies, irritation was not observed 
at the injection sites at ONO-4538 concentrations up to 10 mg/mL. 
In an enhanced pre- and postnatal development study in pregnant monkeys, increases in third 
trimester embryonic or fetal losses or offspring mortality were reported at doses of 10 mg/kg or 
higher but ONO-4538 caused no teratogenicity and did not affect the growth, behavior, and 
immune function of offspring. 
In studies to assess the cross-reactivity of ONO-4538 in normal monkey and human tissues, 
ONO-4538 demonstrated reactivity to the cell membranes of monkey and human lymphocytes, 
in which expression of PD-1 had been reported. As an instance of unexpected reactivity, there 
was cytoplasmic staining of endocrine cells in the pituitary gland in monkeys and humans. 
However, ONO-4538 is an antibody preparation and does not penetrate cell membranes, 
suggesting that it would not have a direct action on the cytoplasm of endocrine cells in the 
pituitary gland. In 4- and 13-week repeated-dose intravenous toxicity studies with monkeys, no 
clinical signs of toxicity were observed with respect to pituitary hormones and organ weights of 
the pituitary gland or in histologic pathology findings. 
ONO-4538 showed no antibody-dependent cellular cytotoxicity (ADCC) and complement-
dependent cytotoxicity (CDC) effects on activated human CD4 T cells in the presence of effector 
cells (human PBMCs were used) or human complements. ONO-4538 did not induce cytokine 
production in human whole blood. 
 


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1.2.2 
Clinical Overview and Summary of Known and Potential Risks and Benefits 
The pharmacokinetics (PK) of ONO-4538 was studied in subjects over a dose range of 0.1 to 
10 mg/kg administered as a single dose or as multiple doses of ONO-4538 every 2 or 3 weeks. 
The geometric mean (CV%) clearance (CL) was 9.5 mL/h (49.7%), the geometric mean volume 
of distribution at steady state (Vss) was 8.0 L (30.4%), and the geometric mean elimination half-
life (t1/2) was 26.7 days (101%). Steady-state concentrations of ONO-4538 were reached by 12 
weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 
approximately 3-fold. The exposure of ONO-4538 increased dose proportionally over the dose 
range of 0.1 to 10 mg/kg administered every 2 weeks. Additionally, ONO-4538 has a low 
potential for drug-drug interactions. The clearance of ONO-4538 increased with increasing body 
weight. The PPK analysis suggested that the following factors had no clinically important effect 
on the CL of ONO-4538: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK 
analysis suggested no difference in the CL of ONO-4538 based on age, gender, race, solid tumor 
type, baseline tumor size, and hepatic impairment. 
Although ECOG Performance Status, baseline glomerular filtration rate (GFR), albumin, body 
weight, and mild hepatic impairment influenced ONO-4538 CL, the effect was not clinically 
meaningful. PPK analysis suggested that ONO-4538 CL in subjects with cHL was lower by 
approximately 32% relative to subjects with NSCLC; however, the lower CL in cHL subjects 
was not considered to be clinically relevant as ONO-4538 exposure was not a significant 
predictor for safety risks in these patients. 
ONO-4538 has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several-type cancers, including NSCLC, melanoma, RCC, cHL, 
small-cell lung cancer, gastric cancer, urothelial cancer, hepatocellular cancer, and colorectal 
cancer. ONO-4538 as monotherapy demonstrated a statistically significant improvement in OS 
as compared with the standard of care in subjects with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or squamous cell carcinoma of the head 
and neck in confirmatory trials. ONO-4538 in combination with ipilimumab demonstrated a 
statistically significant improvement in PFS and a high rate of objective response over 
ipilimumab alone in subjects with unresectable or metastatic melanoma in confirmatory trials. 
Across studies conducted to date, the safety experience with ONO-4538 based on experience in 
approximately 12,300 subjects is accumulated as a monotherapy or in combination with other 
therapeutics. Drug-related adverse events have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, gastrointestinal toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. For ONO-4538 monotherapy and combination 
therapy, the majority of these adverse events have been managed successfully with supportive 
care and, in more severe cases, therapy as instructed in the management guidelines. 
In several ongoing clinical studies, the safety of ONO-4538 in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and molecular 
targeted drugs is being explored. 
For details, refer to the Investigator’s Brochure for ONO-4538. 
 


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2 
STUDY ADMINISTRATIVE STRUCTURE AND 
RESPONSIBILITIES (IF APPLICABLE) 
Please refer to Supplement 1 “Study Administrative Structure.” 
Any amendments to Supplement 1 will be made separately from the study protocol. 
 
3 
STUDY OBJECTIVES 
To compare the efficacy and safety of ONO-4538 in combination with carboplatin, paclitaxel, 
and bevacizumab (treatment administered to ONO-4538 group) to placebo in combination with 
carboplatin, paclitaxel, and bevacizumab (treatment administered to placebo group) in 
chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation in a multicenter, randomized, double-blind study. 
 
3.1 
Primary Objectives of the Study 
∙ To compare the PFS, based on the Independent Radiology Review Committee (IRRC) 
assessment, in chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous 
non-small cell lung cancer unsuitable for radical radiation, regardless of PD-L1 status, 
between the ONO-4538 group and the placebo group. 
∙ To compare the PFS, based on the IRRC assessment, in chemotherapy-naïve subjects with 
stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical 
radiation with tumor PD-L1+ expression (≥ 1%). 
 
3.2 
Secondary Objective of the Study 
To evaluate the efficacy and safety in the ONO-4538 group compared to those in the placebo 
group, from a range of viewpoints, in chemotherapy-naïve subjects with stage IIIB/IV or 
recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation. 
 
4 
STUDY POPULATION 
4.1 
Study Subjects 
Chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation 
 


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4.2 
Inclusion Criteria 
After subjects provide written informed consent before participating in the study, subjects must 
meet all of following inclusion criteria at the time of randomization. When it has been confirmed 
that the subject does not meet any of the following criteria from randomization to the first dose 
of the investigational product, the subject will be withdrawn from the study without receiving 
any investigational products. 
 
1. Males and females 
2. ≥ 20 years of age (at the time of informed consent) 
3. Subjects with histologically- or cytologically-confirmed non-squamous non-small cell lung 
cancer 
4. Subjects who received a diagnosis of stage IIIB/IV or recurrent non-squamous non-small cell 
lung cancer unsuitable for radical radiation according to the UICC-TNM Classification (7th 
edition) with no prior systemic anticancer therapy (including EGFR, ALK and ROS1 
inhibitors) given as primary therapy for advanced or metastatic disease 
Prior adjuvant or neoadjuvant chemotherapy is permitted provided the last administration of 
the prior regimen occurred at least 6 months prior to enrollment. 
5. Subjects with at least one measurable lesion by radiographic tumor assessments per RECIST 
1.1 criteria; radiographic tumor assessments performed within 28 days of randomization 
(target lesions may be located in a previously irradiated field if there is documented disease 
progression after the completion of radiation therapy.) 
6. Subjects who are able to provide tumor tissue specimens. If no fresh specimens are available, 
these will be allowed as archival samples, but they must contain a minimum of 100 evaluable 
tumor cells. Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained 
tumor tissue sections must be submitted for investigational product assignment and 
biomarker evaluation. The tumor tissue sample may be fresh or archival if obtained within 6 
months prior to enrollment, and there was no systemic therapy (eg, adjuvant or neoadjuvant 
chemotherapy) given after the sample was obtained. 
Tissue must be from a core needle biopsy, excisional biopsy, incisional biopsy, or forceps 
biopsy. EBUS-TBNA is acceptable if no tissue can be obtained through the above biopsy 
methods and tumor tissues may be collected by EBUS-TBNA. Fine needle biopsies, biopsies 
of bone lesions that do not have a soft tissue component, or decalcified bone tumor samples 
are not acceptable. In addition, cell block is not acceptable. 
7. ECOG Performance Status of 0 or 1 
8. Life expectancy ≥ 90 days by investigator assessment 
9. Women of childbearing potential (including those who have no menses for medical reasons, 
such as chemotherapy-induced menopause)#1 must agree to follow instructions for method(s) 
of contraception#2 or maintain complete abstinence from the time of informed consent 
through at least 5 months after the last administration of the investigational product (ONO-
4538 or placebo) or at least 6 months after the last administration of bevacizumab, whichever 
is longer. Women of childbearing potential must agree to discontinue breastfeeding from the 
time of informed consent through at least 5 months after the last administration of the 
investigational product or at least 6 months after the last administration of bevacizumab, 
whichever is longer. 


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10. Male subjects who have agreed to follow instructions for method(s) of contraception#2 from 
the start of administration of the investigational product through at least 7 months after the 
last administration of the investigational product or at least 6 months after the last 
administration of bevacizumab, whichever is longer 
11. Subjects with percutaneous oxygen saturation of ≥ 94% by pulse oximetry at rest, without 
oxygen supplementation, within 7 days prior to randomization 
12. Latest laboratory values obtained within 7 days prior to randomization must meet the criteria 
listed below. These values should not reflect granulocyte-colony stimulating factor (G-CSF) 
or blood transfusion given within 14 days before the test day. 
∙ WBC ≥ 2000/mm3 
∙ Neutrophils ≥ 1500/mm3 
∙ Platelets ≥ 100000/mm3 
∙ Hemoglobin ≥ 9.0 g/dL 
∙ AST (GOT) and ALT (GPT) ≤ 3.0 × upper limit of normal (ULN) 
∙ LDH ≤ 2.0 × ULN 
∙ Total bilirubin ≤ 1.5 × ULN 
∙ Creatinine ≤ 1.5 mg/dL or creatinine clearance (observed values or estimates calculated 
by the Cockcroft-Gault formula) > 50 mL/min 
13. Subjects who have been fully informed of the nature of the study through the informed 
consent form by the investigator and gave their consent for voluntary participation in the 
study 
 
#1: Women of childbearing potential are defined as all premenopausal women who have 
reached menarche and who have not undergone sterilization (including hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). Menopause is defined as amenorrhea 
for at least 12 successive months in the absence of significant causes. Women who use 
oral contraceptives or mechanical contraception such as intrauterine devices or barrier 
methods are regarded as having childbearing potential. 
#2: Subjects must agree to dual contraception using any 2 of the following methods: 
vasectomy or condoms in male subjects or male partners, or tubal ligation, contraception 
pessaries, intrauterine devices, or oral contraceptives in female subjects or female partners. 
4.2.1 
Rationale 
1. 
No restrictions need to be placed on the gender of study participants. 
2. 
The age at which the subject can legally decide whether or not to participate in the 
study. 
3. 
To enroll subjects with histology for which the chemotherapy to be investigated in the 
study (carboplatin, paclitaxel, and bevacizumab combination therapy) is the standard 
of care. 
4. 
To select subjects who are eligible for systemic drug therapy. 
5. 
To select subjects with evaluable efficacy data per RECIST 1.1 criteria. 
6. 
To select subjects whose PD-L1 status can be evaluated. 


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7. 
To register subjects with good performance status. 
8. 
To register subjects in whom the efficacy and safety of the investigational product can 
be evaluated properly. 
9, 10. Safety in fetuses and infants has not been established. 
11. 
To register subjects without cardiopulmonary insufficiency. 
12. 
To register subjects without any damage to vital organs. 
13. 
To select subjects who have the ability to provide consent. 
 
4.3 
Exclusion Criteria 
The investigator cannot enroll subjects meeting any of the following criteria at the time of 
randomization. When subjects meet any of the following criteria between randomization to the 
first dose of the investigational product, subjects will be withdrawn from the study without 
receiving any investigational products. 
 
1. Subjects with known EGFR mutations, including deletions in exon 19 and exon 21 (L858R) 
substitution mutations. All subjects must have been tested for EGFR mutation status. Non-
squamous non-small cell lung cancer subjects with unknown or indeterminate EGFR status 
are excluded. 
2. Subjects with known ALK or ROS1 translocations. Subjects with unknown or indeterminate 
ALK or ROS1 status will be eligible for randomization. 
3. Complication or history of severe hypersensitivity reactions to antibody products or 
platinum-containing compounds 
4. Subjects with current or prior ≥ Grade 2 peripheral neuropathy 
5. Subjects with residual effects of adverse drug reactions associated with prior treatment or 
surgery that may have an impact on the safety assessment of the investigational product 
and/or chemotherapy at the investigator’s discretion. 
6. Subjects with autoimmune disease or known chronic or recurrent autoimmune disease. 
Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement 
or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are 
acceptable for enrollment. 
7. Subjects with contraindications to carboplatin, paclitaxel, or bevacizumab 
8. Subjects with current or prior interstitial lung disease or pulmonary fibrosis diagnosed based 
on radiographic tumor assessments or clinical findings. Subjects with radiation pneumonitis 
with fibrosis, which is considered to be stable, and without recurrence are acceptable for 
enrollment. 
9. Subjects with active diverticulitis or symptomatic gastrointestinal ulceration 
10. Subjects with multiple cancers (those with completely resected basal cell carcinoma, stage I 
squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder 
cancer or with a history of other forms of cancer that has not recurred for at least 5 years are 
acceptable for enrollment.) 


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11. Subjects with brain or meningeal metastasis. Subjects with metastatic lesions can be enrolled 
if the metastases are adequately treated with radiotherapy and/or surgery and subjects are 
neurologically returned to baseline (except for residual signs or symptoms related to the CNS 
treatment) at least 14 days prior to randomization and subjects have no documented evidence 
of progression confirmed by CT/MRI. 
12. Subjects with pericardial, pleural, or peritoneal effusion requiring treatment. In subjects who 
have recently undergone aspiration, the date of the procedure (or, in the case of drainage, the 
date of removal of the drain) must be at least 14 days prior to randomization, and there must 
not be any finding of aggravation of pericardial, pleural, or peritoneal effusion. 
13. Subjects with uncontrollable cancer pain 
14. Subjects who have a history of transient ischemic attack, cerebrovascular accident, 
thrombosis, or thromboembolism (pulmonary thromboembolism or deep venous thrombosis) 
within 180 days prior to randomization 
15. Subjects with any of the following uncontrollable or significant cardiovascular disease: 
∙ Myocardial infarction occurring within 180 days prior to randomization; 
∙ Uncontrollable angina occurring within 180 days prior to randomization; 
∙ Congestive heart failure, defined as New York Heart Association (NYHA) functional 
Class III or IV; 
∙ Uncontrollable hypertension even if adequately treated (systolic blood pressure 
≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting for 24 hours or longer); or 
∙ Arrhythmia requiring treatment. 
16. Subjects who are receiving anticoagulants (except antiplatelet therapy including low-dose 
aspirin) or have a disease for which anticoagulant therapy is required 
17. Subjects with uncontrollable diabetes 
18. Subjects who have received systemic adrenocorticosteroids equivalent to prednisone > 10 
mg/day (except for temporary use for examination, prophylaxis, or a similar purpose) or 
immunosuppressants within 28 days prior to randomization 
19. Subjects who have received pleurodesis or pericardial adhesion within 28 days prior to 
randomization 
20. Subjects who have had surgery under general anesthesia within 28 days prior to 
randomization 
21. Subjects who have had surgery under local or surface anesthesia within 14 days prior to 
randomization 
22. Subjects who have received radiotherapy within 28 days prior to randomization, who have 
received stereotactic irradiation for brain metastasis within 14 days prior to randomization or 
who have received chest radiotherapy or radiopharmaceuticals (except for use of 
radiopharmaceuticals for examination and diagnosis) within 56 days prior to randomization 
23. Subjects who have received radiotherapy for pain relief within 14 days prior to randomization. 
Subjects who may require palliative radiotherapy within 4 weeks of randomization are 
strongly encouraged to receive palliative radiotherapy before randomization. 
24. Subjects who have received any other unapproved drugs (including investigational 
treatments, unapproved combination drugs, and drugs with new dosage forms) within 28 
days prior to randomization 
25. Subjects with systemic infection requiring treatment 


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26. Prior treatment with ONO-4538 (MDX-1106 or BMS-936558), anti-PD-1 antibody, anti-PD-
L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or any 
other antibody therapy for regulation of T cells or drug therapies including cancer vaccines 
27. Any positive test for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or 
HCV antibody 
28. Subjects who test positive for HBs antibody or HBc antibody and have detectable HBV-DNA 
levels despite testing negative for HBs antigen 
29. Subjects who are pregnant, breastfeeding, or may be pregnant 
30. Subjects who are judged to lack the ability to provide consent for reasons such as dementia 
31. Subjects disqualified from participation in the study at the investigator’s discretion 
32. Subjects who have received a live/attenuated vaccine within 28 days prior to randomization 
 
4.3.1 
Rationale 
1, 2. 
In consideration of effective standard of care. 
3 to 8. 
In consideration of subject safety. 
9 to 12. 
To exclude potential influences on efficacy and safety assessments in the study. 
13 to 16. 
In consideration of subject safety. 
17 to 23. 
To exclude potential influences on efficacy and safety assessments in the study. 
24. 
To eliminate the effects of an investigational product with undetermined 
therapeutic efficacy. 
25. 
In consideration of subject safety. 
26. 
To exclude potential influences on efficacy and safety assessments in the study. 
27, 28. 
To ensure the safety of subjects and those who collect or measure blood samples. 
29. 
Safety in fetuses and infants has not been established. 
30. 
To protect the human rights of the subject. 
31. 
In consideration of unsuitable conditions other than those mentioned in 1 to 30 
and 32. 
32. 
To exclude potential influences on safety assessments in the study. 
5 
STUDY PROCEDURES 
5.1 
Study Design 
5.1.1 
Study Design 
This study is a multicenter, randomized, double-blind, placebo controlled phase 3 study in 
chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation. The study is intended to evaluate the superiority of the 


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ONO-4538 group over the placebo group, with PFS, based on an IRRC assessment, as the 
primary endpoint. 
The study will consist of the screening period, treatment period, and follow-up period. In a 
double-blind fashion, subjects will be randomized in a 1:1 ratio into either the ONO-4538 group 
or the placebo group and stratified by PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or 
indeterminate), ECOG Performance Status (0 vs 1), and gender (male vs female). 
In the ONO-4538 group, ONO-4538, carboplatin, paclitaxel, and bevacizumab will be 
administered every 3 weeks. In the placebo group, placebo, carboplatin, paclitaxel, and 
bevacizumab will be administered every 3 weeks. Subjects will receive ONO-4538 360 mg or 
placebo in combination with carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab 
(15 mg/kg). In both groups, carboplatin and paclitaxel will be administered for up to 4 cycles and 
if deemed safe, treatment may continue for up to a maximum of 6 cycles. Even after the 
completion of treatment with carboplatin and paclitaxel, the investigational product (ONO-4538 
or placebo) and bevacizumab will be administered intravenously on Day 1 of each cycle in both 
treatment groups until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. 
Upon completion of the investigational product and chemotherapy, subjects will enter the 
follow-up period. 
In this study, one interim analysis of PFS among randomized subjects is planned for early 
stopping in case of superior efficacy, at the time when approximately 82.4% of the target number 
of events are observed. 
An overview of the study design is shown in Figure 2-1. 
 
5.1.1.1 
Rationale for study design 
Clinical practice guidelines recommend the use of platinum-based chemotherapy with a third- or 
later-generation anticancer drug as standard of care for chemotherapy-naïve subjects with stage 
IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation. 
The use of platinum-based chemotherapy with a third- or later-generation anticancer drug and 
bevacizumab combination therapy is also one of the therapies recommended.3 However, clinical 
benefit of the use of platinum-based chemotherapy with a third- or later-generation anticancer 
drug as standard of care has a median PFS of 4.5 to 6.2 months, and a median OS of 10.3 to 12.3 
months4 5. Therefore, conventional therapies are not effective for treating stage IIIB/IV or 
recurrent non-small cell lung cancer unsuitable for radical radiation, and there is an urgent need 
for development of novel therapeutic drugs in these patient populations. 
Phase 1 studies (ONO-4538-04 and CA209012) are in progress to evaluate the safety and 
efficacy of ONO-4538 in combination with chemotherapy including platinum-based drugs in 
chemotherapy-naïve subjects with advanced non-small cell lung cancer. 
In ONO-4538-04, ONO-4538 10 mg/kg was administered in combination with cisplatin and 
gemcitabine (Arm A), cisplatin and pemetrexed (Arm B), or carboplatin, paclitaxel, and 
bevacizumab (Arm C). In CA209012, ONO-4538 10 mg/kg was administered in combination 
with cisplatin and gemcitabine or cisplatin and pemetrexed. ONO-4538 10 mg/kg or 5 mg/kg 
was also given concomitantly with carboplatin and paclitaxel. In ONO-4538-04, the response 
rate was 50% (3/6 subjects) in Arm A, 50% (3/6) in Arm B, and 100% (6/6) in Arm C. The 


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median PFS was 6.28 months in Arm A, 9.63 months in Arm B, and not reached in Arm C.20 In 
CA209012, the response rate was 33% (4/12 subjects) in the cisplatin/gemcitabine group (ONO-
4538 10 mg/kg), 47% (7/15) in the cisplatin/pemetrexed group (ONO-4538 10 mg/kg), 47% 
(7/15) in the carboplatin/paclitaxel group (ONO-4538 10 mg/kg), and 43% (6/14) in the 
carboplatin/paclitaxel group (ONO-4538 5 mg/kg).21 In ONO-4538-04 and CA209012, 
administration of ONO-4538 in combination with chemotherapy resulted in a comparable or 
higher response rate compared to those cited in previous reports on chemotherapy, and the 
duration of response also tended to be longer. 
In CA209012, efficacy was also evaluated by PD-L1 expression and was observed in subjects 
with both PD-L1 expressing and non-expressing tumors. At the 1% expression level, the 
response rate was 48% and 43% for expressors and non-expressors, respectively. The 1-year 
overall survival was 70% and 76% for expressors and non-expressors, respectively. Thus, the 
efficacy was consistent between expressors and non-expressors. 
As for safety, adverse events observed in the combination-therapy groups seem to be manageable 
in all studies. Although most of immune-related adverse events occurred more frequently in 
subjects receiving ONO-4538 plus chemotherapy than in those treated with ONO-4538 alone, no 
adverse events leading to death were observed. 
Thus, to evaluate the efficacy and safety of ONO-4538 in combination with carboplatin, 
paclitaxel, and bevacizumab, one of the standards of care, in chemotherapy-naïve subjects with 
stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical 
radiation, a randomized, double-blind study is to be conducted by using placebo in combination 
with carboplatin, paclitaxel, and bevacizumab as a comparator. 
 
5.1.2 
Planned Sample Size 
The target sample size is approximately 265 subjects per group, and approximately 530 subjects 
in total for the entire study. 
 
5.1.2.1 
Rationale 
This study is intended to evaluate the superiority of the ONO-4538 group over the placebo 
group, with PFS as the primary endpoint, in randomized or PD-L1+ (≥ 1%) chemotherapy-naïve 
subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for 
radical radiation. Subjects will be randomized in a 1:1 ratio into either the ONO-4538 group or 
the placebo group and stratified by PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or 
indeterminate), ECOG Performance Status (0 vs 1), and gender (male vs female). 
In this study, one interim analysis of PFS among randomized subjects is planned for early 
stopping in case of superior efficacy, at the time when approximately 82.4% of the target number 
of events are observed. To adjust the multiplicity of tests, a significance level for interim and 
final analyses will be calculated using the Lan-DeMets α spending function (O’Brien-Fleming). 
The Hochberg method will be used to adjust the multiplicity of tests associated with final 
analysis in randomized subjects and PD-L1+ (≥ 1%) subjects. 


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Given that PFS followed an exponential distribution in the placebo group and followed a 
piecewise exponential distribution with consideration for time to ONO-4538 response in the 
ONO-4538 group in both PD-L1+ (≥ 1%) subjects and PD-L1− (< 1%) subjects, the hazard ratio 
of the ONO-4538 group to the placebo group was assumed to be 1.0 for the first 2 months and 
0.60 thereafter (the median PFS was 7.0 months in the placebo group and 10.3 months in the 
ONO-4538 group). Since past clinical study data on ONO-4538 reported that the proportion of 
PD-L1+ (≥ 1%) subjects to NSCLC subjects was in the range of 52% to 70%9 21 to 24, the 
proportion of PD-L1+ (≥ 1%) subjects to randomized subjects was assumed to be 55%. To detect 
a statistically significant difference via the log-rank test in either randomized subjects or PD-L1+ 
(≥ 1%) subjects with a two-sided significance level of 5% and a statistical power of 
approximately 90%, 340 events were required. 
Assuming an accrual period of 24 months and a minimum follow-up of 16 months, 530 subjects 
may be required to observe the required number of events taking into account the number of 
censored subjects. Therefore, the target sample size was set at 530 subjects. The required number 
of events and the target sample size in the protocol were calculated by simulation with SAS 
statistical analysis software (version 9.4). 
 
<Rationale for 7.0-month PFS (median) in the placebo group> 
Based on the report that the PFS ranges from 6.2 to 6.9 months in subjects treated with 
carboplatin, paclitaxel, and bevacizumab in studies in chemotherapy-naïve subjects with non-
squamous non-small cell lung cancer,5 25 PFS was set at 7.0 months in the placebo group. 
 
<Rationale for a period of 2 months to ONO-4538 response> 
The time to ONO-4538 response was determined by referring to the results from the phase 3 
study evaluating the efficacy and safety of ONO-4538 monotherapy in chemotherapy-naïve 
subjects with non-small cell lung cancer (CA209026).11  
 
5.1.3 
Planned Study Period 
Mar-2017 to Jul-2022 
 


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5.2 
Enrollment of Subjects 
Subjects will be enrolled in the study according to the following procedures: 
 
 
 
 
 
 
 
 
*: See 12 Subject Informed Consent. 
 
After providing written informed consent, subjects will be enrolled in the study through the 
Interactive Web Response System (IWRS) (enrollment). Specific procedures for using the IWRS 
will be provided separately to each study site. The investigator or a person designated by the 
investigator will enroll the subjects according to predetermined procedures. The following data 
are required for subjects enrolled after informed consent: 
∙ Date of informed consent 
∙ Date (including year) of birth 
∙ Gender. 
 
After completion of enrollment, subjects who have met all the eligibility criteria will be 
randomized. Eligible subjects will start to receive the investigational product within 3 days after 
randomization. 
If subjects failed to proceed to randomization, the investigator will inform that the study has been 
discontinued in these subjects before randomization via the IWRS. If subjects considered eligible 
at randomization discontinue the study before receiving the investigational product for any 
reasons, the investigator will inform that the study has been discontinued in these subjects before 
treatment via the IWRS. The re-enrollment of a subject who failed to proceed to randomization is 
permitted. However, the re-enrollment of a subject who has received subsequent anticancer 
therapy for non-squamous non-small cell lung cancer is not acceptable. 
 
The following data are required for the randomization of subjects: 
∙ Subject identification code 
∙ Date (including year) of birth 
∙ ECOG Performance Status (0 vs 1) 
∙ Gender (male vs female). 
*Informed consent 
Enrollment 
Start of treatment 
Randomization 


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5.3 
Method of Assigning Subjects 
Subjects will be randomized in a 1:1 ratio into either the ONO-4538 group or the placebo group 
and stratified by the following: 
∙ PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or indeterminate) 
∙ ECOG Performance Status (0 vs 1) 
∙ Gender (male vs female). 
 
5.4 
Blinding/Unblinding 
The Sponsor, subjects, investigators, and study site’s staff will be blinded to the investigational 
product assignment. 
 
5.4.1 
Maintenance of Blinding 
The study will be conducted in a double-blind fashion and the Sponsor will provide drugs that 
are indistinguishable in appearance and maintain blinding through the IWRS. The Sponsor will 
not collect the remaining investigational products before key code breaking unless the 
investigational products have been sealed by the investigational product administrator. 
 
5.4.2 
Unblinding 
In this study, unblinding is acceptable for the relevant subject in any of the following 
circumstances: 
1. It becomes urgently necessary to know which investigational product is being used for 
reasons such as the occurrence of a serious adverse event; or 
2. The overall response is PD as assessed by both the investigator and IRRC or the protocol-
specified final examination (except follow-up) is terminated and subsequent anticancer 
therapy is administered. 
3. The sponsor will request breaking the emergency code for the subject via IWRS, if requested 
to report on the type of investigational product allocation for the subject by the regulatory 
authorities, co-developing company, or the like, for the reasons of the onset of serious 
adverse events etc. In such case, the procedure should define that the code-breaking result 
will not be informed to the investigator and study staff. 
 
In this study, the treatment assignment will be unblinded through the IWRS. For the method of 
unblinding, refer to IWRS Procedures. 
In principle, the study site’s staff will not be informed of PD-L1 analysis results. 
 


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5.5 
Endpoints 
5.5.1 
Efficacy Endpoints 
5.5.1.1 
Primary Endpoint 
The primary endpoint of this study is PFS as assessed by the IRRC. 
5.5.1.1.1 Rationale 
The PFS is defined as the time from randomization to tumor growth or death and is used as a 
measure of drug efficacy during the period when the underlying disease does not worsen. The 
primary objective of drug therapy for chemotherapy-naïve subjects with stage IIIB/IV or 
recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation is not to cure 
the disease but to control symptoms and prevent progression. Therefore, prolonged PFS may 
become an indicator of clinical benefit. PFS is not affected by subsequent anticancer therapy 
given after completion of the study, which enables proper assessment of prevention of 
progression by drug therapy. On the other hand, OS enables assessment of survival benefit, 
based on the subject’s status (alive/dead), but if the OS is selected as a primary endpoint, it may 
be difficult to evaluate the efficacy of ONO-4538 due to the influence of subsequent anticancer 
therapy, including immune checkpoint inhibitor given after completion of the study. 
From the above, PFS as assessed by the IRRC was selected as the primary endpoint of the study. 
 
5.5.1.2 
Secondary Endpoints 
1. OS 
2. PFS (as assessed by the study site’s investigator) 
3. Objective response rate (as assessed by the IRRC and study site’s investigator) 
4. Disease control rate (as assessed by the IRRC and study site’s investigator) 
5. Duration of response (as assessed by the IRRC) 
6. Time to response (as assessed by the IRRC) 
7. Best overall response (as assessed by the IRRC and study site’s investigator) 
8. Maximum percentage of change in the sum of diameters of target lesions (as assessed by the 
IRRC) 
 
5.5.1.2.1 Rationale 
These endpoints were selected to evaluate the efficacy of ONO-4538 group for non-squamous 
non-small cell lung cancer from a range of viewpoints. 
 
5.5.2 
Safety Endpoints 
1. Adverse events 
2. Laboratory tests 
3. Vital signs 
4. Chest X-ray 


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5. 12-lead ECG 
6. ECOG Performance Status 
 
5.5.2.1 
Rationale 
These endpoints were selected to evaluate the safety of ONO-4538 group from a range of 
viewpoints. 
 
5.5.3 
Patient Reported Outcomes 
1. QoL questionnaire (EQ-5D) 
2. Questionnaire to assess disease-related symptoms (LCSS) 
 
5.5.4 
Other Tests 
Healthcare resource utilization 
 
5.5.5 
Biomarkers 
 
 
3. Tumor markers (as needed) 
 
5. Tumor tissues 
 
5.5.6 
Pharmacokinetic Assessment 
Serum ONO-4538 concentration 
 
5.5.7 
Immunogenicity Assessment 
Anti-ONO-4538 antibody 
 
6 
INVESTIGATIONAL PRODUCT 
An investigational product, also known as the investigational medicinal product in some regions, 
is defined as the pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with marketing authorization but used or 
combined (formulated or packaged) differently from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 


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The investigational product should be stored in a secure area in accordance with local 
regulations. It is the responsibility of the investigator to ensure that the investigational product is 
only dispensed to study subjects. The investigational product must be dispensed only from 
official study sites by authorized personnel in accordance with local regulations. 
In this study, the investigational product is ONO-4538 or placebo corresponding to ONO-4538. 
 
6.1 
Handling and Dispensing of Investigational Product 
As described below, investigational products will be dispensed to each study site. 
Product 
Description and 
Dosage Form 
Carton 
(content) 
Appearance 
Storage Conditions 
(per label) 
ONO-4538 or 
placebo solution 
for injection 
4 vials 
(100 mg or 
0 mg/10 mL) 
Clear to opalescent colorless 
to pale yellow liquid. May 
contain a few fine particles 
Protect from freezing and 
light. Store at 2°C to 8°C 
 
The investigator should ensure that the investigational product is stored in accordance with the 
environmental conditions (temperature, light, etc.) as determined by the Sponsor. If concerns 
regarding the quality or appearance of the investigational product arise, the investigational 
product should not be dispensed and the Sponsor should be contacted immediately. All drugs for 
basic treatment not supplied by the Sponsor (carboplatin, paclitaxel, and bevacizumab) should be 
stored in accordance with the instructions in the package inserts. 
The investigator must maintain investigational product documentation that includes all processes 
required to ensure the drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents, administration sets). 
It is the responsibility of the investigator and study site to prepare supplies required for 
preparation and administration of the investigational product (eg, filters, diluents, intravenous 
drip infusion bags, administration sets) and pre-medications. 
For details of preparation and administration and storage of the investigational product, refer to 
the current version of the Investigator’s Brochure, pharmacy reference sheets and/or relevant 
package inserts and summary of product characteristics. 
 
6.2 
Investigational Product Management and Return of Unused 
Investigational Product 
6.2.1 
Storage and Management of Investigational Product 
It is the responsibility of the investigator to ensure that a current disposition record of the 
investigational products (those inventoried and dispensed) is maintained at each study site. 
Records or logs must comply with applicable regulations and guidelines and should include: 


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∙ Quantity received and placed in storage area 
∙ Quantity in inventory 
∙ Label identification number or batch number 
∙ Quantity dispensed to and returned by each subject, including subject identification codes 
∙ Quantity transferred to another area/facility for dispensing or storage 
∙ Quantity used for the reasons other than the study procedures (eg, lost, damaged) 
∙ Quantity disposed of at the site (if applicable) 
∙ Amount returned to the Sponsor 
∙ Dates 
of 
confirmation 
by 
person 
responsible 
for 
investigational 
product 
dispensing/accountability and this person’s initials, as per the Delegation of Authority Form. 
 
The Sponsor will provide forms to facilitate inventory control if the study site does not have an 
established system that meets these requirements. 
 
6.2.2 
Destruction of Investigational Product 
For this study, partially used investigational product vials may be destroyed on site. 
Any unused investigational products may not be destroyed unless the investigational product 
containers must be immediately destroyed as required for safety, or to comply with local 
regulations (eg, cytotoxics or biologics). On-site destruction is allowed provided the following 
minimal standards are met: 
∙ On-site disposal practices must not expose humans to risks from the drug. 
∙ On-site disposal practices and procedures must comply with applicable laws and regulations, 
including any special requirements for controlled or hazardous substances. 
∙ Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures and a copy provided to the Sponsor upon 
request. 
∙ Records are maintained that allow for traceability of each container, including the date of 
disposal, quantity disposed, and identification of the person who disposed of the containers. 
The method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor, must be documented. 
∙ Accountability and disposal records should be complete, up-to-date, and available for the 
Sponsor to review throughout the study period. 
 
If conditions for destruction cannot be met, the responsible Sponsor’s Study Monitor will make 
arrangements for return of the investigational product. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 


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6.2.3 
Return of Investigational Product 
If the investigational product is not to be destroyed upon completion or termination of the study, 
all unused investigational product vials that were supplied by the Sponsor, together with cartons, 
must be returned to the Sponsor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
7 
STUDY TREATMENT 
7.1 
Investigational Product and Chemotherapy 
7.1.1 
Dose and Mode of Administration and Duration of Treatment 
Subjects will be randomized in a 1:1 ratio into either the ONO-4538 group or the placebo group 
and then receive all drugs on the same day every 3 weeks. The subjects will be given the 
investigational product first and start to receive chemotherapy at least 30 minutes after 
completion of the investigational product infusion. 
The dose and mode of administration and duration of treatment with the investigational product 
and chemotherapy are as follows. 
 
7.1.1.1 
Dose and Mode of Administration and Duration of Treatment with Investigational 
Product 
The investigational product (ONO-4538 360 mg or placebo) will be administered intravenously 
over 30 minutes every 3 weeks. The investigational product will continue until the subject meets 
any of 7.1.4.1 Investigational Product Discontinuation Criteria. 
No escalations or reductions in the dose of the investigational product will be allowed. Please 
refer to the current version of the Investigator’s Brochure and pharmacy reference sheets for 
proper storage, handling, preparation, and administration of the investigational product. 
 
7.1.1.1.1 Rationale 
In this study, ONO-4538 is to be administered intravenously as repeated doses of 360 mg every 3 
weeks. The rationale is explained below. 
In phase 1 studies of ONO-4538 monotherapy (ONO-4538-01 and CA209003), intravenous 
ONO-4538 when administered repeatedly every 2 weeks has been well tolerated at doses up to 
20 mg/kg in Japanese subjects and 10 mg/kg in non-Japanese subjects. However, given that 
chemotherapy is to be administered in combination with ONO-4538 generally once every 3 
weeks, use of the same dosing regimen for chemotherapy (ie, repeated intravenous 


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administration every 3 weeks) might be preferable in an actual clinical setting and for greater 
convenience for subjects. Based on the above, the Japanese phase 1 study (ONO-4538-04) of 
ONO-4538 in combination with chemotherapy evaluated the safety of ONO-4538 10 mg/kg in 
combination with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with 
advanced non-small cell lung cancer. As for safety profiles, ONO-4538 does not exacerbate the 
adverse drug reactions to chemotherapy and it has been well tolerated. Thus, ONO-4538 was 
considered to be administered once every 3 weeks in this study. 
Taking convenience into consideration, recent studies of ONO-4538 examined the fixed dose 
regimen (mg) of ONO-4538 not adjusted for body weight and clinical trials with ONO-4538 
360 mg (once every 3 weeks) are currently ongoing. A population pharmacokinetic model, 
which included data from 187 Japanese patients with malignant tumor (median weight, 59.1 kg; 
range, 34.1 to 93.4 kg), was used to predict steady-state serum ONO-4538 concentrations 
following repeated intravenous administration of ONO-4538 360 mg every 3 weeks in 1000 
Japanese patients with malignant tumor. Predicted values (medians [90% prediction intervals]) of 
concentration at the end of infusion (Ceoi), trough concentration (Cmin), and average 
concentration (Cavg) are shown in Table 7.1.1-1. These values were considered not to exceed 
steady-state exposure obtained with 10 mg/kg given as repeated intravenous administration every 
2 weeks, a regimen that has been shown to be tolerable in ONO-4538-01 and CA209003. 
Furthermore, these values were also considered not to be below steady-state exposure obtained 
with 3 mg/kg given as repeated intravenous doses every 2 weeks, a regimen that had proven to 
be effective in other tumor types. ONO-4538 is a human monoclonal antibody and very unlikely 
to cause drug interactions with combined chemotherapy. Thus, 360 mg was considered to be 
used as the dose of ONO-4538 in this study. 
Based on the above, ONO-4538 is to be administered as repeated intravenous doses of 360 mg 
every 3 weeks. 
 
Table 7.1.1-1: Predicted Steady-State Exposure of ONO-4538 
Dosing Regimen 
Ceoi [μg/mL] 
Cmin [μg/mL] 
Cavg [μg/mL] 
360 mg Q3W 
185 (91.5–392) 
69.6 (22.6–213) 
99.0 (46.1–224) 
3 mg/kg Q2W 
116 (56.8–239) 
59.6 (17.6–161) 
75.3 (33.6–152) 
10 mg/kg Q2W 
386 (195–791) 
197 (71.5–514) 
252 (125–519) 
Median (90% prediction interval) 
Q3W, dosing every 3 weeks; Q2W, dosing every 2 weeks 
 
7.1.1.2 
Dose and Mode of Administration and Duration of Treatment with Chemotherapy 
Subjects will receive carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg 
every 3 weeks. When calculating doses, in principle, the dose (mg) will be rounded to one 
decimal place. 
It is permissible for the initial dose of paclitaxel and bevacizumab to be calculated based on the 
body weight measured at the time of randomization, instead of that measured on the day of first 


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dosing (predose). The dose will be adjusted in each cycle if the subject’s weight changes by ≥ 
10% compared to the weight used to calculate the initial dose. If the subject’s weight changes by 
≥ 10% compared to the weight used to calculate the initial dose on the day of dosing, dose 
adjustment is acceptable for future infusions. Thereafter, similar action will be taken for any 
further changes in the subject’s weight (≥ 10% compared to the weight used to calculate the dose 
adjusted).  
Carboplatin dose will be calculated using the Calvert formula as follows: 
Carboplatin dose (mg) = Target AUC × [(Creatinine clearance (mL/min) + 25] 
Creatinine clearance calculation is based on the Cockcroft/Gault formula and should include the 
most recent serum creatinine and most recent weight. If calculation of the creatinine clearance by 
the Cockcroft/Gault formula yields a result of > 125 mL/min, then a creatinine clearance should 
be calculated by an alternative formula per institutional standards or capped at 125 mL/min. The 
dose of carboplatin may be capped as per local standards.  
The mode of administration should be based on the procedures specified by the study site and 
recommended procedures are described below. 
Subjects will receive paclitaxel as a 180-minute IV infusion on Day 1 of each cycle (3 weeks). 
On Day 1 of each cycle, subjects will receive carboplatin as a 30-minute IV infusion at least 30 
minutes after paclitaxel treatment completion. On Day 1 of each cycle, subjects will receive 
bevacizumab as an IV infusion at least 30 minutes after carboplatin treatment completion. The 
initial administration of bevacizumab will be given intravenously over 90 minutes, and if well 
tolerated, the duration of the second administration will be reduced to 60 minutes and to 30 
minutes in subsequent cycles. 
Carboplatin and paclitaxel will be administered for up to 4 cycles and if deemed safe, treatment 
may continue for up to a maximum of 6 cycles. Even after the completion of treatment with 
carboplatin and paclitaxel, bevacizumab will be administered intravenously on Day 1 of each 
cycle until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of consent. Even where 
carboplatin and paclitaxel have been discontinued for reasons such as adverse events, 
bevacizumab may be continued if deemed safe. 
 
7.1.1.2.1 Rationale 
To standardize the dose and mode of administration, the dosing regimens of carboplatin, 
paclitaxel, and bevacizumab are based on local standards, such as package inserts and clinical 
practice guidelines used in countries participating in this study. 
 
7.1.2 
Dosing Criteria 
Dosing criteria are defined as follows: 
Discontinuation: The investigational product and/or chemotherapy should not be resumed. 
Delay: 
The dosing interval should be prolonged or protocol-specified dosing should 
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Skip: 
A planned dose of any chemotherapy is skipped to the subsequent dosing 
schedule. 
 
Subjects must receive the investigational product and chemotherapy on the same day. If subjects 
fail to meet any of the criteria listed in 7.1.2.1 Dosing Criteria for Investigational Product or 
7.1.2.2 Dosing Criteria for Chemotherapy, investigational product and chemotherapy will be, in 
principle, delayed. If subjects meet any of the criteria listed in 7.1.4.1 Investigational Product 
Discontinuation Criteria or 7.1.4.2 Chemotherapy Discontinuation Criteria, the investigational 
product or chemotherapy will be discontinued. 
Radiographic tumor assessments will be performed to determine antitumor activity, even if 
dosing is delayed, every 6 weeks until Week 48. Thereafter, assessments will be performed every 
12 weeks. 
 
7.1.2.1 
Dosing Criteria for Investigational Product 
1. No Grade ≥ 3 drug-related adverse event (adverse drug reaction). Any ≥ Grade 3 amylase or 
lipase abnormality that is not associated with symptoms or clinical manifestations of 
pancreatitis does not require dose delay if approved by the Sponsor’s Medical Monitor. 
2. No Grade 1 or 2 drug-related interstitial lung disease (such as interstitial pneumonia, 
organizing pneumonia, pneumonitis, and pulmonary infiltration), or Grade 2 drug-related 
diarrhea or colitis. If subjects resume treatment with the investigational product after the 
interstitial lung disease has resolved, CT scan images should be submitted and treatment may 
be resumed only if approved by the Sponsor’s Medical Monitor. If an interstitial lung disease 
recurs after treatment is resumed, the investigational product should be discontinued. 
3. No Grade ≥ 2 drug-related increase in creatinine. 
4. No Grade ≥ 2 drug-related neurotoxicity. 
5. No drug-related increase by ≥ 2 grades in AST (GOT), ALT (GPT), or total bilirubin from 
baseline (for instance, an increase from Grade 1 to Grade 3 or from Grade 0 to Grade 2). 
6. Subjects are eligible to receive the investigational product at the investigator’s discretion. 
 
Subjects who require a delay in administration of the investigational product should be re-
evaluated weekly or more frequently if clinically indicated and resume the investigational 
product when dosing criteria are met. If any adverse event is thought to be related to the 
investigational product, and only if approved by the Sponsor’s Medical Monitor, then the 
investigational product may be skipped. 
 
7.1.2.2 
Dosing Criteria for Chemotherapy 
1. Neutrophil count ≥ 1500/mm3 
2. Platelets ≥ 100000/ mm3 
3. No ≥ Grade 3 drug-related adverse event, with the following exceptions for hypertension, 
lymphopenia, or increases in AST (GOT), ALT (GPT), or total bilirubin: 


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∙ Subjects with Grade 3 bevacizumab-related hypertension, which can be controlled by 
drugs, may be eligible for dosing if discussed with and approved by the Sponsor’s 
Medical Monitor. 
∙ Grade 3 lymphopenia does not require dose delay. 
∙ No drug-related increase by ≥ 2 grades in AST (GOT), ALT (GPT), or total bilirubin from 
baseline. 
4. Subjects are eligible to receive chemotherapy in the opinion of the investigator. For details 
regarding the dose delay criteria, the investigator should refer to the relevant chemotherapy 
drug package inserts. 
 
If any non-hematologic adverse event violating the dosing criteria above is thought to be related 
to the particular drug(s) in the chemotherapy regimen, then only the drug(s) concerned may be 
skipped in that cycle while the other drugs may be given. If any event that, in the judgment of the 
investigator, requires skipping a planned dose of any chemotherapy occurs, it can be skipped 
only if approved by the Sponsor's Medical Monitor. Once the adverse event has improved and 
the dosing criteria are met, administration of the skipped drug should be resumed with the next 
scheduled cycle so that the three chemotherapeutic drugs are regularly administered on the same 
day. Please refer to 7.1.3.2 Dose Reduction Criteria for Chemotherapy to determine if dose 
reduction of the resumed drug is required. All drugs in the chemotherapy regimen may not be 
skipped simultaneously; however, once the administration of carboplatin and paclitaxel is 
completed, it is acceptable that bevacizumab is skipped and the investigational product alone is 
administered. Subjects who require a delay in administration of chemotherapy should be re-
evaluated weekly or more frequently if clinically indicated and resume the chemotherapy when 
dosing criteria are met. 
 
7.1.3 
Dose Reduction Criteria 
7.1.3.1 
Dose Reduction Criteria for Investigational Product 
There are no dose reduction criteria for the investigational product. 
 
7.1.3.2 
Dose Reduction Criteria for Chemotherapy 
Dose reductions of carboplatin and paclitaxel will be performed according to Table 7.1.3-1 and 
Table 7.1.3-2 below. Even if subjects do not meet any of the criteria listed in Table 7.1.3-2, dose 
reductions of carboplatin and paclitaxel may be performed when the investigator deems that 
subjects need dose reduction. Once carboplatin or paclitaxel is reduced, the subject’s safety 
needs to be carefully monitored by means such as increasing the number of laboratory tests. 
Chemotherapy will be continued at the same dose or be further reduced in subsequent cycles, and 
no dose escalation is permitted. 
No dose reductions of bevacizumab are allowed. 
 


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Table 7.1.3-1: Dose Reductions of Carboplatin and Paclitaxel 
Dose Level 
Carboplatin 
Paclitaxel 
Starting dose 
AUC 6 
200 mg/m2 
First dose reduction 
AUC 5 
150 mg/m2 
Second dose reduction 
AUC 4 
100 mg/m2 
Third dose reduction 
Discontinue 
Discontinue 
 
Table 7.1.3-2: Dose Reduction Criteria for Carboplatin and Paclitaxel 
Adverse Event 
Carboplatin 
Paclitaxel 
Febrile neutropenia, Grade ≥ 3 
Reduce one dose level 
Reduce one dose level 
Platelet count decreased, Grade ≥ 3 
Reduce one dose level 
Reduce one dose level 
Diarrhea, Grade ≥ 3 
No change 
Reduce one dose level 
Peripheral neuropathy, Grade ≥ 2 
No change 
Reduce one dose level 
 
7.1.4 
Treatment Discontinuation Criteria 
During the treatment period, subjects meeting any of the criteria listed below will discontinue 
treatment with the investigational product or chemotherapy. 
 
7.1.4.1 
Investigational Product Discontinuation Criteria 
1. The overall response was PD as assessed by the investigator per RECIST 1.1 criteria. 
2. Subjects experienced a worsening of clinical symptoms associated with disease progression. 
3. Any Grade ≥ 3 interstitial lung disease (such as interstitial pneumonia, organizing pneumonia, 
pneumonitis, and pulmonary infiltration), regardless of whether this was related to the 
investigational product or not. 
4. Any Grade ≥ 2 drug-related eye disorder (eye pain or reduced vision) that does not improve 
to Grade 1 or less by topical therapy. 
5. Any Grade ≥ 3 drug-related bronchospasm, diarrhea, colitis, neurotoxicity, hypersensitivity 
reactions, infusion reactions (including fever, chill, nausea, pain, headache, cough, pruritus, 
or rash), or uveitis. 
6. Any Grade ≥ 3 drug-related thrombocytopenia for > 7 days or associated with bleeding. 
7. Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation: 
∙ AST (GOT) or ALT (GPT) > 5 to 10 × ULN for > 2 weeks 
∙ AST (GOT) or ALT (GPT) > 10 × ULN 
∙ Total bilirubin > 5 × ULN 
∙ AST (GOT) or ALT (GPT) > 3 × ULN and total bilirubin > 2 × ULN 


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8. Subjects did not receive any investigational product due to reasons such as adverse events 
within 6 weeks after the last administration. This does not apply to dosing suspension for > 6 
weeks for steroid tapers. 
9. Subjects were ineligible for continued investigational product for reasons of efficacy or 
safety, in the judgment of the investigator. 
 
If the investigator considers that a subject meeting the above criterion 1 or 8 satisfies all the 
criteria listed below, the investigational product may be continued after consultation with the 
Sponsor’s Medical Monitor. For the above criterion 1, the investigator will confirm the subject’s 
willingness to continue to receive the investigational product before resuming treatment, and 
obtain written consent through the informed consent form prepared separately. 
Treatment with the investigational product must be terminated in subjects with further 
progression defined as an additional ≥ 20% increase in the sum of diameters of all measurable 
lesions per RECIST 1.1 criteria from the time of assessment for continued investigational 
product after initial PD (including all target lesions and new measurable lesionsNote 1]). 
1. No rapid disease progression is noted and continued treatment with the investigational 
product is expected to bring clinical benefit. 
2. The investigational product is well tolerated. 
3. Stable ECOG Performance Status 
4. Continued investigational product will not delay an intervention to prevent serious 
complications of disease progression (such as brain metastases). 
 
The decision to discontinue the investigational product should be made separately from the 
decision to discontinue concomitant chemotherapy. If subjects do not meet 7.1.4.2 
Chemotherapy Discontinuation Criteria but meet 7.1.4.1 Investigational Product Discontinuation 
Criteria before the investigational product plus chemotherapy combination therapy cycles have 
been completed, carboplatin and paclitaxel may be administered for up to 6 cycles and 
bevacizumab treatment may be continued until RECIST 1.1 defined PD, unacceptable toxicity, 
or withdrawal of consent. 
 
Note 1): New lesions are considered measurable at the time of initial PD if the longest diameter 
is at least 10 mm (a short axis of at least 15 mm for pathological lymph nodes). Any 
new lesion considered non-measurable at the time of initial PD may become 
measurable if the longest diameter increases to at least 10 mm (a short axis of at least 
15 mm for pathological lymph nodes) and therefore be included in the measurement of 
all measurable lesions. 
 
7.1.4.2 
Chemotherapy Discontinuation Criteria 
1. The overall response is PD as assessed by the investigator per RECIST 1.1 criteria. 
2. Subjects experienced a worsening of clinical symptoms associated with disease progression. 
3. Any Grade ≥ 3 peripheral neuropathy; however, bevacizumab may be continued. 


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4. Any Grade ≥ 3 drug-related thrombocytopenia associated with clinically significant bleeding. 
5. Any drug-related liver function test abnormality that meets the following criteria: 
∙ AST (GOT) or ALT (GPT) > 5 to 10 × ULN for > 2 weeks 
∙ AST (GOT) or ALT (GPT) > 10 × ULN 
∙ Total bilirubin > 5 × ULN 
∙ AST (GOT) or ALT (GPT) > 3 × ULN and total bilirubin > 2 × ULN. 
6. Any drug-related adverse event (7.1.3.2 Dose Reduction Criteria for Chemotherapy) that 
recurs after two prior dose reductions for the same drug-related adverse event requires 
discontinuation of the chemotherapy, with the exception of bevacizumab. 
7. Any Grade ≥ 3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the chemotherapeutic drug(s) thought to be causing the reaction. The 
drug(s) not thought to be related to the hypersensitivity reaction or infusion reaction may be 
continued. 
8. Any Grade 4 drug-related adverse event that the investigator deems inappropriate to be 
managed by dose reduction(s) requires discontinuation of the drug(s) thought to be causing 
the event. The drug(s) not thought to be related to the event may be continued. 
9. Any adverse event that leads to delay in dosing of any chemotherapeutic drug(s) lasting > 6 
weeks from the previous dose requires discontinuation of that drug(s) thought to be causing 
the event. Resuming treatment is allowed in the following cases only if approved by the 
Sponsor's Medical Monitor prior to re-initiating treatment: 
・ Re-initiation following dosing delays lasting > 6 weeks from the previous dose that occur 
for non-drug-related reasons. 
・ Re-initiation of a drug(s) unrelated to an adverse event that leads to a dosing delay lasting 
> 6 weeks. 
10. Any adverse event, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued chemotherapy 
dosing. The investigator should consult the package insert for the chemotherapy drug(s) for 
additional guidance on dose discontinuation. 
 
The decision to discontinue chemotherapy should be made separately from the decision to 
discontinue the concomitant investigational product. If subjects meet 7.1.4.2 Chemotherapy 
Discontinuation Criteria before completing chemotherapy with the investigational product, the 
investigational product may be continued until RECIST 1.1 defined PD, unacceptable toxicity, or 
withdrawal of consent. If a subject receiving the investigational product and chemotherapy meets 
any of the discontinuation criteria and the investigator cannot determine whether the adverse 
event is related to either the investigational product or chemotherapy, the subject will discontinue 
receiving all drugs. 
 
7.2 
Concomitant Treatments 
7.2.1 
Treatments Prohibited During the Study 
The following treatments are prohibited during the study (from the time of informed consent 
through completion of the protocol-specified final examination [except outcome survey]); except 


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when the final examination at the completion of treatment period (the discontinuation) is 
completed and the treatment is medically unavoidable. For any drugs other than those mentioned 
below, please refer to the current version of the package inserts for chemotherapy administered 
concomitantly in the study: 
1. Immunosuppressive drugs 
2. Adrenocorticosteroids equivalent to prednisone > 10 mg/dayNote 1) 
3. Antineoplastic drugs except chemotherapy assigned in the study (such as chemotherapy, 
molecular targeted therapy, and immunotherapyNote 2]) 
4. Surgery for malignant tumor 
5. Radiotherapy (including chemoradiation)Note 3) 
6. RadiopharmaceuticalsNote 4) 
7. Bisphosphonates and anti-RANKL antibodiesNote 5) 
8. Transplantation therapy 
9. Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment with the investigational product and until 
100 days after the last dose of the investigational product 
10. Any other unapproved drugs (including investigational treatments, unapproved combination 
drugs, and drugs with new dosage forms). 
 
Note 1): Subjects are permitted the local use of topical, intra-articular, intranasal, ocular, or 
inhalational adrenocorticosteroids or the temporary use of adrenocorticosteroids for 
the treatment or prophylaxis of contrast media allergy or adverse events. The 
Sponsor’s Medical Monitor must be consulted for continued treatment with the 
investigational product or chemotherapy in subjects requiring systemic 
adrenocorticosteroids for treating drug-related adverse events and if necessary, the 
investigator will determine whether or not to continue treatment with the 
investigational product or chemotherapy after consultation with the Sponsor’s 
Medical Monitor. 
Note 2): Including local therapy with Picibanil. 
Note 3): Radiotherapy to brain or meningeal metastasis in the screening period is permitted 
unless subjects meet 4.3 Exclusion Criteria 22. As for palliative radiotherapy, only 
procedures specified in 7.2.2.1 Palliative Radiotherapy are permitted. 
Note 4): Use of radiopharmaceuticals for examination and diagnosis is permitted. 
Note 5): Use of bisphosphonates and anti-RANKL antibodies is acceptable only when their 
administration is started before randomization and the same dosage and 
administration are maintained. 
 
7.2.1.1 
Rationale 
The information is provided because of potential effects on the efficacy and safety assessments 
of ONO-4538 in combination with other therapies. 
 


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7.2.2 
Permitted Therapy 
7.2.2.1 
Palliative Radiotherapy 
Palliative radiotherapy for non-target lesions, except the chest lesion, is permitted only if 
clinically indicated. Radiographic tumor assessments should be performed wherever possible 
before starting palliative radiotherapy. 
The potential for overlapping toxicities of radiotherapy and ONO-4538 is not currently known. 
As concurrent radiotherapy and ONO-4538 have not been formally evaluated, in cases where 
palliative radiotherapy is required for a tumor lesion, then the investigational product and 
chemotherapy should be withheld for at least 1 week before, during, and 1 week after radiation. 
Subjects should be closely monitored for any potential toxicity during and after receiving 
radiotherapy, and adverse events related to radiotherapy should resolve to Grade 1 or less prior to 
resuming administration of the investigational product and chemotherapy. 
 
7.2.2.2 
Prophylactic Administration 
Prophylactic medications for administration of the investigational product or chemotherapy 
should follow the procedures specified by the study site. Recommended medications and 
procedures for administration of the investigational product are described below. 
 
7.2.2.2.1 Prophylactic Medications for Administration of Investigational Product 
Prior prophylactic use of acetaminophen or diphenhydramine is recommended for subjects who 
are at risk of infusion-related reaction after administration of the investigational product. 
 
7.2.2.2.1.1 
Rationale 
For potential effects on the efficacy and safety assessments of ONO-4538 in combination with 
other therapies. 
 
7.3 
Discontinuation for Supply of Investigational Product 
The investigational product may be supplied to subjects by the Sponsor unless subjects meet 
7.1.4 Treatment Discontinuation Criteria or 13 Stopping Rules or Discontinuation Criteria for 
Individual Subjects. The Sponsor will stop the supply of the investigational product if any of the 
following occurs: 
1. The marketing application for this indication is rejected by the relevant regulatory authority; 
2. The study is terminated; 
3. The subject can obtain ONO-4538 with the same dosage regimen as that used in this study 
under public or private health insurance; or 
4. Therapeutic alternatives become available. 


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7.4 
Post-Study Access to Therapy 
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive the investigational product supplied by the Sponsor. The investigational 
product will be provided via an extension of the study, a rollover study requiring approval by the 
responsible health authorities and ethics committee, or through another mechanism at the 
Sponsor’s discretion. 
8 
TIME AND EVENTS SCHEDULE AND OBSERVATIONS 
8.1 
Time and Events Schedule 
The study consists of the screening period, treatment period, and follow-up period. In the 
protocol synopsis, Figure 2-1 shows an overview of the study design. 
 
8.1.1 
Screening Period 
Examinations and assessments during the screening period will be performed after obtaining the 
written consent form from the subject. The investigator will enroll subjects who meet 4.2 
Inclusion Criteria and do not meet 4.3 Exclusion Criteria, and are considered eligible for the 
study. In the protocol synopsis, Table 6-1 shows the assessments and tests in the screening 
period and the time and events schedule. 
 
8.1.2 
Treatment Period 
8.1.2.1 
Investigational Product 
ONO-4538 360 mg or placebo will be administered intravenously over 30 minutes every 3 
weeks. Subjects who meet all 7.1.2.1 Dosing Criteria for Investigational Product and do not meet 
any of 7.1.4.1 Investigational Product Discontinuation Criteria can repeatedly receive ONO-4538 
or placebo. In the protocol synopsis, Table 6-1 shows the assessments and tests in the treatment 
period and the time and events schedule. 
 
8.1.2.2 
Chemotherapy 
Subjects will receive carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg 
every 3 weeks. Carboplatin and paclitaxel will be administered for up to 4 cycles and if deemed 
safe, treatment may continue for up to a maximum of 6 cycles. Even after the completion of 
treatment with carboplatin and paclitaxel, bevacizumab will be administered intravenously on 
Day 1 of each cycle until RECIST 1.1 defined PD, unacceptable toxicity, or withdrawal of 
consent. In the protocol synopsis, Table 6-1 shows the assessments and tests in the treatment 
period and the time and events schedule. 


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8.1.3 
Follow-up Period 
Subjects meeting any of 7.1.4 Treatment Discontinuation Criteria will be evaluated at the 
completion of the treatment period (at discontinuation) and enter the follow-up period. In the 
protocol synopsis, Table 6-1 shows the assessments and tests in the follow-up period and the 
time and events schedule. 
 
8.2 
Observations 
8.2.1 
Demographics 
The investigator and study staff will perform examinations and enter the following items on the 
eCRF during the screening period. Clinical classification and staging will be assessed according 
to the UICC TNM classification, 7th edition (hereinafter called TNM classification). 
∙ Subject identification code (ID) 
∙ Date of obtaining the informed consent 
∙ Gender 
∙ Date (including the year) of birth 
∙ Race 
∙ Ethnicity 
∙ Height 
∙ Body weight 
∙ Past history (past history collected within 1 year before the randomization and possibly other 
clinically significant past history) 
∙ Complications 
∙ Smoking history 
∙ ECOG Performance Status 
∙ Date (including the year) of diagnosis of primary disease 
∙ Staging and TNM classification 
∙ Histology of non-squamous non-small cell lung cancer 
∙ Primary site and metastatic site of non-squamous non-small cell lung cancer 
∙ Site of recurrence (recurrent non-squamous non-small cell lung cancer) 
∙ Tumor diameter of target lesion 
∙ Past treatment for cancers (including a history of surgery, radiotherapy, or medical treatment) 
 
8.2.2 
Drug Administration and Provision of Concomitant Treatments 
8.2.2.1 
Administration of Investigational Product and Chemotherapy 
The investigator and study staff will enter the details of administration (dosage, date of 
administration, time of start of administration, and time of completion of administration) of the 
investigational product and chemotherapy on the eCRF. 


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8.2.2.2 
Administration of Other Drugs and Concomitant Treatments 
All drugs and concomitant treatments used from the start date of administration of the 
investigational product to 100 days after the last administration of the investigational product or 
chemotherapy, whichever comes later will be reviewed. The name of treatment, duration of 
administration, route of administration, reason for administration, and dosage regimen will be 
entered on the eCRF. 
Presence or absence of subsequent anticancer therapy for non-squamous non-small cell lung 
cancer, start date of treatment, and details of therapy in addition to outcome survey will be 
reviewed as much as possible during the follow-up period. 
When drug-related adverse events or adverse events leading to discontinuation are reported at the 
start of follow-up, concomitant treatments administered for these events should be investigated at 
appropriate intervals until no further follow-up is required because the events have resolved or 
are resolving, or the symptoms become stable. 
Results of examinations on subsequent anticancer therapy and concomitant treatments for non-
squamous non-small cell lung cancer will be entered on the eCRF. 
In addition, details of the follow-up are shown in 8.2.10 Follow-up. 
 
8.2.3 
Efficacy Endpoints 
The investigator and study staff will perform measurements and examinations for the following 
items at specified time points. For subjects who discontinue the study, measurements and 
examinations will be performed if possible with sufficiently considering subject safety. 
 
8.2.3.1 
Radiographic Tumor Assessments (Measurement of Tumor Diameter and Evaluation 
of Antitumor Activity) 
CT/MRI scans of the chest, abdomen, and pelvis will be obtained. The same imaging method 
will be used to evaluate the antitumor activity throughout the study. In addition, the presence or 
absence of brain metastasis will be confirmed by CT/MRI of the head before the start of the 
study, and the presence or absence of bone metastasis will be confirmed by X-ray, FDG-PET, or 
bone scintigraphy depending on clinical symptoms. CT/MRI of the head, X-ray, FDG-PET, and 
bone scintigraphy will be performed depending on clinical symptoms after the start of the study. 
The antitumor activity will be evaluated per RECIST 1.1 criteria (refer to APPENDIX 1). In 
addition, radiographic tumor assessments at the completion of the treatment period (at 
discontinuation) and 28 days after the completion of the treatment period will be performed as 
needed if at least 15 days have elapsed since the last examination or if medically indicated; 
except when the last examination is within the time window for completion of the treatment 
period (at discontinuation) or 28 days after completion of the treatment period. 
Radiographic tumor assessments (measurement of tumor diameter and evaluation of antitumor 
activity) will be performed at the following time points. The investigator will determine whether 


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or not treatments can be continued based on radiographic tumor assessments per RECIST 1.1 
criteria. Imaging data should be submitted to the IRRC, and at the time of investigator-assessed 
PD per RECIST 1.1 criteria, the study site must request a radiographic tumor assessment to the 
IRRC. The radiographic tumor assessment by the IRRC will be conducted by a blinded, 
independent radiologist, and subjects whose PD is not confirmed by the IRRC will be required to 
continue radiographic tumor assessments according to the protocol-specified schedule and their 
subsequent tumor images must be submitted to the IRRC (if clinically feasible). Subjects 
receiving the investigational product beyond PD must continue radiographic tumor assessments 
until such treatment has been discontinued. If clinically acceptable, subsequent anticancer 
therapy should, in principle, begin only after RECIST 1.1 defined PD has been assessed based 
upon the radiographic tumor assessment by the IRRC. Subjects who start therapy specified in 
7.2.2.1 Palliative Radiotherapy without prior assessment of RECIST 1.1 defined PD by the IRRC 
must undergo radiographic tumor assessments before receiving such therapy wherever possible 
(if clinically feasible) and their tumor assessment images must be submitted to the IRRC. If 
thoracentesis, pericardiocentesis, or abdominal paracentesis is considered, for example due to 
clinical symptoms, a CT scan should be performed wherever possible before these treatments. 
Radiographic tumor assessments may be discontinued when the investigator and the IRRC both 
assess the subject to have met RECIST 1.1 criteria for PD or subsequent anticancer therapy is 
started. Procedures for CT/MRI and data transmission to the central image analysis laboratory 
will follow the written operating procedures separately specified. 
 
<Time points> 
∙ Screening period 
∙ The latest results are available if the tumor evaluation is conducted within 28 days prior 
to the randomization. 
∙ Treatment period 
∙ The first tumor assessment will be performed 6 weeks after the first day of treatment (+ 
7 days). Subsequent tumor assessments will be performed every 6 weeks (± 7 days) for 
the first 12 months (until Week 48) and after Week 48, assessments will be conducted 
every 12 weeks (± 7 days) until PD. 
∙ At the completion of the treatment period (at discontinuation) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 1) 
∙ Follow-upnote 1) 
 
Note 1): Subjects who discontinue treatment during the treatment period because of safety 
concerns or disease progression despite an overall response of CR, PR, or SD 
should continue radiographic tumor assessments if possible until the start of 
subsequent anticancer therapy for non-squamous non-small cell lung cancer or 
where their condition is assessed as PD or recurrence per RECIST 1.1 (refer to 
APPENDIX 1). Subjects whose PD is not confirmed by the IRRC will be required 
to continue radiographic tumor assessments according to the protocol-specified 
schedule and their subsequent tumor images must be submitted to the IRRC (if 
clinically feasible). If thoracentesis, pericardiocentesis, or abdominal paracentesis is 


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considered, for example due to clinical symptoms, a CT scan should be performed 
wherever possible before these treatments. 
 
8.2.4 
Safety Items 
The investigator and study staff will perform measurements and examinations for the items 
shown in 8.2.4.1 to 8.2.4.7. For subjects who discontinue the study, the investigator and study 
staff will perform measurements and examinations if possible while taking subject safety into 
full consideration. 
 
8.2.4.1 
Vital Signs, Body Weight, Height, 12-Lead Electrocardiogram 
8.2.4.1.1 Vital Signs [Systolic/Diastolic Blood Pressure, Pulse Rate, Percutaneous Oxygen 
Saturation (SpO2), and Body Temperature], Body Weight, Height 
Vital signs, body weight, and height will be measured at the following time points [body weight 
will be measured only during the screening period, on Day 1 (predose) and Day 22 of each cycle 
during the treatment period, at the completion of the treatment period (at discontinuation), and 28 
days after the completion of the treatment period; height will be measured only during the 
screening period]. Systolic/diastolic blood pressure, pulse rate, and SpO2 will generally be 
measured at rest in the same position throughout the study. 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment will be adopted as the time window. 
∙ Treatment period 
∙ Cycle 1: Predose on Day 1, postdose on Day 1, Day 8, and Day 22 
∙ Cycle 2 and subsequent cycles: Predose on Day 1 of each cyclenote 1), Day 22 
∙ At the completion of the treatment period (at discontinuation)note 2) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 2) 
 
Note 1): Data obtained on Day 22 in the previous cycle may be used except when medically 
indicated. However, an examination must be performed if at least 2 days (vital 
signs) and 8 days (body weight) have elapsed since the last examination. An 
examination will be performed as needed if medically indicated. 
Note 2): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 2 days (vital signs) and 8 days (body 
weight) have elapsed since the last examination. An examination will be performed 
as needed if medically indicated. 
 


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8.2.4.1.2 12-Lead Electrocardiogram [Heart Rate (HR), PR Interval, RR Interval, QRS 
Complex, and QT Interval] 
12-lead electrocardiogram (ECG) (HR, PR interval, RR interval, QRS complex, and QT interval) 
will be recorded at rest using each site’s electrocardiograph at the following time points. The 
investigator will confirm abnormal findings after 12-lead ECG. 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Day 22 of Cycles 2, 6, and 8 
∙ At the completion of the treatment period (at discontinuation)note 1) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 1) 
 
Note 1): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 
8.2.4.2 
Chest X-Ray 
Chest X-ray will be taken at the following time points. The investigator will confirm abnormal 
findings after chest X-ray. In addition, for any symptoms/signs or laboratory data indicative of 
respiratory disease, chest X-ray may be performed as needed in addition to scheduled 
examinations during the study (from the time of informed consent through completion of the 
protocol-specified final examination [except outcome survey]). 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Cycle 2 and subsequent cycles: Day 22 of each Cycle 
∙ At the completion of the treatment period (at discontinuation)note 1) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 1) 
 
Note 1): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 


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8.2.4.3 
Laboratory Tests 
8.2.4.3.1 Hematology, Serum chemistry, Urinalysis 
Hematology, serum chemistry, and urinalysis will be performed at the following time points. 
Measurement will be generally performed at each study site. 
 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Cycle 1: Day 8, Day 22 
∙ Cycle 2 and subsequent cycles: Predose on Day 1 of each cyclenote 1), Day 22 
∙ At the completion of the treatment period (at discontinuation)note 2) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 2) 
 
Note 1): Data obtained on Day 22 in the previous cycle may be used except when medically 
indicated. However, an examination must be performed if at least 8 days have 
elapsed since the last examination. An examination will be performed as needed if 
medically indicated. 
Note 2): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 
<Test items> 
Hematology: 
Red blood cell count, MCV, MCH, MCHC, hemoglobin, hematocrit, white 
blood cell count, differential white blood count (neutrophil, lymphocyte, 
eosinophil, basophil, monocyte), platelet count 
Serum chemistry: 
Albumin, ALP, AST (GOT), ALT (GPT), total bilirubin, direct bilirubin, γ-
GTP, total protein, creatinine, blood sugar level, LDH, BUN, uric acid, CK 
(CPK), P, Ca, Na, K, Cl 
Urinalysis: 
Specific gravity, protein, sugar, occult blood, sediment (white blood cell, red 
blood cell) 
 
8.2.4.3.2 Immunological/Hormonal Tests 
Immunological/hormonal tests will be performed at the following time points. Blood samples 
will be collected in the morning as much as possible, and the time of blood samples will be 
recorded on each test day. Measurement will be performed at the designated central laboratory. 


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<Time points> 
∙ Screening period 
∙ The latest results are available if the test is conducted within 28 days prior to the 
randomization. 
∙ Treatment period 
∙ Cycle 2 and subsequent cycles: Day 22 of even cycles 
∙ At the completion of the treatment period (at discontinuation)note 1) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 1) 
 
Note 1): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 
<Test items (blood volume per sample collection: 9 mLnote 2])> 
Immunological test: Rheumatoid factor (RA), C-reactive protein (CRP), antinuclear antibody 
(ANA), SP-D (optional), KL-6 (optional) 
Hormonal test: 
Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), free 
thyroxine (free T4) 
 
The above items will be measured, and if clinically significant changes in RA, CRP, ANA, TSH, 
or free T4 are found, the following items will also be measured as soon as possible. SP-D and 
KL-6 tests are optional. In addition, appropriate items including adrenocorticotropic hormone 
(ACTH, blood volume per sample collection: 2 mL) will be added as needed. 
 
Note 2):  If SP-D and KL-6 are not measured, the blood volume will be 7 mL. 
 
<Added items (blood volume per sample collection: 15 mL)> 
Anti-DNA antibody, anti-SSA antibody (Ro), anti-SSB antibody (La), anti-thyroglobulin 
antibody, anti-LKM antibody, anti-phospholipid antibody, anti-GAD antibody, anti-neutrophil 
cytoplasmic autoantibody, β1C/β1A globulin (C3), β1E globulin (C4), serum complement level 
(CH50), thyroid-stimulating hormone stimulating receptor antibody, antithyroid peroxidase 
antibody 
 
8.2.4.4 
Pregnancy Test (Women of Childbearing Potential Only) 
Women of childbearing potentialnote) (including those who have no menses for medical reasons, 
such as chemotherapy-induced menopause) will undergo a serum or urinary pregnancy test at the 


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following time points. The same approach will be used if possible throughout the study. The test 
will be generally performed at each study site. 
 
Note): 
Women of childbearing potential are defined as all premenopausal women who 
have reached menarche and who have not undergone sterilization (including 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy). Menopause is 
defined as amenorrhea for at least 12 successive months in the absence of 
significant causes. Women who use oral contraceptives, other hormonal 
contraceptives (including intravaginal or injectable contraceptives), or mechanical 
contraception (including intrauterine device or barrier method) are regarded as 
having childbearing potential. 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Cycle 1: Predose on Day 1 
∙ Cycle 2 and subsequent cycles: Predose on Day 1 of odd cyclesnote 1) 
∙ At the completion of the treatment period (at discontinuation) note 2) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 2) 
 
Note 1): In Cycle 2 and subsequent cycles, a pregnancy test will be performed within 7 days 
prior to administration of the investigational product. 
Note 2): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 
8.2.4.5 
Viral Test 
The following tests will be performed during the screening period. However, if any tests were 
performed within 1 year before randomization, no new examinations are required except when 
medically indicated. If subjects test negative for HBs antigen but positive for either the HBs 
antibody or HBc antibody, an HBV-DNA quantitative test will be performed. These tests will be 
generally performed at each study site. 
 
<Test items> 
HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, HBs antibody, HBc antibody, 
HCV antibody 
 


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8.2.4.6 
ECOG Performance Status 
ECOG Performance Status will be evaluated at the following time points. 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Cycle 1: Day 8, Day 22 
∙ Cycle 2 and subsequent cycles: Predose on Day 1 of each cyclenote 1), Day 22 
∙ At the completion of the treatment period (at discontinuation)note 2) 
∙ Follow-up period 
∙ 28 days after the completion of the treatment periodnote 2) 
 
Note 1): Data obtained on Day 22 in the previous cycle may be used except when medically 
indicated. However, an examination must be performed if at least 8 days have 
elapsed since the last examination. An examination will be performed as needed if 
medically indicated. 
Note 2): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. An examination will be performed as needed if medically indicated. 
 
8.2.4.7 
Adverse Events 
All adverse events will be evaluated using NCI-CTCAE Version 4.0. Signs or symptoms that are 
not included in the CTCAE will be treated as adverse events based on the judgment of the 
investigator. 
For adverse events that occur from the start date of administration of the investigational product 
to 100 days after the last administration of the investigational product or chemotherapy, the 
following will be entered on the eCRF: the event name, onset date , grade, judgment on whether 
the investigational product or chemotherapy is to be continued, action taken, seriousness, causal 
relationship with the investigational product or chemotherapy, and outcome at the final 
observation (or resolution date, if the event resolved by the final observation). For subjects who 
enters the follow-up period, if drug-related adverse events and adverse events leading to 
discontinuation are found, observations/measurements for clinical symptoms and laboratory tests 
will be performed and appropriate actions for adverse events will be taken until no further 
follow-up is required because the events have resolved, are resolving, are considered as 
permanent events, or are assessed as lost to follow up for any other reason. Serious adverse 
events will be reported to the Sponsor (or person designated by the Sponsor) according to 9.8 
Action taken for Serious Adverse Events. 
If the investigator regards an adverse event that is a subjective symptom/objective finding and an 
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generally reported as one event (an adverse event as a subjective symptom/objective finding 
only). If a subjective symptom/objective finding and an abnormal change in laboratory values 
cannot be regarded as a series of the same event, the finding and change will be reported as 
separate adverse events. 
 
8.2.5 
Measurement of Serum Drug Concentration 
The serum drug concentration of ONO-4538 will be measured by electrochemi-luminescence 
assay at Pharmaceutical Product Development, LLC (PPD). Measurement methods are described 
in detail in the plan prepared by the person responsible for measuring serum drug concentration 
of ONO-4538. The results will be reported in the ONO-4538 serum concentration measurement 
report. Retrieval and transportation of specimens will follow the written procedures separately 
specified. 
Blood samples (blood volume per sample collection: 2 mL) for serum drug concentration 
measurement will be collected at the following time points. Blood samples will also be collected 
6 to 12 weeks after the last administration of the investigational product, as much as possible. 
In addition, although serum ONO-4538 or anti-ONO-4538 antibodies may be measured using 
specimens for serum drug concentration measurement in an exploratory manner for the purpose 
of technical exploration, the results will not be reported. 
 
<Time points> 
∙ Treatment period 
∙ Cycle 1: Predose of the investigational product on Day 1, immediately before the end of 
infusion of the investigational product on Day 1, Day 22 
∙ Cycle 2 and subsequent cycles: Immediately before the end of infusion of the 
investigational product on Day 1 of Cycle 7, Day 22 of Cycles 2, 6, 8, 12, and 16 
       Not required for the subject who discontinued the investigational product but remained in 
the treatment period. 
∙ Follow-up period 
∙ 28 days after the completion of the treatment period (only if the subject enters the follow-
up period following the discontinuation of the investigational product by Cycle 16) 
∙ 6 to 12 weeks after the last administration of the investigational product (if possible). For 
the subject who discontinued only the investigational product, the measurement may be 
performed during the treatment period. 
 
8.2.6 
Measurement of Anti-ONO-4538 Antibodies 
Anti-ONO-4538 antibodies will be measured by electrochemi-luminescence assay at 
Pharmaceutical Product Development, LLC (PPD). Neutralizing activity will be evaluated at 
BMS as needed. Measurement methods are described in detail in the plan prepared by the person 
responsible for measuring anti-ONO-4538 antibodies. The results will be reported in the serum 


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anti-ONO-4538 antibody measurement report. Retrieval and transportation of specimens will 
follow the written procedures separately specified. 
Blood samples (blood volume per sample collection: 4 mL) for measurement of anti-ONO-4538 
antibodies will be collected at the following time points. Blood samples will also be collected 6 
to 12 weeks after the last administration of the investigational product, as much as possible. 
If there is an insufficient volume of specimens for measurement of anti-ONO-4538 antibodies, 
specimens for measurement of serum drug concentration that were collected at the same time 
point may be used. In addition, although serum ONO-4538 or anti-ONO-4538 antibodies may be 
measured using specimens for measurement of serum anti-ONO-4538 antibodies in an 
exploratory manner for the purpose of technical exploration, the results will not be reported. 
<Time points> 
∙ Treatment period 
∙ Cycle 1: Predose of the investigational product on Day 1, Day 22 
∙ Cycle 2 and subsequent cycles: Day 22 of Cycles 2, 6, 8, 12, and 16 
       Not required for the subject who discontinued the investigational product but remained in 
the treatment period. 
∙ Follow-up period 
∙ 28 days after the completion of the treatment period (only if the subject enters the follow-
up period following the discontinuation of the investigational product by Cycle 16) 
∙ 6 to 12 weeks after the last administration of the investigational product (if possible). For 
the subject who discontinued only the investigational product, the measurement may be 
performed during the treatment period. 
 
8.2.7 
Exploration of Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.2.7.3 
Tumor Markers (As Needed) 
Wherever possible, tumor markers will be continuously measured in subjects who have tumor 
markers exceeding the upper limit of normal. Tumor markers should be measured as needed. 
Measurement will be generally performed at each study site. 
 
 
 
 
 
 
 


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8.2.7.5 
Tumor Tissues 
Formalin-fixed, paraffin-embedded (FFPE) tumor tissues collected within 6 months prior to 
enrollment must be submitted to the central laboratory for determination of PD-L1 status using 
the analytically validated IHC assay. Either a tissue block or a minimum of 10 unstained tumor 
tissue sections are required. Submission of fewer than 10 unstained slides may be acceptable in 
some circumstances following discussion with the Sponsor’s Medical Monitor. PD-L1-stained 
tissue specimens will be evaluated by a pathologist at the central laboratory designated by the 
Sponsor. If at least 1% of the cancer cells among 100 or more evaluable cancer cells have stained 
cell membranes, the specimen is considered to be PD-L1+, and if less than 1%, it is considered to 
be PD-L1−. Specimens must contain at least 100 evaluable cancer cells. Specimens with an 
insufficient number of cancer cells are considered as unevaluable and the subject is not 
randomized. Even where specimens meet the criteria for evaluation, if it is difficult to assess the 
staining of the cell membrane region due to the biological characteristics of the tumor tissue 
specimen rather than the inappropriate preparation and handling of specimens, such specimens 
will be considered indeterminate. 
 
 
 
 
 
 
 
Tumor tissues will be stored frozen at the specified central laboratory for up to 10 years after the 
study concludes. Handling, storage, assessment , and disposal of samples and disclosure of 
genetic information will follow the written operating procedures separately specified. 
 


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8.2.8 
Patient Reported Outcome 
Health-related QoL evaluation is gaining more importance from the viewpoint of clinical 
efficacy. Obtained QoL data elucidate the effects of treatments from the patient’s perspective and 
experience in a way that cannot be obtained from a physician’s report. 
Systemic health status will be measured using EQ-5D. EQ-5D is a standardized evaluation 
instrument used to measure self-reported health status. EQ-5D consists of 5 dimensions (degree 
of movement, management of selfcare, daily activities, pain/discomfort, and anxiety/depression) 
and a visual analogue scale (VAS). Disease-related symptoms will be measured using LCSS. 
LCSS is a standardized evaluation instrument used to measure self-reported disease-related 
symptoms. LCSS consists of 6 symptoms: cough, dyspnea, fatigue, pain, hemoptysis, and 
decreased appetite. It is recommended that efficacy data obtained from EQ-5D and LCSS be 
used for analysis of cost effectiveness analysis; and the data are commonly used. 
To minimize bias, QoL evaluation will be generally performed before study procedures at each 
visit. 
 
<Time points> 
∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Every 6 weeks from the start date of Cycle 1 
∙ At the completion of the treatment period (at discontinuation)note 1) 
∙ Follow-up period 
∙ Follow-upnote 2) 
 
Note 1): Previous test results may be used except when medically indicated. However, an 
examination must be performed if at least 8 days have elapsed since the last 
examination. 
Note 2): EQ-5D will be collected every 3 months in the first year of follow-up and every 6 
months thereafter. 
 
8.2.9 
Other Examinations 
8.2.9.1 
Healthcare Resource Utilization 
Information regarding hospitalization associated with administration of the investigational 
product or diseases and non-protocol specified visits and the like will be collected for all 
randomized subjects. Healthcare resource utilization will be evaluated at the following time 
points. 
 
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∙ Screening period 
∙ Days −7 to −1 starting from the first day of treatment is adopted as the time window. 
∙ Treatment period 
∙ Every 6 weeks from the start date of Cycle 1 
∙ At the completion of the treatment period (at discontinuation) 
 
8.2.10 
Follow-up 
Subjects who discontinue the treatment period because of safety issues or disease progression 
despite an overall response of CR, PR, or SD per RECIST 1.1 criteria (refer to APPENDIX 1) 
should continue radiographic tumor assessments if possible until the start of subsequent 
anticancer therapy for non-squamous non-small cell lung cancer or where their condition is 
assessed as PD or recurrence. The antitumor activity will be assessed according to the RECIST 
1.1 criteria (refer to APPENDIX 1) based on obtained images, and results will be entered on the 
eCRF. 
All adverse events and concomitant treatments will be examined from the start date of 
administration of the investigational product to 100 days after the last administration of the 
investigational product or chemotherapy, whichever comes later. When drug-related adverse 
events or adverse events leading to discontinuation are reported at the start of follow-up, 
concomitant treatments administered for these events should be investigated at appropriate 
intervals until no further follow-up is required because the events have resolved or are resolving, 
or the symptoms become stable. The results of follow-up should be entered on the eCRF. 
An outcome survey (if the subject dies, confirm the date of death and cause of death) for subjects 
who were randomized into the study will be performed as a part of follow-up. The outcome 
survey can be conducted by telephone or letter, which will be performed approximately every 3 
months or as needed depending on the incidence of events. Any new information on survival 
status should be entered on the eCRF accordingly. In addition, the presence or absence of 
subsequent anticancer therapy for non-squamous non-small cell lung cancer, the date of starting 
such therapy, and details of the therapy should also be investigated wherever possible. 
 
8.2.11 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject to provide information on 
the follow-up. Lost to follow-up is defined as the inability to reach the subject after a minimum 
of 3 documented phone calls, faxes, or emails as well as lack of response by subject to 1 
registered mail letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use permissible local methods to obtain the date 
and cause of death. 
If an investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 


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study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records. 
9 
ADVERSE EVENTS AND ITEMS TO ENSURE SUBJECT SAFETY 
9.1 
Definition of Adverse Events 
An adverse event is any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the investigational product 
or chemotherapy whether or not considered related to the investigational product or 
chemotherapy. In addition, the primary disease, associated symptoms of the primary disease, and 
worsening of complications that are medically considered to exceed the range of the natural 
course are regarded as adverse events. Tumor expansion and onset of a new lesion after the start 
of the study (except development of malignant tumor histologically different from the primary 
focus) that are medically considered to exceed the range of the natural course are also regarded 
as adverse events. 
 
9.2 
Definition of Serious Adverse Events 
Events that correspond to any of the following among those meeting the definition for an adverse 
event are considered to be serious adverse events. 
1. Results in death 
2. Is life-threatening 
3. Requires inpatient hospitalization or prolongation of existing hospitalizationnote 1) 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is other medically important event or reactionnote 2) 
 
Note 1): Serious adverse events do not include hospitalization for conduct of the study or those 
listed below. 
∙ Hospitalization or prolongation of existing hospitalization for therapeutic reasons 
planned before the start of the study (including surgery or examinations planned before 
the start of the study) 
∙ Hospitalization or prolongation of existing hospitalization for examinations and 
education (including hospitalization for routine examinations or for education) 
∙ Hospitalization or prolongation of existing hospitalization for surgery as a result of a 
change in the therapeutic policy for handling complications and associated symptoms 
rather than due to exacerbation of complications and associated symptoms  
∙ Hospitalization or prolongation of existing hospitalization for follow-up despite the 
disease having resolved or in the process of resolving 
∙ Hospitalization/residence at hospice, nursing home, or rehabilitation facility 


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∙ Hospitalization or prolongation of existing hospitalization for new treatments for the 
primary disease, including subsequent anticancer therapy after administration of the 
investigational product has ended 
∙ Hospitalization or prolongation of existing hospitalization for social reasons 
(including caregiver’s respite, absence of family members) 
 
Note 2): For other important medical events, medical and scientific judgment should be 
exercised in deciding if an emergency report is required when such events might not 
be immediately life-threatening or resulting in death or hospitalization but might 
jeopardize the subject or might require intervention to prevent such results as 
described in 1 to 5 above, and such events should be, in general, also considered 
serious. Examples of such events are intensive treatment in an emergency room, etc. 
for bronchospasm, blood dyscrasias or convulsions (even if the event does not result in 
hospitalization), development of drug dependency or drug abuse, onset of malignant 
tumors histologically different from the primary focus. If transmission of an infectious 
drug (with or without virulence) via the investigational product is suspected, it should 
be reported as “other medically important event.” 
 
9.3 
Grading 
Adverse events are graded into 5 levels (1 to 5) depending on their severity. If an observed 
adverse event meets the definitions for several grades as listed in CTCAE, it is graded according 
to the nearest match among Grades 1 to 5 based on comprehensive consideration. In addition, in 
subjects who died, if any adverse event within a CTCAE category has been reported as Grade 5, 
the grade of other observed adverse events at the time of death will be determined based on the 
clinical evaluation of the investigator. It is not necessary to follow the CTCAE’s rule (Grade 5 is 
applicable to only 1 adverse event). The grade of adverse events not listed in CTCAE will be 
determined based on the following criteria. 
Grade 1 Mild; no symptoms or mild symptoms; clinical or diagnostic observations only; 
intervention not required 
Grade 2 Moderate; minimal/local/non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADLs)note 1) 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of existing hospitalization indicated; disabling; limiting selfcare 
ADLsnote 2) 
Grade 4 Life-threatening; urgent intervention indicated 
Grade 5 Death related to adverse events 
Semicolon (;) indicates “or” within the explanation on grade. 
 
Note 1):  Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 


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Note 2): Selfcare ADLs refer to bathing, dressing/undressing, feeding self, using the toilet, 
taking medications and not bedridden. 
9.4 
Causal Relationship with Investigational Product or Chemotherapy 
A causal relationship with the investigational product or chemotherapy falls under either of the 
following two categories based on the subject’s condition, past history, concomitant drugs, and 
temporal relationship of onset. In addition, if the investigator determined that the adverse event 
was related to either the investigational product or chemotherapy, the reasons for this 
determination will be entered in the comment field of the eCRF. 
 
1. Related: There is a reasonable causal relationship between study drug administration and the 
adverse event. 
2. Unrelated: There is not a reasonable causal relationship between study drug administration 
and adverse event. 
 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship. 
 
9.5 
Outcome 
The outcome of an adverse event (symptom or abnormal laboratory finding) will be assessed 
according to the following criteria. If the event resolves, the resolution date will be determined, 
and, otherwise, the outcome at the final observation will be determined. 
 
Outcome 
Criteria (for information) 
Resolved 
The symptom resolved, or the test value normalized or returned to the pre-
therapy level. 
Resolving 
The event decreased in intensity, or the symptom showed an improving 
tendency. 
Not resolved 
The symptom or the test value has not improved. 
Resolved with 
sequelae 
The event resolved or was resolving, but with remaining symptoms of 
disability or other sequela. 
Fatal 
The subject died. 
Unknown 
(Lost to follow-up) 
The subject was lost to follow-up. 
 


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9.6 
Continuation of Investigational Product or Chemotherapy 
The investigator’s or subinvestigator’s decision to continue administration of the investigational 
product or chemotherapy for each adverse event will be classified into the following 7 levels and 
recorded. Note that the subject’s decision is not included in this classification. 
 
Decision 
Criteria 
1 Dose not changed 
As a result of the adverse event, the investigator or subinvestigator has judged 
that administration of the investigational product or chemotherapy may be 
continued. 
2 Drug interrupted 
As a result of the adverse event, the investigator or subinvestigator has judged 
that administration of the investigational product or chemotherapy needs to 
be interrupted. The investigational product or chemotherapy has been 
resumed after interruption or is expected to be resumed after early 
interruption. 
3 Drug delayed 
As a result of the adverse event, the investigator or subinvestigator has judged 
that administration of the investigational product or chemotherapy needs to 
be delayed (or skipped). 
4 Dose reduced 
As a result of the adverse event, the investigator or subinvestigator has judged 
that the dose of the investigational product or chemotherapy needs to be 
reduced. 
5 Drug withdrawn 
As a result of the adverse event, the investigator or subinvestigator has judged 
that administration of the investigational product or chemotherapy needs to 
be discontinued. 
6 Not applicable 
The adverse event developed after the end of administration of the 
investigational product or chemotherapy. 
7 Other 
None of the above applies, but as a result of the adverse event the investigator 
or subinvestigator has changed the mode of administration of the 
investigational product or chemotherapy. 
 
9.7 
Treatment 
Treatments for the adverse event will be recorded. 
 
9.8 
Action taken for Serious Adverse Events (SAE) 
All SAEs, whether related or not related to the investigational product or chemotherapy, 
including those thought to be associated with protocol-specified procedures, must be collected 
that occur between first dose and 100 days after the last dose of the investigational product or 
chemotherapy. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (eg, biopsy during the follow-up period). 


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The investigator should report any SAEs that occurs after these time periods and that is believed 
to be related to the investigational product or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to the investigational product or 
chemotherapy, but is potentially related to the conditions of the study (such as withdrawal of 
previous therapy or a complication of a study procedure), the relationship should be specified in 
the narrative section of the SAE Report Form. 
SAEs (including overdose), whether related or not related to the investigational product or 
chemotherapy, and pregnancies must be reported to the Sponsor (or person designated by the 
Sponsor) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The report will be sent to the 
following by e-mail or confirmed fax transmission, and an original of the report will be retained 
at each study site (as for Japan, refer to the country specific amendment for all sites in Japan). 
 
SAE Email Address: 
 
SAE Facsimile Number: Refer to Table 9.8-1. 
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Table 9.8-1. 
 
Table 9.8-1: Facsimile Number and Telephone Contact by Country 
Country 
Facsimile Number 
Telephone Contact 
South Korea 
 
 
Taiwan 
 
 
 
As necessary, the Sponsor will conduct assessment of the details, together with medical experts 
or the Coordinating Committee or Independent Data Monitoring Committee (IDMC), and if 
medical experts, the Coordinating Committee, or the IDMC requests the submission of data such 
as scan images for safety evaluation, the Sponsor will submit these data, with personal 
information masked according to the regulations in the relevant countries. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to the investigational product or 
chemotherapy, or if new information becomes available, a follow-up SAE report should be sent 
within 24 hours to the Sponsor (or person designated by the Sponsor) using the same procedure 
used for transmitting the initial SAE report. 
All SAEs should be followed to resolution, resolving, or stabilization. 
 


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9.9 
Action taken for Pregnancy 
Between the start of administration of the investigational product and 28 days after the 
completion of the treatment period (discontinuation of administration of the investigational 
product and chemotherapy), if it is subsequently discovered that a study subject is pregnant or 
may have been pregnant at the time of investigational product or chemotherapy exposure, the 
investigational product and chemotherapy will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety). 
The investigator must immediately notify the Sponsor (or person designated by the Sponsor) of 
this event and complete and forward a Pregnancy Surveillance Form to the Sponsor (or person 
designated by the Sponsor) within 24 hours and in accordance with SAE reporting procedures 
described in Section 9.8. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor (or person designated by the Sponsor). Information on this pregnancy will be 
collected on the Pregnancy Surveillance Form. 
 
9.10 
Action taken for Overdose 
Overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose of the 
investigational product must be reported as an SAE (refer to Section 9.8 for reporting details). 
 
9.11 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, chest X-ray, and any other potential safety assessment, whether or not 
required by the protocol, should also be recorded as a non-serious or serious adverse event, as 
appropriate, and reported accordingly. 
 
9.12 
Provision of New Information 
If new information is obtained that might adversely affect the safety of the subject, impact the 
conduct of the study, or require a change in the approval of the institutional review board 
regarding study continuation, or information on serious and unexpected adverse drug reactions is 
obtained, the Sponsor will promptly report it in writing to all investigators and study staff and the 
heads of the study sites involved in the study. If the investigator agrees that there is a need to 
revise the written informed consent forms, such documents should be revised promptly. In 
addition, the Sponsor will revise the protocol/Investigator’s Brochure if and when required. 


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10 
STATISTICAL ANALYSIS 
Statistical analysis will be performed by ONO PHARMACEUTICAL CO., LTD. Although the 
analysis procedure is described below, a more detailed version of the analytical method will be 
included in the interim analysis plan and statistical analysis plan prepared by the person 
responsible for statistical analysis and the person in charge of statistical analysis. 
Version 1.0 of the interim analysis plan and statistical analysis plan will be fixed by cutoff data 
lock for interim analysis. After fixation of version 1.0, revision will be carried out as needed. 
If analysis other than that described in the statistical analysis plan is performed, it will be 
reported in the clinical study report. 
 
10.1 
Explanation of Statistical Methods including Timing of Planned 
Interim Analysis 
One interim analysis for PFS per IRRC will be performed in the ITT population to determine 
whether to stop the study early for superiority based on the stratified log-rank test with allocation 
factors (PD-L1 expression level, ECOG PS, and gender) as stratification factors when 
approximately 82.4% (n = 280) of the target number of PFS events over the entire study 
(n = 340) have occurred. To control the overall type I error rate at no more than 5% (two-sided), 
the significance levels used in the interim and final analyses will be calculated by the Lan-
DeMets α spending function (O’Brien-Fleming type) based on the actual number of events. 
When the planned interim analysis is performed when exactly 280 PFS events have been 
reported, the nominal two-sided significance levels for the interim and final analyses are 
calculated as shown in Table 10.1-1. 
Whether the study is to be stopped for superiority based on the interim analysis will be decided 
by the IDMC. The details of the interim analysis are separately specified in the IDMC procedural 
manual and the interim analysis plan. 
 
Table 10.1-1: Criteria for Success at Interim and Final Analyses 
Analysis 
Timing 
Nominal two-sided significance level 
Interim analysis 
280 events 
2.70% 
Final analysis 
340 events 
4.22%a) 
a): In the final analysis using the ITT and the PD-L1 1% Positive Set, Hochberg’s method will also be used to adjust 
multiplicity. 
 
10.2 
Independent Data Monitoring Committee (IDMC) 
The IDMC will be established to independently monitor safety, efficacy, and the conduct of the 
study. It will evaluate data regularly to ensure that the safety of subjects is carefully monitored. 
In addition, the IDMC will hold extraordinary meetings as needed. After each meeting, the 
IDMC will recommend continuation, change, or discontinuation of the study depending on the 


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observed toxicity. In addition, the IDMC will review the results of the interim analysis to decide 
whether or not it meets the discontinuation criteria on superiority at the time of interim analysis. 
For details of the committee’s activities, refer to the written operating procedures separately 
prepared. 
 
10.3 
Significance Level Used 
10.3.1 
Efficacy 
To control the overall type I error rate at ≤ 5% (two-sided), a significance level for interim and 
final analyses will be calculated using the Lan-DeMets α spending function (O’Brien-Fleming) 
based on the actual number of events. In addition, multiplicity of the test for final analysis will 
be adjusted using the Hochberg’s method. The significance level of the analysis for secondary 
endpoints is to be 5% (two-sided). In addition, interaction will be examined using a two-sided 
significance level of 15%. 
 
10.3.2 
Safety 
Not established because the test will not be performed. 
 
10.4 
Selection of Subjects to Be Included in Analyses 
10.4.1 
Definition of Analysis Sets 
The analysis sets for efficacy endpoints are the ITT and the PD-L1+ (≥ 1%) set (PD-L1 1% 
Positive Set: PDL1-PS). 
The analysis set for safety endpoints is the Safety Set (SAF). 
The analysis set for Immunogenicity endpoints is the Anti-Drug Antibody Set. 
Definition of each analysis set is as follows. 
 
10.4.1.1 Enrolled Set (ENR) 
The Enrolled Set (ENR) will consist of all subjects enrolled (enrollment) in this study via IWRS. 
 
10.4.1.2 ITT/Randomized Set (RND) 
The ITT and Randomized Set (RND) will consist of all randomized (randomization) subjects. 
 


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10.4.1.3 SAF 
The SAF will consist of all subjects who received the investigational product or chemotherapy at 
least once. 
 
10.4.1.4 PDL1-PS 
The PDL1-PS will consist of all subjects included in the ITT and who are PD-L1+ (≥ 1%). 
 
10.4.1.5 Anti-Drug Antibody Set 
The ADA will consist of all subjects who meet the following item in the SAF population. 
1. Subjects have had their anti-ONO-4538 antibodies (samples with potential positive 
measurement result at screening assay without obtaining result by confirmatory assay are not 
included) measured at at least 1 time point after administration of ONO-4538 and before 
administration of ONO-4538. 
 
10.4.2 
Criteria for Handling of Subjects 
Details of handling of subjects are shown below. 
 
10.4.2.1 Non-randomized Subjects 
Subjects who were not randomized through the IWRS after enrollment are defined as non-
randomized subjects. 
 
10.4.2.2 Untreated Subjects 
Subjects who have not received any of the investigational products or chemotherapy are defined 
as untreated subjects. 
 
10.4.2.3 Incomplete Anti-Drug Antibody Subjects 
Subjects with missing anti-ONO-4538 antibody measurements before administration of ONO-
4538 or missing all anti-ONO-4538 antibody measurements after administration of ONO-4538 
are defined as incomplete anti-drug antibody subjects. 
 
For unexpected, problematic cases other than above, the Sponsor will examine such cases and 
decide how cases will be handled in the analysis by the data lock point. 
 


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10.4.3 
Criteria for Handling of Time Points 
When analysis by time point is performed, if the test day specified in the protocol is different 
from the actual test day, only data measured within the time window described in Table 6-1 
should be adopted. 
 
10.5 
Analytical Methods 
10.5.1 
Examinations on Reliability of Study 
10.5.1.1 Presence of Subjects Who Are Excluded 
Frequency of subjects who are included or excluded in each analysis set and frequency by reason 
for exclusion will be summarized by treatment group. 
 
10.5.1.2 Discontinuations from Study 
Discontinuations from the study will be summarized by treatment group. 
 
10.5.2 
Administration of Investigational Product and Chemotherapy 
Administration of the investigational product and chemotherapy will be summarized by 
treatment group. 
 
10.5.3 
Distribution of Background Factors 
Frequency distribution and summary statistics will be calculated by treatment group for the 
following items to ascertain comparability between treatment groups. 
 
10.5.3.1 Demographic Variables 
Categorical data including gender, age, race, and ethnicity will be summarized using frequency 
distribution by treatment group. In addition, continuous variables including height, body weight, 
and BMI will be summarized using summary statistics (mean, standard deviation, median, 
minimum, and maximum) by treatment group. 
 
10.5.3.2 Patient Characteristics 
Past history, complications, smoking history, ECOG Performance Status, period from the date of 
diagnosis of primary disease through randomization, staging (Stage) and TNM classification, 
histology of non-squamous non-small cell lung cancer, primary site and metastatic site of non-
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cell lung cancer), and previous treatment for cancers (including history of surgery, radiotherapy, 
or medical treatment) will be summarized by treatment group. 
 
10.5.3.3 Baseline Values during Observation Period 
The sum of tumor diameters of target lesions will be summarized using summary statistics 
(mean, standard deviation, median, minimum, and maximum) by treatment group. 
 
10.5.4 
Efficacy Endpoints 
10.5.4.1 Objectives 
To verify the superiority, with PFS (as assessed by the IRRC) as the primary endpoint, of ONO-
4538 in combination with chemotherapy over placebo in combination with chemotherapy in 
chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung 
cancer unsuitable for radical radiation. 
 
10.5.4.2 Hypothesis 
Efficacy in the ONO-4538 group is superior to that in the placebo group in terms of PFS (as 
assessed by the IRRC). 
 
10.5.4.3 Analysis Item and Handling of Data 
1. Analysis item 
PFS (as assessed by the IRRC) 
2. Handling of data 
PFS (as assessed by the IRRC) will be calculated using the following formula: 
PFS (days) = “date when overall response is assessed as PD or date of death (for any 
reason), whichever comes first” – “date of randomization” + 1 
If the overall response is not assessed as PD and the subject is alive, the date on which the 
final evaluable radiographic tumor assessment is performed will be defined as the date of 
censoring. If no evaluable radiographic tumor assessments have been performed and the 
subject is alive, the date of randomization will be the date of censoring. If the subject 
received subsequent anticancer therapy for non-squamous non-small cell lung cancer 
before the overall response is assessed as PD or the subject dies, the day on which the final 
evaluable radiographic tumor assessment is performed before subsequent anticancer 
therapy for non-squamous non-small cell lung cancer will be the date of censoring. 
Details on the assessment of events or censoring will be provided in the statistical analysis 
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10.5.4.4 Analytical Methods 
10.5.4.4.1 
Analytical Methods (Interim Analysis) 
1) 
Analysis for primary endpoint 
PFS (as assessed by the IRRC) will be analyzed as follows using the ITT as the analysis set. A 
significance level α for analysis will be adjusted using the Lan-DeMets α spending function 
(O’Brien-Fleming) based on the actual number of events. 
 
(1) 
Primary analysis 
Comparison between treatment groups will be performed via the log-rank test stratified by 
randomization factors (PD-L1 expression level, ECOG Performance Status, and gender). 
 
(2) 
Secondary analysis 
The hazard ratio of the ONO-4538 group to the placebo group and its two-sided 100* (1-α)% 
confidence interval will be calculated using the Cox proportional hazard model stratified by 
randomization factors used for the primary analysis. 
The Kaplan-Meier curves by treatment group will be displayed. In addition, the medians and 
their two-sided 100* (1-α)% confidence intervals by treatment group will be calculated using the 
Kaplan-Meier method. To determine the confidence interval using the Kaplan-Meier method, the 
Brookmeyer and Crowley method utilizing double log transformation will be used. 
 
10.5.4.4.2 
Analytical Methods (When Study Is Continued Based on Results of Interim 
Analysis) 
1) 
Analysis for primary endpoint 
PFS (as assessed by the IRRC) will be analyzed as follows using the ITT and PDL1-PS as the 
analysis sets. A significance level α for analysis will be adjusted using the Lan-DeMets α 
spending function (O’Brien-Fleming) and Hochberg’s method based on the actual number of 
events. 
 
(1) 
Primary analysis 
Analysis will be performed by adjusting multiplicity using the Hochberg’s method according to 
the following procedures 1 to 4. 
1. For PFS (as assessed by the IRRC), comparison between treatment groups will be performed 
in the ITT via the log-rank test stratified by randomization factors (PD-L1 expression level, 
EOCG Performance Status, and gender). 


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2. For PFS (as assessed by the IRRC), comparison between treatment groups will be performed 
in the PDL1-PS via the log-rank test stratified by randomization factors (PD-L1 expression 
level, EOCG Performance Status, and gender). 
3. The p value in the ITT and PDL1-PS obtained from the stratified log-rank test in 1. and 2. 
above refer to p(1) and p(2) in ascending order, then its corresponding null hypotheses refer to 
H0(1) and H0(2), respectively. 
 
Example: If the p value in the PDL1-PS < the p value in the ITT: 
H0(1): In the PDL1-PS, the survival function for the ONO-4538 group is equal to that for the placebo 
group. 
H0(2): In the ITT, the survival function for the ONO-4538 group is equal to that for the placebo 
group. 
 
4. Superiority of the ONO-4538 group to the placebo group will be verified using p(1) and p(2). 
a. If p(2) < α, both null hypotheses H0(1) and H0(2) will be rejected. 
b.  If p(2) ≥ α and p(1) < α/2, only null hypothesis H0(1) will be rejected. 
 
(2) 
Secondary analysis 
As a result of primary analysis of the primary endpoint, if the superiority of the ONO-4538 
group over the placebo group is verified in the ITT, the ITT will be used as the analysis set. On 
the other hand, if the superiority of the ONO-4538 group over the placebo group is not verified 
in the ITT, the ITT and PDL1-PS will be used as the analysis sets. 
An analysis same as 10.5.4.4.11)(2) Secondary analysis will be performed. 
 
10.5.5 
Efficacy Secondary Endpoints 
10.5.5.1 Objective 
To evaluate the efficacy of ONO-4538 in combination with other therapies for non-squamous 
non-small cell lung cancer from a range of viewpoints 
 
10.5.5.2 Analysis Items and Handling of Data 
10.5.5.2.1 
Analysis Items 
1. OS 
2. PFS (as assessed by the study site’s investigator) 
3. Objective response rate (ORR [as assessed by the IRRC and study site’s investigator]) 
4. Disease control rate (DCR [as assessed by the IRRC and study site’s investigator]) 
5. Duration of response (DOR [as assessed by the IRRC]) 
6. Time to response (TTR [as assessed by the IRRC]) 


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7. Best overall response (BOR [as assessed by the IRRC and study site’s investigator]) 
8. Maximum percentage of change in the sum of diameters of target lesions (as assessed by the 
IRRC) 
 
10.5.5.2.2 
Handling of Data 
The overall response and the best overall response will be determined based on radiographic 
tumor assessments per RECIST 1.1 criteria, and clinical deterioration will not be included in the 
results of radiographic tumor assessments. Evaluable diagnostic images should be those with the 
assessment of overall response other than NE. 
Handling of each endpoint is shown below. 
 
1. OS will be calculated using the following formula: 
OS (days) = “date of death (for any reason)” – “date of randomization” + 1 
If the subject cannot be followed up or the subject is alive at the date of data cutoff, the 
date on which survival was last confirmed will be the date of censoring. 
2. PFS will be calculated according to 10.5.4.3 Analysis Item and Handling of Data. 
3. ORR represents the proportion of subjects whose best overall response was assessed as CR 
or PR. 
4. DCR represents the proportion of subjects whose best overall response was assessed as CR, 
PR, or SD. 
5. DOR will be calculated using the following formula: 
DOR (days) = “date on which overall response was first assessed as PD or date of death 
(for any reason) after confirmed response, whichever comes first” – “date on which 
response was first assessed as confirmed CR or PR” + 1 
Subjects whose response was assessed as confirmed CR or PR throughout the study will be 
evaluated. 
6. TTR will be calculated using the following formula: 
TTR (days) = “date on which response was first assessed as confirmed CR or PR” – “date 
of randomization” + 1 
TTR data in subjects without response will be censored at the maximum time to response + 
1 day of subjects with response in each treatment group. 
7. Maximum percentage of change in the sum of diameters of target lesions 
Maximum percentage of change in the sum of diameters of target lesions assessed 
according to the RECIST 1.1 criteria will be calculated in subjects with target lesions using 
the following formula. However, the sum of tumor diameters of target lesions, after overall 
response was assessed as PD, after subsequent anticancer therapy was performed for non-
squamous non-small cell lung cancer, or after investigations on subsequent anticancer 
therapy were completed, will not be used for calculation of the maximum percentage of 
change. 


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Maximum percentage of change in the sum of tumor diameters of target lesions (%) 
= ൬
“Minimum sum of tumor diameters of target lesions after administration”
“Sum of tumor diameters of target lesions before administration of the investigational product” –  1൰
×  100 
For PFS and DOR, details of the assessment of events or censoring will be provided in the 
statistical analysis plan. 
 
10.5.5.3 Analytical Methods 
In the case of early efficacy stop based on the results of the interim analysis, the ITT will be used 
as the analysis set. In addition, if the study is continued based on the results of the interim 
analysis and the superiority of the ONO-4538 group over the placebo group is verified in the ITT 
at the final analysis, the ITT will be used as the analysis set. On the other hand, if the superiority 
of the ONO-4538 group over the placebo group is not verified in the ITT, the ITT and PDL1-PS 
will be used as the analysis sets. 
 
1. For analysis items 1 and 2, comparison between treatment groups will be performed via the 
log-rank test stratified by randomization factors. In addition, the hazard ratio of the ONO-
4538 group to the placebo group and its two-sided 95% confidence interval will be calculated 
using the Cox proportional hazard model stratified by randomization factors. 
2. For analysis items 1, 2, 5, and 6, the Kaplan-Meier curves by treatment group will be 
displayed. In addition, the medians and the two-sided 95% confidence intervals by treatment 
group will be calculated using the Kaplan-Meier method. To determine the confidence 
interval using the Kaplan-Meier method, the Brookmeyer and Crowley method utilizing 
double log transformation will be used. 
3. For analysis items 3 and 4, comparison between treatment groups will be performed via the 
Cochran-Mantel-Haenszel test stratified by randomization factors. In addition, the Cochran-
Mantel-Haenszel method will be used to calculate the odds ratio of the ONO-4538 group to 
the placebo group adjusted by the same stratification factors and its two-sided 95% 
confidence interval as well as differences in the proportion and its two-sided 95% confidence 
interval. 
4. For analysis items 3 and 4, the proportion by treatment group and its two-sided 95% 
confidence interval (Clopper-Pearson method) will be calculated. 
5. For an analysis item 7, the proportions of CR, PR, SD, PD, and NE by treatment group will 
be calculated, and their two-sided 95% confidence intervals (Clopper-Pearson method) for 
the proportions of CR, PR, and SD will be calculated. 
6. For an analysis item 8, a waterfall plots by treatment group will be created. 
 
10.5.6 
Examination of Interactions 
Interactions between treatment groups and background factors will be examined using the Cox 
proportional hazard model stratified by randomization factors for the primary endpoint. The 


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background factors used for examining the interactions will be presented in the statistical 
analysis plan. 
 
10.5.7 
Adjusted Analysis 
If it is found that some of the background factors show imbalance between the treatment groups 
or some of the background factors are affecting the assessment, using such factors as adjusted 
factors, the Cox proportional hazard model stratified by randomization factors will be used to 
adjust the analysis for the primary endpoint. Adjusted factors used for the adjusted analysis will 
be described in the statistical analysis plan. 
 
10.5.8 
Safety Analysis 
10.5.8.1 Objective 
To evaluate the safety of ONO-4538 in combination with other therapies from a range of 
viewpoints 
 
10.5.8.2 Analysis Items 
1. Adverse events 
2. Laboratory tests 
3. Vital signs 
4. Chest X-ray 
5. 12-lead ECG 
6. ECOG Performance Status 
 
10.5.8.3 Analytical Methods 
1. The number of subjects with adverse events and adverse drug reactions will be summarized 
by treatment group. 
2. Adverse events and drug-related adverse events in each treatment group will be summarized 
by SOC, PT, and grade. 
3. A shift table of the worst grade after administration compared to the baseline grade will be 
created for test parameters the grades of which are defined in the CTCAE, version 4.0 by 
treatment group. 
4. The number of subjects with abnormal hepatic function or abnormal thyroid function will be 
summarized by treatment group. 
 
10.5.9 
Blinded Review 
After data collection, distribution of background factors will be preliminarily examined using 
blinded data before data lock to confirm appropriateness of the planned analytical methods. 


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10.5.10 Other Items 
1. Sub-group analysis will be performed for efficacy and safety endpoints. 
2. Patient reported outcome will be analyzed. 
3. Anti-ONO-4538 antibody will be analyzed. 
In addition, other items associated with efficacy, safety, and biomarkers will be analyzed in an 
exploratory manner as needed. Pharmacokinetic (PK) analysis and 
pharmacokinetic/pharmacodynamic (PK/PD) analysis may be performed as needed. If 
performed, a report will be separately prepared. 
 
11 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
11.1 
Good Clinical Practice 
This study will be conducted in accordance with ethical principles underlying Good Clinical 
Practice (GCP), as defined by International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH). 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
as well as the subject informed consent form will receive the approval/favorable opinion of the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) prior to initiation of the 
study. 
All potential serious breaches must be reported to the Sponsor immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety, or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
Personnel at a study site involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
 
11.2 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before study initiation, the investigator must have the documented and dated approval/favorable 
opinion from the IRB/IEC for the protocol, informed consent form, subject recruitment materials 
and methods (eg, advertisements), and any other written information to be provided to subjects. 
The investigator or Sponsor should also provide the IRB/IEC with a copy of the Investigator’s 
Brochure or product labeling information to be provided to subjects and any updates. 
The investigator or Sponsor (or person designated by the Sponsor) should provide the IRB/IEC 
with reports, updates and other information (eg, expedited safety reports, amendments, and 
administrative letters) according to the regulatory requirements or study site’s procedures. 


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11.3 
Protection of Subject’s Privacy 
Protection of subject’s privacy should be fully considered. Subject Identification Codes will be 
used in place of subjects’ names to distinguish individuals on the eCRFs and in other data. In 
addition, the prepared eCRF will be used only for study purposes. Moreover, information 
obtained by the Sponsor should never be leaked to a third party. 
 
12 
SUBJECT INFORMED CONSENT 
12.1 
Informed Consent 
The investigator must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which subjects volunteer to 
participate. 
In situations where consent cannot be given by the subjects themselves, their legally acceptable 
representatives (according to local guidelines) should be clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which the subject 
volunteers to participate. 
The Sponsor (or person designated by the Sponsor) will provide the investigator with an 
appropriate (ie, global or local) sample of the informed consent form, which will include all 
elements required by ICH-GCP and applicable regulatory requirements. The sample informed 
consent form will comply with the ethical principles that have their origin in the Declaration of 
Helsinki. 
The investigator must: 
1. Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language must 
be non-technical and easy to understand. 
2. Allow time necessary for the subject or subject’s legally acceptable representative to inquire 
about the details of the study. 
3. Obtain an informed consent form signed and personally dated by the subject or subject’s 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4. Obtain the IRB/IEC’s documented approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the beginning 
of the study, and after any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject. 
6. Revise the informed consent form whenever important new information becomes available 
that is relevant to the subject’s consent. The investigator, or a person designated by the 


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investigator, should fully inform the subject or the subject’s legally acceptable representative 
or legal guardian, of all pertinent aspects of the study and of any new information relevant to 
the subject’s willingness to continue participation in the study. This communication should 
be documented. 
 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements and the subjects’ signed 
informed consent form. 
The informed consent form must also include a statement that the Sponsor and regulatory 
authorities have direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over the interests of science and society. 
 
12.2 
Withdrawal of Consent 
Subjects who request to discontinue the investigational product will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to this 
is when a subject specifically withdraws consent for any further contact with him/her or persons 
previously authorized by the subject to provide this information. Subjects should notify the 
investigator of their decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator as to whether the withdrawal is from further study treatments only or from the 
follow-up after completion of study procedures and/or treatments, and entered on the appropriate 
CRF page. In the event that vital status (whether the subject is alive or dead) is being measured, 
publicly available information will be used to determine vital status only as appropriately 
directed in accordance with the local law. 
 
13 
STOPPING RULES OR DISCONTINUATION CRITERIA FOR 
INDIVIDUAL SUBJECTS 
If any of the following applies, the subject will be immediately discontinued from the treatment 
period or follow-up period, the investigator will provide the subject with the appropriate 
treatment and also observe/measure clinical symptoms and laboratory tests at discontinuation if 
possible. The date of discontinuation, reason for discontinuation, and treatment and clinical 
course after discontinuation will be entered on the eCRF and the Sponsor (or person designated 
by the Sponsor) will be promptly contacted. If subjects did not visit on the scheduled day and 
cannot receive the investigational product and/or chemotherapy, the investigator will follow up 
the reason and the course by telephone or letter, confirm the subject’s status, and enter the details 
on the eCRF. 
1. The subject requests that the study be discontinued. 
2. It is revealed that inclusion criteria are not met. 


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3. It is revealed that exclusion criteria are met. 
4. The investigator considers that it is difficult to continue the study because of adverse events, 
regardless of whether a causal relationship with the investigational product and 
chemotherapy exists. 
5. The investigator considers that it is not appropriate to continue the study because of disease 
progression. 
6. The subject did not visit on the scheduled day and cannot continue the study. 
7. The investigator considers that it is not appropriate to continue the study for any other reason. 
 
14 
STUDY MANAGEMENT 
14.1 
Compliance with the Protocol and Protocol Revisions 
The study will be conducted as described in this approved protocol. The investigator should not 
deviate from or change the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of any amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: 
∙ IRB/IEC for review and approval/favorable opinion 
∙ Sponsor 
∙ Regulatory Authority(ies), if required by local regulations 
 
Documentation of approval signed by the chairperson or designee of the IRB/IEC must be sent to 
the Sponsor. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the informed consent form must be revised and submitted to the IRB/IEC for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects currently enrolled in the study if subjects are affected by the amendment; and (3) the 
new form must be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, the investigator and study staff must inform 
their IRB/IEC. 
 


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ENTRY OF DATA ON ELECTRONIC CASE REPORT FORM 
(ECRF) 
15.1 
eCRF 
The investigator and study staff will promptly enter data on the eCRF after completion of each 
observation of the subject according to the provisions of the protocol for all subjects who have 
provided written informed consent to participate in the study. The study staff are permitted only 
to transcribe data from the source document. In addition, data that are derived from source 
documents and reported on the eCRF must be consistent with the source documents or the 
discrepancies must be explained by the investigator. The investigator will confirm that all entries 
on the eCRF (including audit trail and responses to queries) are accurate and complete and verify 
the entries by electronically signing the eCRF. An electronic signature has the same legal 
binding force as a hand-written signature, and electronically signed content cannot be repudiated 
later. Entry/change or amendment of the eCRF and procedures for electronic signature will 
follow the written operating procedures separately specified. 
In addition, the investigator and study staff must meet the Sponsor’s training requirements and 
access to the Sponsor’s EDC system using the unique user account provided by the Sponsor. 
User accounts are not to be shared or reassigned to other individuals. 
 
16 
MONITORING 
Representatives of the Sponsor must be allowed to visit all study site locations periodically to 
assess the data quality and study integrity. On site, representatives of the Sponsor will review 
study records and directly compare them with source documents, discuss the conduct of the 
study with the investigator, and verify that the facilities remain acceptable. 
In addition, the study may be evaluated by the Sponsor’s internal auditors and regulatory 
inspectors who must be allowed access to eCRFs, source documents, other study files, and study 
facilities. The Sponsor’s audit reports should be kept confidential. 
The investigator must notify the Sponsor promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to the Sponsor. 
 
17 
PROCEDURES FOR CONFIRMING COMPLIANCE WITH 
ADMINISTRATION TO SUBJECTS AND OTHER AGREEMENTS 
The investigator will confirm compliance with administration of the investigational product and 
appropriate on-site collection of blood. 
 


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ARCHIVING OF ESSENTIAL DOCUMENTS 
18.1 
Archiving of Records 
Essential documents to be archived should be retained until 2 years have elapsed from the date of 
approval of a marketing application in ICH regions and clearance of marketing application status 
or planned marketing application status in ICH regions or after 2 years have elapsed from the 
date on which it was decided to terminate development of the investigational product. In 
addition, the expiration date of essential documents is the day defined by the local regulatory 
authority or the day agreed to by the Sponsor, whichever comes later. These essential documents 
should not be discarded or moved to another storage place without prior notification in writing to 
the Sponsor. If storage of these essential documents is not required, this should be notified to the 
investigator or the study site. 
 
19 
PUBLICATION OF RESULTS 
Results of the study conducted in accordance with this protocol are the property of the Sponsor. 
Any publications of the study results require prior approval by the Sponsor. Issues related to 
publication will be resolved by discussions between the Sponsor and coordinating investigator. 
 


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20 
REFERENCES 
1. Lindsey A, Freddie Bray, Rebecca L.Siegel, Jacques Ferlay, Joannie Lortet-Tieulent, 
Ahmedin Jemal, et al. Global Cancer Statistics, 2012. CA CANCER CLIN. 2015;65:87-
108. 
2. American Cancer Society [homepage on the Internet]. [update November 22, 2016]. 
What is non‒small cell lung cancer?. Available from: 
http://www.cancer.org/cancer/lungcancer-non-small cell/detailedguide/non-small-cell-
lung-cancer-what-is-non-small-cell-lung-cancer 
3. “NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): NSCLC,” 
Version v4.2016. 
4. Scagliotti GV, Parikh P, von Pawel J, 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;28:3543-50. 
5. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowtali A, et al. Paclitaxel-
carboplatin alone or with bevacizumab for non-small-cell lung cancer. NEJM. 
2006;355(24):2542-50. 
6. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD 1 immunoinhibitory receptor 
by a novel B7 family member leads to negative regulation of lymphocyte activation. J 
Exp Med 2000;192(7):1027-34. 
7. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and 
inhibits T cell activation. Nat Immunol 2001;2(3):261-8. 
8. Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ 
and CD8+ T cells and is overcome by IL-2. Eur J Immunol 2002;32(3):634-43. 
9. Julie Brahmer, Karen L. Reckamp, Paul Baas, Lucio Crinò, Wilfried E.E. Eberhardt, 
Elena Poddubskaya, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell 
Non–Small-Cell Lung Cancer. NEJM. 2015;373(3):123-35. 
10. H. Borghaei, L. Paz-Ares, L. Horn, D.R. Spigel, M. Steins, N.E. Ready, et al. Nivolumab 
versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. NEJM. 
2015;373(17):1627-39. 
11. M. Socinski, B. Creelan, L. Horn, M. Reck, L. Paz-Ares, M. Steins, et al. CheckMate 
026: A phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet 
chemotherapy (PT-DC) as first-line therapy for stage iv/ recurrent programmed death 
ligand 1 (PD-L1)-positive NSCLC. Annals of Oncology 27 (Supplement 6): The 
European Society for Medical Oncology 2016; abstr LBA7_PR. 
12. Zhu Y, Liu N, Xiong SD, Zheng YJ, Chu YW. CD4+Foxp3+ regulatory T-cell 
impairment by paclitaxel is independent of toll-like receptor 4. Scand J Immunol. 
2011;73(4):301-8. 
13. Shurin GV, Tourkova IL, Kaneno R, Shurin MR. Chemotherapeutic agents in 
noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-
dependent mechanism. J Immunol. 2009;183(1):137-44. 


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14. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer 
chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting 
cells. Immunity. 2013;38(4):729-41. 
15. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and 
targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39(1):74-
88. 
16. Martino EC, Misso G, Pastina P, Costantini S, Vanni F, Gandolfo C, et al. Immune-
modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients. Cell 
Death Discov. 2016:eCollection 2016. 
17. Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, et al. The contribution of 
vascular endothelial growth factor to the induction of regulatory T-cells in malignant 
effusions. Anticancer Res. 2009;29(3):881-8. 
18. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. 
Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the 
effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171-80. 
19. Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, et al. The effect of anti-
VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer 
Immunol Immunother. 2008;57(8):1115-24. 
20. Kanda S, Goto K, Shiraishi H, Kubo E, Tanaka A, Utsumi H, et al. Safety and efficacy of 
nivolumab and standard chemotherapy drug combination in patients with advanced non-
small-cell lung cancer: a four arms phase Ib study. Ann Oncol. 2016;27(12):2242-2250. 
21. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. 
Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line 
Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(25):2969-
79. 
22. Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab 
Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin 
Oncol. 2016;34(25). 
23. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab 
versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J 
Med. 2015;373(17):1627-39. 
24. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity 
and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with 
advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, 
single-arm trial. Lancet Oncol. 2015;16(3):257-65. 
25. Niho S, Kunitoh H, Nokihara H, Horai T, Ichinose Y, Hida T. Randomized phase II study 
of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with 
advanced non-squamous non-small-cell lung cancer. Lung Cancer. 2012;76(3):362-7. 


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APPENDIX 1 
Criteria for Antitumor Activity Used in the Study 
 
In this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 
criterianote 1). 
 
Note 1): Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009 Jan;45(2):228-47. 
 
A. Imaging Evaluation according to the RECIST 1.1 Criteria 
A-1 Examinations Used for Response Assessment 
∙ Chest, abdominal, and pelvic CT (slice thickness of 5 mm is recommended) (or MRI as 
needed) 
∙ Tumor marker 
 
A-2 Baseline Evaluations 
At baseline assessment, tumor lesions and lymph nodes will be categorized as measurable or 
non-measurable according to the criteria in A-3 and A-4. 
Tumor diameter will be measured using images in the axial plane on CT scan rather than 3-
dimensional images in the sagittal or coronal plane. 
Baseline evaluation will be performed using current images taken within 28 days prior to 
randomization into the study. After randomization, if imaging is repeated before the start of 
administration of the investigational product, the newest images should be used. 
 
A-3 Definition of Measurable Lesions 
Non-lymph node lesions (tumor lesions) 
Measurable lesions are defined as those where a maximal diameter (longest diameter) in the 
plane of measurement is double or more the slice thickness and 10 mm or more by CT or MRI. 
 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis (CT scan slice thickness recommended to be no greater than 5 mm). 
 
A-4 Definition of Non-measurable Lesions 
All lesions other than measurable lesions. However, the following lesions, irrespective of the 
tests and size, will be considered non-measurable: 


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∙ Bone lesions (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 [blastic bone lesions are non-measurable]) 
∙ Cystic lesions (“Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions if the lesions meet the definition of measurability. However, if non-cystic 
lesions are present in the same subject, these are preferentially selected as target lesions.) 
∙ Lesions previously treated with local therapies including radiotherapy (except lesions that 
have become larger confirmed by radiographic tumor assessments after radiotherapy) 
∙ 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 
 
A-5 Target Lesions 
Measurable lesions up to a maximum of five lesions in total (and a maximum of two lesions per 
organ) in descending order of diameter (longest diameter for non-lymph node lesions and short 
axis for lymph node lesions) should be identified as target lesions. Target lesions should be 
representative of all involved organs. In addition, the lesions should be those that lend 
themselves to reproducible repeated measurements (lesions with a longest diameter but are 
difficult to measure should be avoided). 
The sum of diameters is defined as the sum of diameters of all target lesions (longest diameter 
for non-lymph node lesions and short axis for lymph node lesions). 
 
A-6 Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions. It is possible to record multiple non-target lesions involving the same organ as 
a single item (eg, multiple enlarged pelvic lymph nodes or multiple liver metastases). 
 
A-7 Response Criteria 
Evaluation of Target Lesions 
CR: Complete Response 
Disappearance of all (non-lymph node) target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in the short axis to < 10 mm. 
PR: Partial Response 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 


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PD: Progressive Disease 
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. 
SD: Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters on study. 
NE: Not Evaluable 
When no imaging/measurement is done at all at a particular time point for any reason or the 
lesion cannot be considered as either CR, PR, PD, or SD. 
 
Percentage reduction in the sum of diameters 
= Baseline sum diameter –  Sum diameter at evaluation
Baseline sum diameter
×  100% 
 
Percentage increase in the sum of diameters 
= Sum diameters at evaluation –  Smallest sum diameter
Smallest sum diameter
×  100% 
 
* All lesions recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, <5 mm). However, when target lesions are 
“too small to measure,” and if the lesion has likely disappeared, the measurement should be 
recorded as 0 mm, irrespective of CT slice thickness. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
* If the shrinkage rate qualifies for PR and the increase rate qualifies for PD at the same time, 
PD should be recorded. 
* When lesions fragment, the individual lesion diameters should be added together to calculate 
the target lesion sum. 
* When lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the coalesced lesion. 
 


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Evaluation of Non-target Lesions 
CR: Complete Response 
Disappearance of all (non-lymph node) non-target lesions and normalization of tumor marker 
level (ie, ≤ upper normal limit of the study site). All lymph nodes must be non-pathological in 
size (< 10mm short axis). 
Non-CR/Non-PD 
Persistence of one or more (non-lymph node) non-target lesion(s) and/or presence of one or 
more (lymph node) non-target lesion(s) with the short axis of ≥ 10 mm and/or maintenance of 
tumor marker level above the normal limits of the study site. 
PD: Progressive Disease 
“Unequivocal progression” of existing non-target lesions (including recurrence) 
To achieve “unequivocal progression”, there must be an overall level of substantial worsening 
in non-target disease such that the overall tumor burden has increased sufficiently to merit 
discontinuation of study treatment. In presence of SD or PR in target lesions, “unequivocal 
progression” will be selected if there is substantial worsening in non-target lesions beyond the 
extent of reduction in target lesion burden. If not, “Non-CR/Non-PD” should be selected. 
When the patient has no target lesions, “unequivocal progression” will be selected if, as a 
rough guide, the increase in overall non-target lesion burden is apparently greater than a 20% 
increase in diameter or a 73% increase in volume. 
NE: Not Evaluable 
When no imaging/measurement is done at all at a particular time point for any reason or 
assessment is impossible as either CR, Non-CR/Non-PD, or PD. 
 
New Lesions 
A lesion, which did not exist at baseline, found after start of administration of the investigational 
product denotes the appearance of a “new lesion.” 
However, a “new lesion” should not be the result of differences in the scanning technique from 
that used at baseline, or changes on the image due to a change in imaging modality or findings 
thought to represent something other than a tumor. A lesion newly identified in an anatomical 
location that was not considered essential to scan at baseline qualifies as a new lesion. 
If a lesion disappears and reappears at a subsequent time point, it should continue to be 
measured. However, the subject’s response at the point in time when the lesion reappears will 
depend upon the status of his/her other lesions. If the subject’s tumor had reached CR status and 
the lesion reappeared, then the subject would be considered PD at the time of reappearance. In 
contrast, if the tumor status was PR or SD and one lesion that had disappeared then reappears, its 
maximal diameter should be added to the sum of the remaining lesions for a calculated response; 
in other words, the reappearance of an apparently “disappeared” single lesion amongst many that 
remain is not in itself enough to qualify for assignation of PD: that requires the sum of all lesions 
to meet the PD criteria. This is based upon the realization that most lesions do not actually 


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“disappear” but are not visualized because the lesions are beyond the resolving power of the 
imaging modality employed. 
If a lesion could be new but cannot be confirmed, it is not regarded as a new lesion, and imaging 
is repeated after a clinically appropriate interval. If repeated imaging confirms that it is a new 
lesion, the new lesion is considered to have appeared on the date when imaging confirmed it as a 
new lesion. 
 
A-8 Overall Response 
Overall response is assessed by a combination of effect on target lesions, effect on non-target 
lesions, and appearance of new lesions according to the following Table A. Overall response 
when no non-target lesions exist at baseline is assessed by target lesion assessment and 
appearance of new lesions, and that when no target lesions exist at baseline is assessed by non-
target lesion evaluation and appearance of new lesions according to Table B. 
 
Table A: Criteria for overall response (with target lesions) 
Assessment of target 
lesions 
Assessment of non-
target lesions 
Appearance of new 
lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 


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Table B: Criteria for overall response (without target lesions) 
Assessment of non-target 
lesions 
Appearance of new lesion 
Overall response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
A-9 Best Overall Response 
The best overall response is determined based on the overall response determined until the end of 
the study. However, CR and PR should be confirmed and determined according to the criteria in 
Table C. In addition, overall response after the start of subsequent anticancer therapy for non-
squamous non-small cell lung cancer or after the end of the follow-up investigation and overall 
response after determination of PD will not be used to evaluate the best overall response. In 
order for the best overall response to be assessed as SD in this study, the overall response as 
assessed on or after Day 43 including at least one SD or better rather than PD should be 
obtained. Also, to determine the best overall response to be CR, the assessment including at least 
2 successive determinations of CR at no less than 4-week (28 days) intervals should be obtained, 
and to classify best overall response as PR, the assessment including at least 2 successive 
determinations of PR or better (CRs or PRs) at no less than 4-week (28 days) intervals should be 
obtained. In addition, if a subject is considered as having no target lesion as a result of imaging 
assessment before the start of administration, assessment of the best overall response is “NE.” 
 


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Table C: Criteria for best overall response 
Overall response First 
time point 
Overall response 
Subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR# 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
NE 
NE 
NE 
#: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
 


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APPENDIX 2 
Performance Status Scale/Scores ECOG 
 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
 


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APPENDIX 3 
List of Autoimmune Diseases (reference) 
Subjects who have complications of any of the following autoimmune diseases or previously had 
any chronic or recurrent autoimmune disease should not be enrolled in this study, as a rule. For a 
subject with any other autoimmune disease, the investigator should carefully consider the 
eligibility of the patient and, if there are safety concerns, should not enroll the subject in this 
study. 
· 
Acute disseminated 
encephalomyelitis 
· 
IgA nephropathy 
· 
Addison’s disease 
· 
Inflammatory bowel disease 
· 
Alopecia universalis 
· 
Interstitial cystitis 
· 
Ankylosing spondylitis 
· 
Lambert–Eaton myasthenic 
syndrome 
· 
Antiphospholipid syndrome 
· 
Lupus erythematosus 
· 
Aplastic anemia 
· 
Lyme disease (chronic) 
· 
Asthma 
· 
Meniere’s syndrome 
· 
Autoimmune hemolytic anemia 
· 
Mooren ulcer 
· 
Autoimmune hepatitis 
· 
Morphea 
· 
Autoimmune hypophysitis 
· 
Multiple sclerosis 
· 
Autoimmune hypoparathyroidism 
· 
Myasthenia gravis 
· 
Autoimmune myocarditis 
· 
Neuromyotonia 
· 
Autoimmune oophoritis 
· 
Opsoclonus myoclonus syndrome 
· 
Autoimmune orchitis 
· 
Optic neuritis 
· 
Autoimmune thrombocytopenic 
purpura 
· 
Ord’s thyroiditis 
· 
Behcet’s disease 
· 
Pemphigus 
· 
Bullous pemphigoid 
· 
Pernicious anemia 
· 
Celiac disease 
· 
Polyarteritis nodosa 
· 
Chronic fatigue syndrome 
· 
Polyarthritis 
· 
Chronic inflammatory 
demyelinating polyradiculopathy 
· 
Autoimmune polyglandular 
syndrome 
· 
Churg–Strauss syndrome 
· 
Primary biliary cirrhosis 
· 
Crohn’s disease (gastrointestinal 
ulceration) 
· 
Psoriasis 
· 
Dermatomyositis 
· 
Reiter’s syndrome 
· 
Type 1 diabetes mellitus 
· 
Rheumatoid arthritis 
· 
Dysautonomia 
· 
Sarcoidosis 
· 
Eczema 
· 
Scleroderma 
· 
Sjögren’s syndrome 
· 
Acquired epidermolysis bullosa 
· 
Stiff-man syndrome 
· 
Pemphigoid gestationis 
· 
Takayasu’s arteritis 
· 
Giant cell arteritis 
· 
Ulcerative colitis 
· 
Goodpasture’s syndrome 
· 
Graves’ disease 
· 
Vogt–Koyanagi–Harada syndrome 
· 
Guillain–Barre syndrome 
· 
Vulvodynia 
· 
Hashimoto’s disease 
· 
Wegener’s granulomatosis 
· 
Kawasaki’s disease 
 
 
 
 
 




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History of the clinical protocol (Protocol No.: ONO-4538-52) 
Version 1.0: Prepared on March 7, 2017 
Version 2.0: Prepared on July 6, 2017 
Version 3.0: Prepared on October 30, 2017 
Version 4.0: Prepared on June 29, 2018 
Version 5.0: Prepared on October 17, 2019 

SAP_001.pdf: 
 
 
 
 
1 
 
 
ONO-4538 PHASE III STUDY 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND 
TRIAL IN SUBJECTS WITH NON-SQUAMOUS NON-
SMALL CELL LUNG CANCER  
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
ONO PHARMACEUTICAL CO., LTD. 
 
 
 
Protocol No.: ONO-4538-52 
Version No.: 2.0 
Date of preparation: MAY 7, 2020 
 
 
 




 
 
 
 
3 
 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
25OCT2018 
 
Not Applicable – First Version 
2.0 
07MAY2020 
 
Descriptions for efficacy endpoint were 
modified and updated. 
Minor update for overall descriptions. 
 
 
 


 
 
 
 
4 
 
TABLE OF CONTENTS 
1 
DEFINITIONS OF STATISTICAL ANALYSIS PLAN .............................................8 
2 
SAMPLE SIZE .............................................................................................................9 
2.1 
Planned Sample Size ..................................................................................................9 
3 
DETERMINATION OF SUBJECTS INCLUDED IN ANALYSIS..........................11 
3.1 
Definitions of Analysis Sets .....................................................................................11 
3.2 
Criteria for Handling of Subjects .............................................................................12 
3.3 
Criteria for Handling of Time Points .......................................................................12 
4 
SIGNIFICANCE LEVEL TO BE USED ...................................................................13 
4.1 
Efficacy ....................................................................................................................13 
4.2 
Safety .......................................................................................................................13 
5 
GENERAL METHODS .............................................................................................14 
6 
RELIABILITY OF THE STUDY ..............................................................................15 
6.1 
Analysis Set ..............................................................................................................15 
6.2 
Analytical Items and Data Handling ........................................................................15 
6.3 
Analytical Methods ..................................................................................................16 
7 
EXTENT OF EXPOSURE AND ADMINISTRATION OF STUDY 
TREATMENT ............................................................................................................17 
7.1 
Analysis Set ..............................................................................................................17 
7.2 
Analytical Items and Data Handling ........................................................................17 
7.3 
Analytical Methods ..................................................................................................19 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................21 
8.1 
Analysis Set ..............................................................................................................21 
8.2 
Analytical Items and Data Handling ........................................................................21 
8.3 
Analytical Methods and Classification ....................................................................22 
9 
PRIMARY ENDPOINT .............................................................................................27 
9.1 
Analysis Sets ............................................................................................................27 
9.2 
Analytical Item and Data Handling .........................................................................27 
9.3 
Analytical Methods (when the study stopped for superiority based on the 
results of Interim Analysis) ......................................................................................29 
9.3.1 
Primary Analysis ...................................................................................................29 
9.3.2 
Sensitivity Analysis for Primary Analysis ............................................................30 
9.3.3 
Secondary Analysis ...............................................................................................30 


 
 
 
 
5 
 
9.4 
Analytical Methods (when the study continued based on the results of 
Interim Analysis) ......................................................................................................31 
9.4.1 
Primary Analysis ...................................................................................................31 
10 
EFFICACY SECONDARY ENDPOINT...................................................................33 
10.1 
Analysis Set ..............................................................................................................33 
10.2 
Analytical Items and Data Handling ........................................................................33 
10.3 
Analytical Methods ..................................................................................................38 
10.4 
Subgroup Analyses for the Efficacy Endpoints .......................................................38 
10.4.1 
Analysis Sets .........................................................................................................38 
10.4.2 
Analytical Item and Data Handling .......................................................................39 
10.4.3 
Analytical Methods ...............................................................................................41 
10.5 
Interaction Analysis .................................................................................................42 
10.6 
Adjusted Analysis ....................................................................................................42 
10.7 
Exploratory Analysis ................................................................................................42 
11 
ANALYSIS OF SAFETY ..........................................................................................45 
11.1 
Analysis Sets ............................................................................................................45 
11.2 
Analytical Items and Data Handling ........................................................................45 
11.3 
Analytical Methods ..................................................................................................48 
11.4 
Subgroup Analyses for the Safety Endpoints ..........................................................52 
12 
PATIENT REPORTED OUTCOMES .......................................................................53 
12.1 
Analysis Sets ............................................................................................................53 
12.2 
Analytical Items and Data Handling ........................................................................53 
12.3 
Analytical Methods ..................................................................................................55 
13 
ANTI-DRUG ANTIBODY ANALYSIS ...................................................................57 
13.1 
Analysis Sets ............................................................................................................57 
13.2 
Analytical Item and Data Handling .........................................................................57 
13.3 
Analytical Methods ..................................................................................................57 
14 
INTERIM STATISTICAL ANALYSIS.....................................................................58 
15 
BLINDED REVIEWS ................................................................................................59 
15.1 
Objectives .................................................................................................................59 
15.2 
Analysis Sets ............................................................................................................59 
15.3 
Analytical Items and Data Handling ........................................................................59 
15.4 
Analytical Methods ..................................................................................................59 


 
 
 
 
6 
 
16 
TECHNICAL MATTERS ..........................................................................................61 
16.1 
SAS Programming in Analyses ................................................................................61 
16.2 
Imputation of Missing Value ...................................................................................61 
16.2.1 
Imputing the Date of Death and Date of Severity CTCAE Grade5 (AE 
grade 5 start date) ..................................................................................................61 
16.2.2 
Imputing Other Date ..............................................................................................62 
17 
REFERENCE .............................................................................................................63 
18 
CHANGES IN THE STATISTICAL ANALYSIS PLAN FROM THE 
STUDY SPECIFIC PROTOCOL ...............................................................................64 
18.1 
Changes in the Statistical Analysis Plan from the Study Specific Protocol ............64 
18.2 
Changes in the Statistical Analysis Plan from the Statistical Analysis Plan 
version 1.0 ................................................................................................................64 
19 
APPENDIX.................................................................................................................67 
 


 
 
 
 
7 
 
LIST OF TABLES 
Table 7.2-1 Duration of Treatment, cumulative dose, relative dose intensity of ONO-
4538 ............................................................................................................................18 
Table 7.2-2 Duration of Treatment, cumulative dose, relative dose intensity of 
chemotherapies ...........................................................................................................18 
Table 8.3-1 Classification of analytical item .................................................................................23 
Table 9.2-1 Definition of event and censoring for the primary definition of PFS .........................28 
Table 10.2-1 Definition of event and censoring for the secondary definition of PFS ...................34 
Table 10.2-2 Definition of event and censoring in DOR ...............................................................36 
Table 10.4-1 Classification of analytical item ...............................................................................39 
Table 12.2-1 Time windows for QOL evaluations ........................................................................54 


 
 
 
 
8 
 
1 DEFINITIONS OF STATISTICAL ANALYSIS PLAN 
This statistical analysis plan (SAP) refers to the definition of terminologies, valid analytical 
methods and the detailed contents of statistical analysis for ONO-4538 Phase III study (protocol 
number: ONO-4538-52).  
The SAP will be developed in accordance with the protocol, Core SAP (2017/05/26, Ver.1.0), 
and Core ADA-SAP (2017/05/26, Ver.1.0) for ONO-4538 study. The SAP Ver.1.0 will be 
finalized before the cutoff data lock for interim analysis. The analysis principles are outlined in 
Section 10 “Statistical Analysis” in the study-specific protocol. 
If additional analyses not stated in the SAP are performed or endpoints not stated in the SAP are 
analyzed, the reasons for performing the analyses or analyzing the endpoints will be reported in 
the clinical study report, including the dates when the analyses were planned or the endpoints 
were derived. 
 


 
 
 
 
9 
 
2 SAMPLE SIZE 
2.1 
Planned Sample Size 
The target sample size is approximately 265 subjects per group, and approximately 530 subjects 
in total for the entire study. 
 
<Rationale for sample size calculation>  
This study is intended to evaluate the superiority of the ONO-4538 group over the placebo group, 
with PFS as the primary endpoint, in randomized or PD-L1+ (≥ 1%) chemotherapy-naïve subjects 
with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical 
radiation. Subjects will be randomized in a 1:1 ratio into either the ONO-4538 group or the placebo 
group and stratified by PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or indeterminate), 
ECOG Performance Status (0 vs 1), and gender (male vs female). 
In this study, one interim analysis of PFS among randomized subjects is planned for early stopping 
in case of superior efficacy, at the time when approximately 82.4% of the target number of events 
are observed. To adjust the multiplicity of tests, a significance level for interim and final analyses 
will be calculated using the Lan-DeMets α spending function (O’Brien-Fleming). The Hochberg 
method will be used to adjust the multiplicity of tests associated with final analysis in randomized 
subjects and PD-L1+ (≥ 1%) subjects. 
Given that PFS followed an exponential distribution in the placebo group and followed a piecewise 
exponential distribution with consideration for time to ONO-4538 response in the ONO-4538 
group in both PD-L1+ (≥ 1%) subjects and PD-L1− (< 1%) subjects, the hazard ratio of the ONO-
4538 group to the placebo group was assumed to be 1.0 for the first 2 months and 0.60 thereafter 
(the median PFS was 7.0 months in the placebo group and 10.3 months in the ONO-4538 group). 
Since past clinical study data on ONO-4538 reported that the proportion of PD-L1+ (≥ 1%) 
subjects to NSCLC subjects was in the range of 52% to 70%, the proportion of PD-L1+ (≥ 1%) 
subjects to randomized subjects was assumed to be 55%. To detect a statistically significant 
difference via the log-rank test in either randomized subjects or PD-L1+ (≥ 1%) subjects with a 
two-sided significance level of 5% and a statistical power of approximately 90%, 340 events were 
required. 
Assuming an accrual period of 24 months and a minimum follow-up of 16 months, 530 subjects 
may be required to observe the required number of events taking into account the number of 


 
 
 
 
10 
 
censored subjects. Therefore, the target sample size was set at 530 subjects. The required number 
of events and the target sample size in the protocol were calculated by simulation with SAS 
statistical analysis software (version 9.4). 
 
<Rationale for 7.0-month PFS (median) in the placebo group> 
Based on the report that the PFS ranges from 6.2 to 6.9 months in subjects treated with carboplatin, 
paclitaxel, and bevacizumab in studies in chemotherapy-naïve subjects with non-squamous non-
small cell lung cancer, PFS was set at 7.0 months in the placebo group. 
 
<Rationale for a period of 2 months to ONO-4538 response> 
The time to ONO-4538 response was determined by referring to the results from the phase 3 
study evaluating the efficacy and safety of ONO-4538 monotherapy in chemotherapy-naïve 
subjects with non-small cell lung cancer (CA209026). 
 
 


 
 
 
 
11 
 
3 DETERMINATION OF SUBJECTS INCLUDED IN ANALYSIS 
The analysis sets for efficacy endpoints are the Intention-to-Treat (ITT) and the PD-L1+ (≥ 1%) 
set (PD-L1 1% Positive Set: PDL1-PS). 
The analysis set for safety endpoints is the Safety Set (SAF). 
The analysis set for anti-drug antibody endpoints is the Anti-Drug Antibody Set (ADA). 
Individual sets of subjects are defined below. 
 
3.1 
Definitions of Analysis Sets 
1) Informed Consent Set (INF) 
 The INF will consist of all subjects who signed an informed consent. 
2) Enrolled Set (ENR) 
 The Enrolled Set (ENR) will consist of all subjects enrolled (enrollment) in this study via 
IWRS. 
3) ITT/Randomized Set (RND) 
 The ITT and Randomized Set (RND) will consist of all randomized (randomization) subjects. 
4) SAF 
 The SAF will consist of all subjects who received the investigational product or chemotherapy 
at least once. 
5) PDL1-PS 
 The PDL1-PS will consist of all subjects included in the ITT and who are PD-L1+ (≥ 1%). 
6) Anti-Drug Antibody Set  
 The ADA will consist of all subjects who meet the following item in the SAF population. 
1) Subjects have had their anti-ONO-4538 antibodies (samples with potential positive 
measurement result at screening assay without obtaining result by confirmatory assay are 
not included) measured before administration of ONO-4538 and at least 1 time point after 
administration of ONO-4538. 
 


 
 
 
 
12 
 
3.2 
Criteria for Handling of Subjects 
Details of handling of subjects are shown below. 
1) Non-enrolled Subjects 
Subjects who were not enrolled after signed to informed consent are defined as non-enrolled 
subjects. 
2) Non-randomized Subjects 
Subjects who were not randomized through the IWRS after enrollment are defined as non-
randomized subjects. 
3) Untreated Subjects 
Subjects who have not received both of the investigational product and chemotherapy are 
defined as untreated subjects. 
4) PD-L1 negative subjects 
Subjects who are PD-L1 negative (< 1%) are defined as PD-L1 negative subjects. 
5) Incomplete Anti-Drug Antibody Subjects 
Subjects with missing anti-ONO-4538 antibody measurements before administration of the 
investigational product or missing all anti-ONO-4538 antibody measurements after 
administration of the investigational product are defined as incomplete anti-drug antibody 
subjects. 
For unexpected, problematic cases other than above, the Sponsor will examine such cases and 
decide how they will be handled in the analysis before database lock. 
 
3.3 
Criteria for Handling of Time Points 
When analysis by time point is performed, if the test day specified in the protocol is different 
from the actual test day, only data measured within the time window described in Table 6-1 in 
the study-specific protocol should be adopted. 
 


 
 
 
 
13 
 
4 
SIGNIFICANCE LEVEL TO BE USED 
4.1 
Efficacy 
To preserve the overall type I error rate at ≤ 5% (two-sided), a significance level for interim and 
final analyses will be calculated using the Lan-DeMets α spending function (O’Brien-Fleming) 
based on the actual number of observed PFS events (as assessed by the Independent Radiology 
Review Committee (IRRC)). In addition, multiplicity of the test for final analysis will be 
adjusted using the Hochberg’s method. The significance level of the analysis for secondary 
endpoints is to be 5% (two-sided). In addition, interaction will be examined using a two-sided 
significance level of 15% and adjusted analysis will be performed using two-sided significance 
level of 5%. 
 
4.2 
Safety 
Not established because the test will not be performed. 
 


 
 
 
 
14 
 
5 
GENERAL METHODS 
Unless otherwise noted, analysis will be conducted based on treatment group randomized by 
IWRS. In the following sections, treatment group will refer to ONO-4538 group and placebo 
group. Investigational product will refer to ONO-4538 or placebo and chemotherapy will refer to 
carboplatin, paclitaxel and bevacizumab. The treatment group “As Randomized” will be 
retrieved from IWRS. The treatment group “As Treated” will be the same as the arm randomized 
by IWRS. However, if a subject received the incorrect treatment for the entire period of 
treatment, the subject’s treatment group will be defined as the incorrect treatment the subject 
actually received. Efficacy analysis will be conducted by “As Randomized” while safety analysis 
will be conducted by “As Treated”. 
For evaluation by IRRC, if both the Reader 1 and Reader 2 complete assessment without 
discordance, it will be adopted for the Reader’s assessment that the value of 10.2 1) (8) 
Maximum percentage of change in the sum of diameters of target lesions (as assessed by the 
IRRC) will be larger. If both Reader 1 and Reader 2 do not evaluate target lesions including the 
case of unmeasurable or non-target lesions, the assessment of reader will be adopted in 
alphabetical order. 
 


 
 
 
 
15 
 
6 
RELIABILITY OF THE STUDY 
 
6.1 
Analysis Set 
INF will be the analysis set for Analytical Item (1). 
SAF will be the analysis set for Analytical Item (2). 
ITT will be the analysis set for Analytical Item (3), (4) and (5). 
 
6.2 
Analytical Items and Data Handling 
1) Analytical Item 
(1) Reason for being excluded from each analysis set 
(2) Reason for discontinuation of the study treatment (Protocol 7.1.4) 
(3) Reason for withdrawals and dropouts from the study (Protocol 13) 
(4) The number of randomized subjects per study site 
(5) Important protocol deviation 
2) Handling of data 
The following deviations will be considered as important protocol deviations. 
Eligibility: 
・Subjects who failed to fulfill inclusion criteria #3 
・Subjects who failed to fulfill inclusion criteria #4 
・Subjects who failed to fulfill inclusion criteria #7 
・Subjects who failed to fulfill exclusion criteria #10 
On-study: 
・Subjects receiving any concurrent anticancer therapy (ie. chemotherapy, hormonal therapy, 
immunotherapy, surgery, or radiation therapy) while on study therapy 
・Subjects treated differently as randomized (subjects who received the wrong treatment 
excluding the never treated.) 
 


 
 
 
 
16 
 
6.3 
Analytical Methods 
1) Frequency of subjects who are included or excluded in each analysis set and frequency by 
reason for exclusion will be summarized by treatment group. Frequency of subjects who 
continuing or discontinued study treatment or study will also be summarized by treatment 
group. 
2) Reason for discontinuations of study treatment will be summarized by treatment group. 
3) Reason for lost to follow-up will be summarized by treatment group. 
4) For the number of subjects randomized per study site, frequency distribution and summary 
statistics will be summarized by treatment group. 
5) Frequency of important protocol deviation will be summarized by treatment group. 


 
 
 
 
17 
 
7 
EXTENT OF EXPOSURE AND ADMINISTRATION OF STUDY 
TREATMENT 
 
7.1 
Analysis Set 
The SAF will be the analysis set. 
 
7.2 
Analytical Items and Data Handling 
1) Analytical Items 
(1) Duration of treatment period 
(2) Number of doses received  
(3) Duration of treatment 
(4) Number of cycles 
(5) Cumulative dose 
(6) Relative dose intensity 
2) Handling of data 
(1) Duration of treatment period 
Duration of Treatment period = Last dose date of investigational product or each 
chemotherapy - First dose date of investigational product or each chemotherapy + 1 
(2) Number of cycles 
The number of cycles will be calculated for a cycle proceeding to the next cycle. A 
discontinued cycle or cycle in which no investigational products are administered will 
also be included for the number of cycles of investigational products. The same handling 
rules will be applied to each chemotherapy. 
(3) Duration of Treatment, Cumulative dose, Relative dose intensity 
To calculate duration of treatment, cumulative dose, and relative dose intensity for ONO-
4538, refer to Table 7.2-1 and to calculate those for the chemotherapies (carboplatin, 
paclitaxel, and bevacizumab), refer to Table 7.2-2. 


 
 
 
 
18 
 
Table 7.2-1 Duration of Treatment, cumulative dose, relative dose intensity of ONO-4538 
 
Table 7.2-2 Duration of Treatment, cumulative dose, relative dose intensity of 
chemotherapies 
 
paclitaxel 
carboplatin 
bevacizumab 
Cumulative 
dose 
Cumulative dose 
(mg/m2) is the sum of 
doses (mg/m2) 
administered to a subject 
during the treatment 
period. 
Dose (mg / m2) = Dose 
administered of 
Paclitaxel (mg) / 
Baseline BSA 
BSA (Body Surface 
Area) will be calculated 
by DuBois formula: 
[Body weight at 
screening (kg)]0.425 x 
Cumulative dose 
(AUC) is the sum of 
doses (AUC) 
administered to a 
subject during the 
treatment period. 
Dose (AUC) =Dose 
administered of 
Carboplatin (mg) / 
(Creatinine Clearance 
at screening + 25) 
Creatinine Clearance 
(CrCl) at screening will 
be calculated by 
Cumulative dose (mg/kg) 
is the sum of doses 
(mg/kg) administered to 
a subject during the 
treatment period. 
Dose (mg/ kg) = Dose 
administered of 
Bevacizumab (mg) / 
Baseline Body weight (at 
screening) 
 
ONO-4538 
Cumulative dose 
Cumulative dose (mg) is the sum of doses (mg) administered to a 
subject during the treatment period. 
Relative dose 
intensity (%) 
Cumulative dose (mg) / [Date of the last dose – Date of the first dose + 
21] (days) x 360 (mg) / 21 (days) x 100 
Duration of 
treatment (overall) 
Date of the last dose – Date of the first dose + 1 


 
 
 
 
19 
 
[Height at screening 
(cm)]0.725 x 0.007184 
Cockcroft-Gault 
formula. 
If value of the CrCl 
yields a result of > 125 
mL/min, it should be 
used 125 mL/min for 
the dose calculation. 
Relative 
dose 
intensity 
(%) 
Cumulative dose 
(mg/m2) / [Date of the 
last dose – Date of the 
first dose + 21] (days) x 
200 (mg/m2) / 21 (days) 
x 100 
Cumulative dose 
(AUC) / [Date of the 
last dose – Date of the 
first dose + 21] (days) x 
6 (AUC) / 21 (days) x 
100 
Cumulative dose (mg/kg) 
/ [Date of the last dose – 
Date of the first dose + 
21] (days) x 15 (mg/kg) / 
21 (days) x 100 
Duration of 
treatment 
(overall) 
Date of the last dose – 
Date of the first dose + 1 
Date of the last dose − 
Date of the first date + 
1 
Date of the last dose − 
Date of the first dose + 1 
 
7.3 
Analytical Methods 
1) For duration of treatment period, frequency distributions and summary statistics will be 
calculated by treatment group. 
2) For number of doses received, summary statistics will be calculated by investigational product 
and each chemotherapy. 
3) For duration of treatment, frequency distributions and summary statistics will be calculated by 
investigational product and each chemotherapy. 
4) For number of cycles, frequency distributions and summary statistics will be calculated by 
investigational product and each chemotherapy. 
5) For cumulative dose, summary statistics will be calculated by investigational product and each 
chemotherapy. 


 
 
 
 
20 
 
6) For relative dose intensity, frequency distributions and summary statistics will be calculated 
by investigational product and each chemotherapy. 


 
 
 
 
21 
 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
Analysis Set 
The ITT will be the analysis set. 
 
8.2 
Analytical Items and Data Handling 
1) Analytical Items 
(1) Demographic Variables 
Location, gender (eCRF source), age, race, ethnicity, height, body weight and body mass 
index (BMI)  
(2) Baseline Characteristics 
Past history, complications, smoking history, ECOG Performance Status (eCRF source), 
period from the date of diagnosis of primary disease through randomization, staging 
(Stage) and Tumor Node Metastasis (TNM) classification (at first diagnosis of the primary 
disease), histology of non-squamous non-small cell lung cancer, primary site and 
metastatic site of non-squamous non-small cell lung cancer, site of recurrence (for recurrent 
non-squamous non-small cell lung cancer), and previous treatment for cancers (including 
history of surgery, radiotherapy, or medical treatment) 
(3) Baseline Values of Observation 
 Sum of tumor diameters of target lesions (IRRC) 
(4) Biomarkers 
PD-L1 (test result source) 
(5) Randomization factors 
PD-L1 (IWRS source), Gender (IWRS source), ECOG Performance Status (IWRS 
source) 
(6) Subsequent anticancer therapy 
Surgery, radiotherapy, and medical treatment 
(7) Concomitant medication 
Immune modulating concomitant medication 
2) Handling of data 
(1) BMI 


 
 
 
 
22 
 
BMI (kg/m2) = “Body weight (kg)” / “[Height (m)] 2” 
(2) Period from the date of diagnosis of primary disease through randomization 
Period from the date of diagnosis of primary disease through randomization (months)  
= (“Date of randomization” − “Date of diagnosis of the primary disease” + 1) / 
30.4375 
 
8.3 
Analytical Methods and Classification 
1) Each analytical item displayed in 8.2 Analytical Items and Data Handling will be 
summarized by treatment group according to Table 8.3-1. Also, each analytical item will be 
summarized for each treatment group by location. 
2) Previous medical treatment for cancer will be summarized for each treatment group by 
generic name. 
3) Details of subsequent anticancer therapy (surgery, radiotherapy, and medical treatment) will 
be summarized by treatment group. 
4) For immune modulating concomitant medications, the number of subjects who received 
immune modulating concomitant medication for management of adverse event, management 
of concurrent disease, management of drug-related select adverse events classified by 
specific category (any grade, grade 3-5), management of IMAEs classified by specific 
category (any grade, grade 3-5), prevention, and other use will be calculated separately for 
each treatment group by medication class (WHODD: ATC Level 4) and generic name. 
5) Cross-tabulation between stratification factors (IWRS source) and stratification factors 
(eCRF source or test result source) will be provided by treatment group. 
(1) PD-L1 expression level (IWRS source) vs PD-L1 expression level (test result source) 
(2) ECOG Performance Status (IWRS source) vs ECOG Performance Status (eCRF source) 
(3) Gender (IWRS source) vs Gender (eCRF source) 
 
<Method of classification > 


 
 
 
 
23 
 
Classification for the ordinal scale or the continuous value will be determined based on clinical 
symptom or equipartition of the number of subjects (i.e., 1/3, 1/4, 1/5). 
Each classification of analytical item is displayed in the following table. 
 
Table 8.3-1 Classification of analytical item 
Analytical Item 
Stratum 
Analytical Method 
Location 
Japan, Taiwan, South Korea 
Frequency distributions 
Gender (IWRS source) 
Female, Male 
Frequency distributions 
Gender (eCRF source) 
Female, Male 
Frequency distributions 
Age 
 
Category1 
<65, >=65 
 
Category2 
<65, 65 - <75, >=75 
Summary statistics,   
Frequency distributions 
Race 
Asian, American Indian or Alaska 
Native, African American, Native 
Hawaiian or Other Pacific Islander, 
White 
Frequency distributions 
Ethnicity 
Not Hispanic or Latino, Hispanic or 
Latino 
Frequency distributions 
Height (cm) 
<160, 160 - <165, 165 - <170, >=170 
Summary statistics, 
Frequency distributions 
Body weight (kg) 
<50, 50 - <60, 60 - <70, >=70 
Summary statistics, 
Frequency distributions 
BMI (kg/m2) 
<18.5, 18.5 - <25.0, >=25.0 
Summary statistics,   


 
 
 
 
24 
 
Frequency distributions 
Past history 
No, Yes 
Frequency distributions 
Complications 
No, Yes 
Frequency distributions 
Smoking history 
(smoking status) 
Never, Current, Former, Unknown 
Frequency distributions 
Smoking history (years) 
<15, 15 - <30, 30 - <45, >=45 
Summary statistics,  
Frequency distributions 
ECOG Performance 
Status (IWRS source) 
0, 1, 2, 3, 4 
Frequency distributions 
ECOG Performance 
Status (eCRF source) 
0, 1, 2, 3, 4 
Frequency distributions 
Period from the date of 
diagnosis of primary 
disease through 
randomization (months) 
<1, 1 - <2, >=2 
Summary statistics, 
Frequency distributions 
Staging (Stage) 
IIIB, IV, Recurrent 
Frequency distributions 
Tumor Node Metastasis 
(TNM) classification 
T: TX, T1a, T1b, T2a, T2b, T3, T4 
N: NX, N0, N1, N2, N3 
M: MX, M0, M1a, M1b 
Frequency distributions 
Histology of non-
squamous non-small cell 
lung cancer 
Adenocarcinoma, Large cell 
carcinoma, Other 
Frequency distributions 
Primary site of non-
squamous non-small cell 
Right Upper Lobe, Right Middle 
Lobe, Right Lower Lobe, Left Upper 
Frequency distributions 


 
 
 
 
25 
 
lung cancer 
Lobe, Left Lower Lobe, Unknown, 
Other 
Metastatic site of non-
squamous non-small cell 
lung cancer 
Lung (Right Upper Lobe, Right 
Middle Lobe, Right Lower Lobe, 
Left Upper Lobe, Left Lower Lobe, 
Unknown, Other), Bone, Liver, 
Brain, Lymph Node, Bone Marrow, 
Pleura, Peritonea, Adrenal Gland, 
Skin, Other 
Frequency distributions 
Site of recurrence (for 
recurrent non-squamous 
non-small cell lung 
cancer) 
Lung (Right Upper Lobe, Right 
Middle Lobe, Right Lower Lobe, 
Left Upper Lobe, Left Lower Lobe, 
Unknown, Other), Bone, Liver, 
Brain, Lymph Node, Bone Marrow, 
Pleura, Peritonea, Adrenal Gland, 
Skin, Other 
Frequency distributions 
Previous treatment for 
cancers (history of 
surgery) 
No, Yes 
Frequency distributions 
Previous treatment for 
cancers (history of 
radiotherapy) 
No, Yes 
Frequency distributions 
Previous treatment for 
cancers (history of 
medical treatment) 
No, Yes 
Frequency distributions 
Sum of tumor diameters 
of target lesions 
<40, 40 - <60, 60 - <80, >=80 
Summary statistics,  
Frequency distributions 


 
 
 
 
26 
 
PD-L1 (IWRS source) 
① <1% or indeterminate 
② 1% - 49% 
③ >= 50% 
Frequency distributions 
PD-L1 (test result 
source) 
① <1% or indeterminate 
② 1% - 49% 
③ >= 50% 
Frequency distributions 


 
 
 
 
27 
 
9 
PRIMARY ENDPOINT 
9.1 
Analysis Sets 
In the case of early efficacy stopping based on the results of the interim analysis, the ITT will be 
used as the analysis set. 
If the study is continued based on the results of the interim analysis, the ITT and PDL1-PS will 
be used as the analysis sets for primary and sensitive analysis. Additionally, if the superiority of 
the ONO-4538 group over the placebo group is verified in the ITT in the primary analysis, the 
ITT will be used as the analysis set for secondary analysis. On the other hand, if the superiority 
of the ONO-4538 group over the placebo group is not verified in the ITT, the ITT and PDL1-PS 
will be used as the analysis sets for secondary analysis. 
 
9.2 
Analytical Item and Data Handling 
1) Analytical Item 
PFS (per IRRC, primary definition). 
2) Handling of data 
Primary definition of PFS will be calculated by the following equation. 
PFS (days) = [date when overall response is assessed as PD or date of death (for any reason), 
whichever comes first] – [date of randomization] + 1 
Overall response will not take into account any clinical deterioration and evaluable radiographic 
tumor assessment will be those without an overall response of “NE”. 
Event/censored assessment in the primary definition of PFS will be performed according to 
Table 9.2-1, depending on the situation. If the date on which the overall response is assessed as 
PD for the first time and the date of the start of subsequent anticancer therapy are the same, the 
event will be handled at the date on which the overall response is assessed as PD. Additionally, if 
the date of radiographic tumor assessment which overall response is not PD or NE and the date 
of the start of subsequent anticancer therapy are the same, PFS will be censored at that date. 
When a subject corresponds to more than one situation, the shortest PFS will be handled as the 
PFS of the subject. 
 
 


 
 
 
 
28 
 
Table 9.2-1 Definition of event and censoring for the primary definition of PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline radiographic 
tumor assessments 
Date of randomization 
Censored 
No death without an 
overall response of PD 
Date of the last evaluable 
radiographic tumor 
assessment*1 
Censored 
No death without evaluable 
radiographic tumor 
assessment 
Date of randomization 
Censored 
Assessment of overall 
response will not be done 
for more than 98 days 
before overall response of 
PD or death 
Date of the last evaluable 
radiographic tumor 
assessment*1, *2 before overall 
response of PD or death 
Censored 
Subsequent anticancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
radiographic tumor 
assessment*1 on or before 
initiation of subsequent 
anticancer therapy 
Censored 
End of investigating 
subsequent anticancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
radiographic tumor 
assessment*1 on or before end 
of investigating subsequent 
anticancer therapy 
Censored 
No subsequent anticancer 
Date of the last evaluable 
Censored 


 
 
 
 
29 
 
therapy before an overall 
response of PD or death 
radiographic tumor 
assessment*1 on or before no 
subsequent anticancer therapy 
Death without evaluable 
radiographic tumor 
assessment after 
randomization 
Date of death 
Event 
Death 
Date of death 
Event 
Overall response of PD 
Date of the first overall 
response of PD 
Event 
*1 The date of randomization will be used as the date of censoring when the subject does not 
have any evaluable radiographic tumor assessment after randomization. 
*2 The date of randomization will be used instead of date of the last evaluable radiographic 
tumor assessment when the subject does not have any evaluable radiographic tumor assessment 
between the date of randomization and the date of assessment of PD or death. 
 
9.3 
Analytical Methods (when the study stopped for superiority based on 
the results of Interim Analysis) 
9.3.1 
Primary Analysis 
To preserve the overall type I error rate at ≤ 5% (two-sided), a significance level α for analysis 
will be calculated using the Lan-DeMets α spending function (O’Brien-Fleming). 
The distribution of PFS will be compared between the two treatments groups using the two-sided 
stratified log-rank test with the three stratification factors (IWRS source) presented below. 
1) PD-L1 expression level (≥ 50% vs 1% to 49% vs < 1% or indeterminate) 
2) ECOG Performance Status (0 vs 1) 
3) Gender (male vs female) 
 


 
 
 
 
30 
 
9.3.2 
Sensitivity Analysis for Primary Analysis 
1) The distribution of PFS will be compared between the two treatment groups using the 
unstratified log-rank test. 
2) The distribution of PFS will be compared between the two treatment groups by using the 
stratified log-rank test adjusted by the three stratification factors (Gender and ECOG 
Performance Status from eCRF source and PD-L1 expression from test result source), if 
there exist more than 10% discrepancy in at least one factor between stratification factors 
(IWRS source) and stratification factors (eCRF source / test result source). 
 
9.3.3 
Secondary Analysis 
1) The number of events and censors will be tabulated for each treatment group. The status of 
subjects who are censored in the Kaplan-Meier analysis will also be tabulated by treatment 
groups using the following categories:  
a) Censored on date of randomization 
b) Censored on date of last evaluable tumor assessment 
a. To confirm to receive subsequent anticancer therapy before an overall response of 
PD or death 
b. To confirm the end of investigating subsequent anticancer therapy before an 
overall response of PD or death 
c. To confirm that assessment of overall response will not be done for more than 98 
days before an overall response of PD or death 
d. On-study: Not meet the above condition a, b and c and continuing the treatment 
period or follow-up period (excluding the case to confirm the alive in outcome 
survey even if the subject requested that the study be discontinued)  
e. Off-study: Lost to follow-up and not meet all the above condition a, b, c and d 
2) The hazard ratio and the corresponding two-sided 100 (1-α) % confidence interval (CI) 
(adjusted using Lan-DeMets alpha spending function (O’Brien-Fleming type) based on the 
number of observed PFS events) for the ONO-4538 group relative to the placebo group will 


 
 
 
 
31 
 
be estimated using a stratified Cox proportional hazard model with the stratification factors 
(IWRS source) presented above and with the treatment group as the single covariate. The 
hazard ratio and the corresponding two-sided 95 % CI for ONO-4538 group relative to the 
placebo group for each stratification factor will be estimated using an unstratified Cox 
proportional hazard model with the treatment group as the single covariate. 
3) The Kaplan-Meier curve will be plotted for each treatment group. 
4) Using the Kaplan-Meier method, the median PFS and the corresponding two-sided 100 (1- 
α) % CI (adjusted using Lan-DeMets alpha spending function (O’Brien-Fleming type) based 
on the number of observed PFS events) will be estimated for each treatment group. CI for 
median PFS will be calculated using the Brookmeyer and Crowley method based on a log-
log transformed CI for the survivor function. 
5) For each treatment group, PFS rates at Months 6, 12, 18, 24, 30 and 36 after randomization 
will be derived from the Kaplan-Meier method and the corresponding two-sided 95% CI will 
be derived based on Greenwood’s formula for variance derivation and on log-log 
transformation applied on the survivor function. 
6) The analyses described in 9.3.3 Secondary Analysis 1), 3) and 4) will be performed by the 
three stratification factors (IWRS source) presented 9.3.1 Primary Analysis 1) to 3). 
 
9.4 
Analytical Methods (when the study continued based on the results of 
Interim Analysis) 
9.4.1 
Primary Analysis 
The analysis will be performed by adjusting multiplicity using the Hochberg’s method according 
to the following procedures 1 to 4. A significance level α for analysis will be calculated using the 
Lan-DeMets α spending function (O'Brien-Fleming). 
1) For PFS, comparison between treatment groups will be performed in the ITT via the stratified 
log-rank test stratified by randomization factors (PD-L1 expression level, ECOG Performance 
Status, and gender). 


 
 
 
 
32 
 
2) For PFS, comparison between treatment groups will be performed in the PDL1-PS via the 
stratified log-rank test stratified by randomization factors (PD-L1 expression level, ECOG 
Performance Status, and gender). 
3) If the p value in the ITT and the p value in the PDL1-PS obtained from the stratified log-rank 
tests in 1 and 2 above are referred to as p (1) and p (2) in ascending order, then its corresponding 
null hypotheses referred to as H0(1) and H0(2), respectively. 
4) Superiority of the ONO-4538 group to the placebo group will be verified using p (1) and p (2). 
(1) If p (2) < α, both null hypotheses H0 (1) and H0 (2) will be rejected. 
(2) If p (2) ≥ α and p (1) < α/2, only null hypothesis H0 (1) will be rejected. 
 
9.4.2 
Sensitivity Analysis for Primary Analysis 
The analyses described in 9.3.2 Sensitivity Analysis for Primary Analysis will be performed. 
 
9.4.3 
Secondary Analysis 
The analyses described in 9.3.3 Secondary Analysis will be performed. 
 


 
 
 
 
33 
 
10 EFFICACY SECONDARY ENDPOINT 
 
10.1 
Analysis Set 
In the case of early efficacy stopping based on the results of the interim analysis, the ITT will be 
used as the analysis set.  
If the study is continued based on the results of the interim analysis and the superiority of the 
ONO-4538 group over the placebo group is verified in the ITT in the final analysis for primary 
endpoint, the ITT will be used as the analysis set. On the other hand, if the superiority of the 
ONO-4538 group over the placebo group is not verified in the ITT, the ITT and PDL1-PS will be 
used as the analysis sets. 
 
10.2 
Analytical Items and Data Handling 
1) Analytical Item 
(1) Overall Survival (OS) 
(2) PFS (as assessed by the study site’s investigator) 
(3) Objective response rate (ORR as assessed by the IRRC and study site’s investigator) 
(4) Disease control rate (DCR as assessed by the IRRC and study site’s investigator)  
(5) Duration of response (DOR as assessed by the IRRC) 
(6) Time to response (TTR as assessed by the IRRC) 
(7) Best overall response (BOR as assessed by the IRRC and study site’s investigator) 
(8) Maximum percentage of change in the sum of diameters of target lesions (as assessed by 
the IRRC) 
2) Handling of data 
(1) PFS (per study site’s investigator) 
i. Primary definition of PFS (per study site’s investigator) 
Refer to 9.2 1) Analytical Item and 9.2 2) Handling of data 
ii. Secondary definition of PFS (per study site’s investigator) 


 
 
 
 
34 
 
PFS (per study site’s investigator, secondary definition) will be calculated by the following 
equation. 
PFS (days) = [date when overall response is assessed as PD, date of clinical deterioration, 
or date of death (for any reason), whichever comes first] – [date of randomization] + 1 
 
Evaluable radiographic tumor assessment will be those without an overall response of “NE”. 
Event/censored assessment in the secondary definition of PFS will be performed according 
to Table 10.2-1, depending on the situation. If the date on which the overall response is 
assessed as PD or clinical deterioration for the first time and the date of the start of 
subsequent anticancer therapy are the same, the event will be handled at the date on which 
the overall response is assessed as PD or clinical deterioration. Additionally, if the date of 
radiographic tumor assessment which overall response is not PD or NE and the date of the 
start of subsequent anticancer therapy are the same, PFS will be censored at that date. When 
a subject corresponds to more than one situation, the shortest PFS will be handled as the PFS 
of the subject. 
 
Table 10.2-1 Definition of event and censoring for the secondary definition of PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline radiographic 
tumor assessments 
Date of randomization 
Censored 
No death without an 
overall response of PD and 
clinical deterioration 
Date of the last evaluable 
radiographic tumor 
assessment*1 
Censored 
No death without evaluable 
radiographic tumor 
assessment and clinical 
deterioration 
Date of randomization 
Censored 


 
 
 
 
35 
 
Assessment of overall 
response will not be done 
for more than 98 days 
before overall response of 
PD, clinical deterioration 
or death 
Date of the last evaluable 
radiographic tumor 
assessment*1,*2 before overall 
response of PD, clinical 
deterioration or death 
Censored 
Subsequent anticancer 
therapy before an overall 
response of PD, clinical 
deterioration or death 
Date of the last evaluable 
radiographic tumor 
assessment*1 on or before 
initiation of subsequent 
anticancer therapy 
Censored 
End of investigating 
subsequent anticancer 
therapy before an overall 
response of PD, clinical 
deterioration or death 
Date of the last evaluable 
radiographic tumor 
assessment*1 on or before end 
of investigating subsequent 
anticancer therapy 
Censored 
No subsequent anticancer 
therapy before an overall 
response of PD, clinical 
deterioration or death 
Date of the last evaluable 
radiographic tumor 
assessment*1 on or before no 
subsequent anticancer therapy 
Censored 
Death without evaluable 
radiographic tumor 
assessment after 
randomization 
Date of death 
Event 
Death 
Date of death 
Event 
Overall response of PD 
Date of the first overall 
response of PD 
Event 


 
 
 
 
36 
 
Clinical deterioration 
Date of the first clinical 
deterioration 
Event 
*1 The date of randomization will be used as the date of censoring when the subject does not 
have any evaluable radiographic tumor assessment after randomization. 
*2 The date of randomization will be used instead of date of the last evaluable radiographic 
tumor assessment when the subject does not have any evaluable radiographic tumor assessment 
between the date of randomization and the date of assessment of PD, clinical deterioration or 
death 
 
(2) DOR 
DOR will be calculated by the following equation. The target of the evaluation is a subject 
whose best overall response is CR or PR. 
DOR (days) = [date on which overall response was first assessed as PD or date of death 
(for any reason) after confirmed response, whichever comes first] – [date on which 
response was first assessed as confirmed CR or PR] + 1 
Event/censored assessment in DOR will be performed according to Table 10.2-2, depending 
on the situation. If the date on which the overall response is assessed as PD for the first time 
and the date of the start of subsequent anticancer therapy are the same, the event will be handled 
at the date on which the overall response is assessed as PD. Additionally, if the date of 
radiographic tumor assessment which overall response is not PD or NE and the date of the start 
of subsequent anticancer therapy are the same, DOR will be censored at that date. Also, when 
a subject corresponds to more than one situation, the shortest DOR will be handled as the DOR 
of the subject. 
 
Table 10.2-2 Definition of event and censoring in DOR 
Situation 
Date of Response or Censoring 
Outcome 
No death without an 
overall response of PD 
Date of the last evaluable 
radiographic tumor assessment 
Censored 
No death without evaluable 
radiographic tumor 
Date of the confirmation of 
Censored 


 
 
 
 
37 
 
assessment after the 
confirmation of response 
response 
Assessment of overall 
response will not be done 
for more than 98 days 
before overall response of 
PD or death 
Date of the last evaluable 
radiographic tumor assessment 
before overall response of PD 
or death 
Censored 
Subsequent anticancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
radiographic tumor assessment 
on or before initiation of 
subsequent anticancer therapy 
Censored 
End of investigating 
subsequent anticancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
radiographic tumor assessment 
on or before end of 
investigating subsequent 
anticancer therapy 
Censored 
No subsequent anticancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
radiographic tumor assessment 
on or before no subsequent 
anticancer therapy 
Censored 
Death without evaluable 
radiographic tumor 
assessment after the 
confirmation of response 
Date of death 
Event 
Death 
Date of death 
Event 
Overall response of PD 
Date of the first overall 
response of PD 
Event 
 


 
 
 
 
38 
 
(3) OS, ORR, DCR, TTR, and Maximum percentage of change in the sum of diameters of 
target lesions 
Refer to Core SAP section 3. 
Last confirmed to be alive in Core SAP section 3.1 means last date of data confirmed to be 
alive from all of date of data (visit date, performed or assessed) in this study. 
 
10.3 
Analytical Methods 
1) For item 1, the analyses in Core SAP section 5.1 1) to 5) will be performed. 
2) For items 2, the analyses in Core SAP section 5.2 1) to 5) will be performed. Description of 
Core SAP section 5.2 1) refer to 9.3.3 Secondary Analysis 1). 
3) For item 3 and 4, the analyses in Core SAP section 5.4 1) and 3) and section 5.5 1) and 3) will 
be performed, respectively. Also, the relative risk and the corresponding two-sided 95% CI of 
the ONO-4538 group relative to the placebo group adjusted with the same stratification factor 
will be calculated using the Cochran-Mantel-Haenszel method. 
4) For items 5 and 6, the analyses in Core SAP section 5.6 1) and 2) and section 5.7 1) and 2) will 
be performed, respectively. Description of Core SAP section 5.6 1) refer to 9.3.3 Secondary 
Analysis 1) b). 
5) For item 7, the analysis in Core SAP section 5.10 1) will be performed. 
6) For item 8, the analysis in Core SAP section 5.9 will be performed. 
Note: the confidence level will be 95%. PFS rate and OS rate will be calculated at 6, 12, 18, 24, 
30, and 36 months after randomization. 
 
10.4 
Subgroup Analyses for the Efficacy Endpoints 
10.4.1 
Analysis Sets 
In the case of early efficacy stopping based on the results of the interim analysis, the ITT will be 
used as the analysis set. In addition, if the study is continued based on the results of the interim 
analysis and the superiority of the ONO-4538 group over the placebo group is verified in the ITT 
in the final analysis for primary endpoint, the ITT will be used as the analysis set. On the other 
hand, if the superiority of the ONO-4538 group over the placebo group is not verified in the ITT, 
the ITT and PDL1-PS will be used as the analysis sets. 
 


 
 
 
 
39 
 
10.4.2 
Analytical Item and Data Handling 
1) Analytical Items 
(1) PFS (per IRRC and study site’s investigator, primary definition) 
(2) OS 
(3) ORR (per IRRC and study site’s investigator) 
2) Handling of data 
(1) Stratification factor and Method of classification 
The stratification factors will be chosen from Section 8.2 Analytical Items and Data 
Handling. The stratification factors will be classified as the following Table 10.4-1. 
Unless otherwise noted, ECOG Performance Status and Gender which are used for 
randomization will be extracted from IWRS. The others except for PD-L1 expression 
level will be extracted from eCRF. PD-L1 expression will be extracted from test result. 
Subsequent anticancer therapy (Immunotherapy) will only be used for OS. 
 
Table 10.4-1 Classification of analytical item 
Analytical Item 
Stratum 
Location 
Japan, Taiwan, South Korea 
Gender (IWRS source) 
Female, Male 
Gender (eCRF source) 
Female, Male 
Age 
 
Category 1 
<65, >=65 
 
Category 2 
<65, 65 - <75, >=75 
Body weight (kg) 
<50, 50 - <60, 60 - <70, >=70 


 
 
 
 
40 
 
BMI (kg/m2) 
<18.5, 18.5 - <25.0, >=25.0 
Smoking history 
(smoking status) 
Never, Current, Former, Unknown 
Smoking history (years) 
<15, 15 - <30, 30 - <45, >=45 
ECOG Performance 
Status (IWRS source) 
0, 1, >=2 
ECOG Performance 
Status (eCRF source) 
0, 1, >=2 
Period from the date of 
diagnosis of primary 
disease through 
randomization (months) 
<1, 1 - <2, >=2 
Histology of non-
squamous non-small cell 
lung cancer 
Adenocarcinoma, Large cell carcinoma, Other 
Brain metastases 
No, Yes 
Liver metastases 
No, Yes 
Bone metastases 
No, Yes 
Staging (Stage) 
IIIB, IV, Recurrent 
Previous treatment for 
cancers (history of 
surgery) 
No, Yes 
Previous treatment for 
cancers (history of 
No, Yes 


 
 
 
 
41 
 
radiotherapy) 
Previous treatment for 
cancers (history of 
medical treatment) 
No, Yes 
Subsequent anticancer 
therapy 
(Immunotherapy) 
No, Yes 
PD-L1 (IWRS source) 
① <1% or indeterminate 
② 1% - 49% 
③ >= 50% 
PD-L1 (test result 
source) 
① <1% or indeterminate 
② 1% - 49% 
③ >= 50% 
10.4.3 
Analytical Methods 
1) For OS and PFS, forest plots will be created to present the number of events, the median and 
the corresponding 95% CI for each treatment group and the hazard ratio and the corresponding 
95% CI for the ONO-4538 group relative to placebo group. Number of events, the median and 
the corresponding 95% CI will be calculated using Kaplan Meier method for each treatment 
group. Also, the hazard ratio and the corresponding 95% CI for the ONO-4538 group relative 
to placebo group will be calculated using the unstratified Cox proportional hazard model with 
the treatment group as the single covariate in each subgroup. 
2) For ORR, forest plots will be created to present the percentage and the corresponding two-
sided 95% CI, and the associated odds ratio and the corresponding two-sided 95% CI. The 
percentage and the corresponding two-sided 95% CI will be calculated using the Clopper-
Pearson method for each treatment group. Also, the associated odds ratio and corresponding 
two-sided 95% CI for ONO-4538 group relative to placebo group will be calculated using the 
unstratified logistic regression model with the treatment group as the single covariate in each 
subgroup. 
 


 
 
 
 
42 
 
10.5 
Interaction Analysis 
In the case of early efficacy stopping based on the results of the interim analysis, the ITT will be 
used as the analysis set. In addition, if the study is continued based on the results of the interim 
analysis and the superiority of the ONO-4538 group over the placebo group is verified in the ITT 
in the final analysis for primary endpoint, the ITT will be used as the analysis set. On the other 
hand, if the superiority of the ONO-4538 group over the placebo group is not verified in the ITT, 
the ITT and PDL1-PS will be used as the analysis sets. 
Analyses specified in the Core SAP 5.11 1) will be performed using the unstratified Cox 
proportional hazard model. 
 
10.6 
Adjusted Analysis 
In the case of early efficacy stopping based on the results of the interim analysis, the ITT will be 
used as the analysis set. In addition, if the study is continued based on the results of the interim 
analysis and the superiority of the ONO-4538 group over the placebo group is verified in the ITT 
in the final analysis for primary endpoint, the ITT will be used as the analysis set. On the other 
hand, if the superiority of the ONO-4538 group over the placebo group is not verified in the ITT, 
the ITT and PDL1-PS will be used as the analysis sets. 
Analyses specified in the Core SAP 5.12 1) will be performed. The confidence level will be 
95%.  
 
10.7 
Exploratory Analysis 
The ITT will be used as the analysis set. 
1) For OS and PFS (per IRRC and study site’s investigator, primary definition), the point 
estimate of Restricted Mean Survival time (RMST) 1), 2) at months 6, 12, 18, 24, 30 and 36 
after randomization and the corresponding two-sided 95% CI will be calculated by the 
treatment group. Also, the difference between the RMST of ONO-4538 group and placebo 
group and the corresponding 95% CI at each time point will be calculated. 
For treatment group i (i = 1, 2; 1=ONO-4538 group, 2=placebo group) and time point j (j = 
6, 12, 18, 24, 30 and 36), RMST and its standard error are expressed as RMSTij and SEij 


 
 
 
 
43 
 
respectively and these values will be derived by TIMELIM option of SAS’s LIFETEST 
procedure. Using these values, 95% CI of RMSTij will be calculated by the following 
equation where z2.5 denotes the upper 2.5% critical value for the standard normal 
distribution. 
RMST𝑖𝑖𝑖𝑖± 𝑧𝑧2.5𝑆𝑆𝐸𝐸𝑖𝑖𝑖𝑖  
Also, difference of RMST between ONO-4538 group and placebo group and its 95% CI will 
be calculated by the following equation respectively. 
RMST1𝑗𝑗−RMST2𝑗𝑗, 
RMST1𝑗𝑗−RMST2𝑗𝑗± 𝑧𝑧2.5ට𝑆𝑆𝑆𝑆1𝑗𝑗
2 + 𝑆𝑆𝑆𝑆2𝑗𝑗
2  
2) For OS, to evaluate the effect of subsequent anticancer therapy (immunotherapy), the 
adjusted hazard ratio and the corresponding two-sided 95% CI for the ONO-4538 group 
relative to the placebo group will be estimated using the two-stage accelerated failure time 
model (two-stage model) 3). The Weibull model will be used as the accelerated failure time 
model. The following factors are considered as those related to the use of subsequent 
anticancer therapy (immunotherapy), and are included in the model as covariates when 
estimating acceleration factor. Note that the value at the closest measurement point at the 
time of discontinuation of all treatments and at the measurement point before the date of 
discontinuation of all treatments will be used as covariates values except for PD-L1 
expression level (test result source). 
 
PD-L1 expression level (test result source : <1% or indeterminate, 1% - 49% and 
>= 50%) 
 
Value of LDH at the time of discontinuation of all treatments 
 
Value of CRP at the time of discontinuation of all treatments 
 
Value of NLR at the time of discontinuation of all treatments 
NLR = Neutrophil count / Lymphocyte count 
The specific procedure for estimating the adjusted hazard ratio and the corresponding two-
sided 95% CI for the ONO-4538 group relative to the placebo group in OS using the 
accelerated failure time model is as follows. 


 
 
 
 
44 
 
(1) Classify the subjects in the placebo group into the following three groups: 
A) Subjects who are continuing the treatment period 
B) Subjects who discontinued the treatment period and received a subsequent 
anticancer therapy (immunotherapy) once or more 
C) Subjects who discontinued the treatment period and have not received any 
subsequent anticancer therapy (immunotherapy) 
(2) Compare a survival time after the date of discontinuation in group B and C using the 
accelerated failure time model (Weibull model) with group (B or C) and factors related 
to the use of subsequent anticancer therapy (immunotherapy) described above as 
covariates and estimate the acceleration factor. The acceleration factor will be calculated 
by e coefficient of group. 
(3) Using the acceleration factor estimated in (2), calculate an adjusted overall survival for 
each subject in group B if the subjects had not received any subsequent anti-cancer 
therapy (immunotherapy). The adjusted overall survival will be calculated as follows: 
The adjusted overall survival (month) = “time from randomization to discontinuation of 
all treatments” + “(survival time after discontinuation of all treatments) / value of the 
acceleration factor” 
3) Using the overall survival in ONO-4538 group and group A, C and the adjusted over survival 
in group B, the hazard ratio and the corresponding two-sided 95 % CI for ONO-4538 group 
relative to the placebo group will be estimated using the stratified Cox proportional hazard 
model with the stratification factors (IWRS source) presented above and with the treatment 
group as the single covariate. 
 
 


 
 
 
 
45 
 
11 ANALYSIS OF SAFETY 
11.1 
Analysis Sets 
The SAF will be the analysis set. 
 
11.2 
Analytical Items and Data Handling 
1) Analytical Items 
(1) Adverse events, drug-related adverse events and deaths 
(2) Select adverse events and drug-related select adverse events 
(3) Time to onset or resolution/resolving of select adverse events and drug-related select 
adverse events 
(4) Immune-mediated adverse events and drug-related immune-mediated adverse events 
(5) Time to onset or resolution/resolving of immune-mediated adverse events and drug-related 
immune-mediated adverse events 
(6) Laboratory tests 
a) Hematology Tests 
Hemoglobin, White blood cell count, Neutrophil count, Lymphocyte count, Platelet 
count 
b) Serum chemistry Tests 
ALP, AST (GOT), ALT (GPT), Total bilirubin, Creatinine 
(7) Hormone Tests 
Thyroid-stimulating hormone (TSH), Free triiodothyronine (free T3), Free thyroxine (free 
T4) 
(8) 12-lead ECG 
Heart Rate (HR), PR Interval, RR Interval, QRS Complex, QT Interval, QTcF Interval 
2) Handling of data 


 
 
 
 
46 
 
(1) For analytical items (1), (2), (3), (6), (7) and (8), handling of data refers to the Core SAP 
section 6. All of the items (1), (2) and (3) occurring between the start date of the first 
administration of the investigational product or each chemotherapy and 30 days after the 
last dose of investigational product or each chemotherapy (30-day safety window) / 100 
days after the last dose of investigational product or each chemotherapy (100-day safety 
window) will be tabulated by treatment group.  
Drug-related AEs will be defined as any AEs for which a causal relationship to the 
investigational product or chemotherapies is “Related” or missing. 
AEs and drug-related AEs leading to discontinuation of treatment group will be defined as 
any AEs and drug-related AEs leading to discontinuation of the last treatment in treatment 
group, refer to 19 Appendix. 
AEs leading to discontinuation of investigational product will be defined as any AEs with 
action taken with investigational product = “Drug Withdrawn”. 
Drug-related AEs leading to discontinuation of investigational product will be defined as 
any AEs leading to discontinuation of investigational product with causal relationship to 
the investigational product assessed as “Related” or missing. 
AEs leading to discontinuation of 4 drugs will be defined as any AEs with action taken 
with investigational product and all chemotherapies = “Drug Withdrawn”. 
Drug-related AEs leading to discontinuation of 4 drugs will be defined as any AEs leading 
to discontinuation of 4 drugs with causal relationship to the investigational product or 
chemotherapies assessed as “Related” or missing. 
AEs leading to dose delay of treatment group will be defined as any AEs with action taken 
with any of treatment(s) = “Drug Delayed”. 
Drug-related AEs leading to dose delay of treatment group will be defined as any AEs 
leading to dose delay of treatment group with causal relationship to that treatment assessed 
as “Related” or missing. 
The observation period of AEs for the tabulation by period will be from the date of the start 
of the administration of the investigational product to the date of 1) - 3) shown below, 
whichever comes first. 


 
 
 
 
47 
 
1) 30 days after the final administration of the investigational product and each 
chemotherapy (For 100-day safety window analysis, 100 days after the final administration 
of the investigational product and each chemotherapy) 
2) The date of death or the last date of survival confirmation 
3) The date of data cutoff 
Definition of select AEs will be described in clinical study report. 
For the items (6), (7) and (8), test results measured between the start date of the first 
administration of the investigational product or each chemotherapy and 30 days after the 
last dose of investigational product or each chemotherapy will be used for tabulation. As 
baseline, the value at the time point closest to the start date of the first administration of the 
investigational product or each chemotherapy during the screening period (including 
unscheduled) will be used for summarization. If the assessment date and start date of the 
first administration are the same date and if it is confirmed that the assessment was 
conducted before the first administration, the value on the date will be handled the data as 
baseline. On the other hand, if it is unknown that the assessment was conducted before the 
first administration, the value on the date will be handled the data as post dose of 
administration. Also, for the item (8), QTcF Interval will be calculated by the following 
equation. 
QTcF = QT / RR0.33 
(2) Deaths 
For subjects who died due to Grade 5 drug-related adverse events, the cause of death will 
be defined as ‘Drug toxicity’ as priority. Otherwise, the reason of death in outcome survey 
will be used for summary. 
(3) Multiple events of adverse events 
Analyses that take into account the multiple occurrences of a given adverse event will be 
conducted. This data will be presented as the rate per 100 person-years of exposure. The 
analyses will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total exposure time. The person-year exposure will be computed as the 
sum over the subject’s exposure expressed in years where the exposure time is defined as  


 
 
 
 
48 
 
“(Min (30 days after last dose of study treatment (100 days for 100-day safety window) or 
date of death or last known date alive or data cutoff date – date of first dose of study 
treatment) + 1) / 365.25” 
(4) Immune-mediated adverse events (IMAEs) 
IMAEs occurring between the start date of the first administration of the investigational 
product or each chemotherapy and 100 days after the last dose of investigational product or 
each chemotherapy (100-day safety window) will be tabulated. Analyses for IMAEs will be 
limited to subjects who are included in SAF and received immunosuppressive medication 
for treatment of the event, with the exception of endocrine events that are defined as 
specific category of ADRENAL INSUFFICIENCY, 
HYPOTHYROIDISM/THYROIDITIS, HYPERTHYROIDISM, DIABETES MELLITUS 
and HYPOPHYSITIS, which will be included in the analysis regardless of treatment since 
endocrine events are often managed without immunosuppression. For analytical items (5), 
handling of data is the same as time to onset or resolution/resolving of selected AEs. 
Definition of IMAEs will be described in clinical study report. 
 
11.3 
Analytical Methods  
1) Adverse events, drug-related adverse events 
Analyses specified in the Core SAP 8.1 except for 2) and the following analyses will be 
performed using 30-day / 100-day safety window. Note that a cutoff value of incidence rate used 
for summarizing AEs and drug-related AEs which incidence rate is greater than or equal to 
certain level will be set as 5%. 
(1) Drug-related AEs and drug-related SAEs by the worst CTCAE grade (grade 1, 2, 3, 4, 
and 5) in each investigational product will be summarized by SOC and PT. 
(2) AEs leading to discontinuation of investigational product and drug-related AEs leading to 
discontinuation of investigational product by the worst CTCAE grade (grade 1, 2, 3, 4, 
and 5) in each investigational product will be summarized by SOC and PT. 
(3) Drug-related AEs and drug-related SAEs by the worst CTCAE grade (any grade, grade 3-
4, and grade 5) in each investigational product will be summarized by SOC and PT. 


 
 
 
 
49 
 
(4) AEs leading to discontinuation of investigational product and drug-related AEs leading to 
discontinuation of investigational product by the worst CTCAE grade (any grade, grade 
3-4, and grade 5) in each investigational product will be summarized by SOC and PT. 
(5) Analyses specified in the Core SAP 8.1 3) will also be performed for SAEs, drug-related 
SAEs, AEs leading to discontinuation of treatment group and drug-related AEs leading to 
discontinuation of treatment group. 
(6) AEs leading to discontinuation of 4 drugs and drug-related AEs leading to 
discontinuation of 4 drugs in each treatment group will be summarized by SOC and PT. 
2) Deaths 
Number of all deaths and deaths within 30 days/100 days after the last dose of investigational 
product or each chemotherapy as well as the frequency by the reason of death will be 
summarized by treatment group. 
3) Multiple events of AEs and drug-related AEs 
The total number and rate (exposure adjusted) of occurrences for all AEs and drug-related AEs 
in each treatment group will be summarized by SOC and PT using 30-day / 100-day safety 
window. 
4) Select adverse events and drug-related select adverse events 
Analyses specified in the Core SAP 8.2 and the following additional analyses will be performed 
using 30-day / 100-day safety window replacing ‘SOC’ with ‘specific category and subcategory’. 
For Core SAP 8.2 1), it will be tabulated by specific category and subcategory. 
(1) Drug-related select AEs and serious drug-related select AEs by the worst CTCAE grade 
(grade 1, 2, 3, 4 and 5) in each investigational product will be summarized by specific 
category, subcategory and PT. 
(2) Select AEs leading to discontinuation of investigational product and drug-related select 
AEs leading to discontinuation of investigational product by the worst CTCAE grade 
(grade 1, 2, 3, 4 and 5) in each investigational product will be summarized by specific 
category, subcategory and PT. 


 
 
 
 
50 
 
(3) Drug-related select AEs and serious drug-related select AEs by the worst CTCAE grade 
(any grade, grade 3-4 and grade 5) in each investigational product will be summarized by 
specific category, subcategory and PT. 
(4) Select AEs leading to discontinuation of investigational product and drug-related select 
AEs leading to discontinuation of investigational product by the worst CTCAE grade 
(any grade, grade 3-4 and grade 5) in each investigational product will be summarized by 
specific category, subcategory and PT. 
(5) Analyses specified in the Core SAP 8.2 2) will also be performed for serious select AEs, 
serious drug-related select AEs, select AEs leading to discontinuation of treatment group 
and drug-related select AEs leading to discontinuation of treatment group. 
5) Time to onset or resolution/resolving of select adverse events and drug-related select adverse 
events 
Analyses specified in the Core SAP 8.3 and 8.4 will be performed using 30-day /100-day safety 
window.  
Additionally, following analyses will be performed for the time to resolution / resolving of any 
select AEs, any drug-related select AEs, CTCAE grade 3 or more select AEs and CTCAE grade 
3 or more drug-related select AEs by specific category and subcategory using 30-day / 100-day 
safety window. 
(1) Subjects who received immune modulating medication will be calculated. 
(2) Subjects in whom events are resolved / resolving will be calculated. 
(3) Subjects with immune modulating medication in whom events are resolved / resolving 
will be calculated. 
6) Immune-mediated adverse events and drug-related immune-mediated adverse events 
Same analyses specified in the Core SAP 8.2 and the following additional analyses will be 
performed using 100-day safety window replacing "select AEs" with IMAEs and ‘SOC’ with 
‘specific category’. For Core SAP 8.2 1), it will be tabulated by specific category. 
(1) Drug-related IMAEs and serious drug-related IMAEs by the worst CTCAE grade (grade 
1, 2, 3, 4 and 5) in each investigational product will be summarized by specific category 
and PT. 


 
 
 
 
51 
 
(2) IMAEs leading to discontinuation of investigational product and drug-related IMAEs 
leading to discontinuation of investigational product by the worst CTCAE grade (grade 1, 
2, 3, 4 and 5) in each investigational product will be summarized by specific category and 
PT. 
(3) Drug-related IMAEs and serious drug-related IMAEs by the worst CTCAE grade (any 
grade, grade 3-4 and grade 5) in each investigational product will be summarized by 
specific category and PT. 
(4) IMAEs leading to discontinuation of investigational product and drug-related IMAEs 
leading to discontinuation of investigational product by the worst CTCAE grade (any 
grade, grade 3-4 and grade 5) in each investigational product will be summarized by 
specific category and PT. 
(5) Analyses specified in the Core SAP 8.2 2) will also be performed for serious IMAEs, 
serious drug-related IMAEs, IMAEs leading to discontinuation of treatment group and 
drug-related IMAEs leading to discontinuation of treatment group. 
7) Time to onset or resolution/resolving of immune-mediated adverse events and drug-related 
immune-mediated adverse events 
Same analyses described in 11.3 5) Time to onset or resolution/resolving of select adverse events 
and drug-related select adverse events will be performed using 100-day safety window replacing 
"select AEs" with IMAEs and “specific category and subcategory” with “specific category”. 
8) Laboratory tests 
Analyses specified in the Core SAP 8.5 1) and 2) will be performed using the data occurring 
between the start date of the first administration of the investigational product or each 
chemotherapy and 30 days after the last dose the investigational product or each chemotherapy. 
9) Hormone Tests 
Analyses specified in the Core SAP 8.7 1) will be performed using the data occurring between 
the start date of the first administration of the investigational product or each chemotherapy and 
30 days after the last dose the investigational product or each chemotherapy. 
10) 12-lead ECG 


 
 
 
 
52 
 
Analyses specified in the Core SAP 8.9 1) will be performed using the data occurring between 
the start date of the first administration of the investigational product or each chemotherapy and 
30 days after the last dose the investigational product or each chemotherapy. 
 
11.4 
Subgroup Analyses for the Safety Endpoints 
For each treatment group as well as for the stratification factors presented in 10.4 Subgroup 
Analyses for the Efficacy Endpoints, the overall summary table of any AEs, drug-related AEs, 
serious AEs and drug-related serious AEs by the worst CTCAE grade (any grade, grade 3-4, 
grade 5) will be presented by SOC and PT using 30-days safety window. 
 


 
 
 
 
53 
 
12 PATIENT REPORTED OUTCOMES 
12.1 
Analysis Sets 
The ITT will be the analysis set. 
 
12.2 
Analytical Items and Data Handling 
1) Analytical Items 
(1) Patient with questionnaire completion 
(2) EuroQol 5 Dimension (EQ-5D) 
(3) EQ-5D index scores (Japan based scoring) 
(4) Change from baseline of EQ-5D index scores (Japan based scoring) 
(5) EuroQol visual analogue scale (EQ-VAS) scores 
(6) Change from baseline of EQ-VAS scores 
(7) LCSS questionnaire completion rate 
(8) The LCSS disease-related symptom improvement rate at week 12 
(9) Change from baseline of the average symptom burden scale index score at each LCSS 
assessment 
2) Handling of data 
(1) EQ-5D index scores (Japan based scoring) 
EQ-5D questionnaire asks the patients to describe their current health state on 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with each 
dimension having 3 response choices (1 = no problem, 2 = some problem, and 3 = extreme 
problem). For example, if mobility = 2, self-care = 2, usual activities = 1, pain/discomfort = 
1, and anxiety/depression = 1, then “Health State” would be “22111”. 
(At least one 3 (N3), M2 (Mobility = 2), M3 (Mobility = 3), SC2 (Self Care = 2), SC3 (Self 
Care = 3), UA2 (Usual Activities = 2), UA3 (Usual Activities = 3), PD2 (Pain/Discomfort = 
2), PD3 (Pain/Discomfort = 3), AD2 (Anxiety/Depression = 2), AD3 (Anxiety/Depression = 
3)) 


 
 
 
 
54 
 
If Full health “11111”, the value set is equal to 1. In other cases, the below mathematical 
representation is used. 
 
Japan Value Set: 1 - 0.152 - 0.075MO2 - 0.418MO3 - 0.054SC2 - 0.102SC3 - 0.044UA2 - 
0.133UA3 - 0.080PD2 - 0.194PD3 - 0.063AD2 - 0.112AD3 
 
If there is any question for which the answer is not given for these 5 questions, the EQ-5D 
index score will also not be available. 
(2) LCSS questionnaire completion rate 
LCSS questionnaire completion rate is defined as the proportion of questionnaires actually 
received out of the expected number (i.e., the number of patients still on treatment or in follow 
up). 
(3)  The LCSS disease-related symptom improvement rate at week 12 
Disease-related symptom improvement rate by Week 12 is defined as the proportion of 
randomized patients who had a 10 point or greater decrease from baseline in average symptom 
burden scale index score at any time between baseline and Week 12. 
(4) The average symptom burden scale index score 
The average symptom burden index score at each assessment is defined as the mean of the 6 
symptom-specific questions of the LCSS. 
(5) Time window for QOL evaluations 
All questionnaires completed at baseline and on-study will be assigned to a time-point 
according to the windowing criteria in Table 12.2-1 Time windows for QOL evaluations. 
 
Table 12.2-1 Time windows for QOL evaluations 
Nominal Time-Point 
Time Window 
Screening Period 
Treatment Period 
Week 6 (Day 43) 
Week 12 (Day 85) 
The response closest to the first administration of 
investigational product or each chemotherapy during 
screening period including unscheduled will be 
adopted. 
Day 2 to Day 64 


 
 
 
 
55 
 
Week 18 (Day 127) 
…Every 6 weeks thereafter while on treatment 
At the completion of the treatment period (at 
discontinuation) 
Follow-up Period 
∙Follow-up 1 (((date at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 92) 
∙Follow-up 2 (((date at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 183) 
∙Follow-up 3 (((date at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 274) 
∙Follow-up 4 (((date at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 366) 
∙Follow-up 5 ((d(ate at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 548) 
∙Follow-up 6 (((date at the completion of the 
treatment period or date at the 28 days after the 
completion of the treatment period, whichever comes 
last) +1) + 731) 
Day 65  to Day 106 
Day 107 to Day 148 
Scheduled assessed time point (+21 days / -20 days) 
At the completion of the treatment period (at 
discontinuation) or 28 days after completion of the 
treatment period incl. unscheduled. 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) to Day 137 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) + 138 to Day 229 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) + 230 to Day 320 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) + 321 to Day 457 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) + 458 to Day 640 
(Max (date at the completion of the treatment period or 
date at 28 days after the completion of the treatment 
period incl. unscheduled) +1) + 641 to Day 822 
 
12.3 
Analytical Methods 
1) Patient with questionnaire completion 
The percentage of patients with questionnaire completion in each treatment group will be 
summarized at each time point. Percentages will be calculated based on the number of patients 
assessed by treatment group at each assessment time point. 
2) EQ-5D 
The percentages of patients with no health problems, moderate health problems and extreme health 
problems will be calculated for each EQ-5D dimension at each time point by treatment group. 


 
 
 
 
56 
 
Percentages will be calculated based on the number of patients assessed by treatment group at each 
assessment time point for each EQ-5D dimension. 
3) EQ-5D index scores (Japan based scoring) 
(1) For EQ-5D index scores at each time point in each treatment group will be summarized 
using summary statistics. 95% CI for mean scores of EQ-5D index scores at each time 
point in each treatment group will also be calculated. 
(2) For change from baseline of EQ-5D index scores at each time point in each treatment 
group will be summarized using summary statistics. 95% CI for mean scores of change 
from baseline of EQ-5D index scores at each time point in each treatment group will also 
be calculated. 
4) EQ-VAS scores 
(1) 
For EQ-VAS scores at each time point in each treatment group will be summarized using 
summary statistics. 95% CI for mean scores of EQ-VAS scores at each time point in each 
treatment group will also be calculated. 
(2) 
For change from baseline of EQ-VAS scores at each time point in each treatment group 
will be summarized using summary statistics. 95% CI for mean scores of change from 
baseline of EQ-5D index scores at each time point in each treatment group will also be 
calculated. 
5) LCSS questionnaire completion rate 
LCSS questionnaire completion rate will be calculated and summarized by treatment group at 
each assessment point. 
6) The LCSS disease-related symptom improvement rate  
The disease-related symptom improvement rate at week 12 and its corresponding 95% exact CI 
will also be calculated by Clopper-Pearson method for each treatment group.  
7) Change from baseline of the average symptom burden scale index score 
Baseline and change from baseline of the average symptom burden scale index score at each 
LCSS assessment point will be summarized using summary statistics (N, mean, median, SD, 
the 25- and 75-percent points) by treatment group. 


 
 
 
 
57 
 
 
13 ANTI-DRUG ANTIBODY ANALYSIS 
13.1 
Analysis Sets 
The ADA will be the analysis set. 
 
13.2 
Analytical Item and Data Handling 
1) Analytical Item 
Anti-ONO-4538 antibody up-regulated expression. 
2) Handling of data 
Refer to Core ADA-SAP section 3. 
 
13.3 
Analytical Methods 
Refer to Core-ADA SAP section 5.1. 
 


 
 
 
 
58 
 
14 INTERIM STATISTICAL ANALYSIS 
One interim analysis for PFS per IRRC will be performed in the ITT population to determine 
whether to stop the study early for superiority based on the stratified log-rank test with allocation 
factors (PD-L1 expression level, ECOG PS, and gender) as stratification factors when 
approximately 82.4% (n = 280) of the target number of PFS events over the entire study (n = 340) 
have occurred. To control the overall type I error rate at no more than 5% (two-sided), the 
significance levels used in the interim and final analyses will be calculated by the Lan-DeMets α 
spending function (O’Brien-Fleming type) based on the actual number of events. 
During the interim analysis, the Independent Data Monitoring Committee (IDMC) will determine 
early efficacy stop. The details of the interim analysis are described separately in IDMC procedures 
and an interim analysis plan. 
 
When the superiority of the ONO-4538 group over the placebo group is verified with PFS (per 
IRRC, primary definition) at the interim analysis or final analysis, analysis for OS (1st time) will 
be performed at that time. Additionally, analysis of OS (2nd time) will be performed based on a 
cut-off data which cut-off date is one year after a cut-off date of the interim analysis or final 
analysis. 
 
The following analysis will be performed in 2nd time analysis of OS on the ITT. 
1) The analysis in Core SAP section 5.1 1), 2), 3) and 5) will be performed. 
2) The analysis in 10.4.3 Analytical Methods 1) will be performed. 
 
 
 


 
 
 
 
59 
 
15 BLINDED REVIEWS 
15.1 
Objectives 
After data accumulation, distribution of background factors will be preliminarily examined using 
blinded data before data lock to confirm appropriateness of the planned analytical methods. 
15.2 
Analysis Sets 
The ITT will be the analysis set.  
 
15.3 
Analytical Items and Data Handling 
1) Analytical Items 
(1) Patient background factors 
(2) Subsequent anticancer therapy (surgery, radiotherapy, medical treatment) 
(3) Efficacy endpoints 
a) PFS (per IRRC, primary definition) 
b) PFS (per study site’s investigator, primary definition) 
c) OS 
d) ORR (per IRRC) 
(4) Adverse events and drug-related adverse events 
2) Handling of data 
Each item will be analyzed according to the method defined above. 
 
15.4 
Analytical Methods 
1) Frequency distributions and summary statistics will be calculated for section 8.2 1) Analytical 
Items (1) to (5) except for (4), and the classification in 8.3 Analytical Methods and 
Classification will be determined. 
2) Details of subsequent anticancer therapy (surgery, radiotherapy, and medical treatment) will 
be summarized. 
3) To verify the validity of the analysis method or handling of data, the number of events, 
censored and reason for censors of PFS will be tabulated. Additionally, the median PFS and 
the corresponding 95% CI by using Kaplan-Meier method will be estimated. 95% CI for the 


 
 
 
 
60 
 
median PFS will be calculated using the Brookmeyer and Crowley method based on a log-log 
transformed confidence interval for the survivor function. 
4) To verify the validity of the analysis method or handling of data, the number of events and 
censors of OS will be tabulated. Additionally, the median OS and the corresponding 95% CI 
by using Kaplan-Meier method will be estimated. 95% CI for the median OS will be calculated 
using the Brookmeyer and Crowley method based on a log-log transformed confidence interval 
for the survivor function. 
5) To verify the validity of the analysis method, ORR and the corresponding exact (Clopper-
Pearson method) 95% CI will be calculated. As necessary, the missing condition will be 
verified. 
6) Numbers of patients with AEs and drug-related AEs will be summarized as a whole, or by 
System Organ Class (SOC), Preferred Term (PT) and Grade. 
 


 
 
 
 
61 
 
16 TECHNICAL MATTERS 
Refer to Core SAP section 12 
 
16.1 
SAS Programming in Analyses 
1) Cochran-Mantel-Haenszel test 
The Cochran-Mantel-Haenszel test will be performed using the CMH option of the FREQ 
procedure of SAS. 
PROC FREQ DATA = [Analysis data set]; 
TABLES [the stratification variable] * [treatment group] * [response variable] / CMH 
RISKDIFF (COMMON COLUMN=1) ALPHA = 0.05; 
RUN; 
2) The accelerated failure time model (Weibull model) 
When estimating the acceleration factor using the accelerated failure time model (Weibull 
model) in 10.7 2), the following SAS sample program code of LIFEREG procedure will be 
used. 
PROC LIFEREG DATA = [Analysis data set]; 
MODEL [survival time variable] = [treatment group] / DIST = WEIBULL; 
OUPUT OUT = [Output data set] CDF=CDF; 
RUN; 
 
16.2 
Imputation of Missing Value 
16.2.1 Imputing the Date of Death and Date of Severity CTCAE Grade5 (AE grade 5 
start date) 
If the day of death is missing, “01” will be imputed for the day. After that, the derived date of 
death will be derived from the following conditions; 
1) If the imputed date of death < the date of the last survival confirmed, the date of last survival 
confirmed will be the derived date of death. 
2) If the imputed date of death >= the date of the last survival confirmed, the imputed date of 
death will be the derived date of death. 


 
 
 
 
62 
 
If the year or month of death will be missing, the date of the last survival confirmed will be 
the derived date of death. 
 
16.2.2 Imputing Other Date 
Define the derived minimum date as the earliest date within the possible date and the derived 
maximum date as the latest date within the possible date.  
If day and month are missing, minimum date and maximum date to be derived is following; 
1) Derived minimum date; 01 JAN 
2) Derived maximum date; 31 DEC 
If day is missing, minimum date and maximum date to be derived is following; 
1) Derived minimum date; first date of that month 
2) Derived maximum date; last date of that month 
For AE start date (AE grade start date except for Grade 5) with completely missing, the first 
administration date of investigational product or each chemotherapy will be the derived date. 
For AE start date (AE grade start date except for Grade 5) with partially missing (day and month 
are unknown or day is unknown), the derived date will be derived from the following conditions; 
1) If the derived minimum date >= the first administration date of investigational product or 
each chemotherapy, the derived minimum date will be the derived date. 
2) If the derived minimum date < the first administration date of investigational product or each 
chemotherapy <= the derived maximum date, the first administration date of investigational 
product or each chemotherapy will be the derived date. 
3) If the first administration date of investigational product or each chemotherapy > the derived 
maximum date, the derived maximum date will be the derived date. 
4) If the first administration date of investigational product or each chemotherapy is missing, 
the derived minimum date will be the derived date. 
For the date of diagnosis of primary disease with partially missing (day and month are 
unknown), the derived date will be derived from the following conditions; 
1) If the year of diagnosis of primary disease = the year of previous treatment for cancers 
(including history of surgery, radiotherapy, or medical treatment), the date performed 
previous treatment for cancers will be the derived date.  
2) If the year of diagnosis of primary disease is not equal to the year of previous treatment for 
cancers, the derived minimum date will be the derived date. 
 
 


 
 
 
 
63 
 
17 REFERENCE 
1) Royston P, Parmar MK. The use of restricted mean survival time to estimate the treatment 
effect in randomized clinical trials when the proportional hazards assumption is in doubt. 
Stat Med. 2011;30:2409-2421. 
2) Uno H, Claggett B, Tian L, et al. Moving beyond the hazard ratio in quantifying the 
between-group difference in survival analysis. J Clin Oncol . 2014;32:2380-2385. 
3) Latimer NR, Henshall C, Siebert U, et al. Treatment Switching: statistical and decision 
making challenges and approaches. Int J Technol Assess Health Care. 2016;32:160-166. 
 
 


 
 
 
 
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18 CHANGES IN THE STATISTICAL ANALYSIS PLAN FROM THE 
STUDY SPECIFIC PROTOCOL  
18.1 
Changes in the Statistical Analysis Plan from the Study Specific 
Protocol 
1) Safety analysis items 
(1) Changes 
Vital signs, Chest X-ray and ECOG Performance Status were deleted from safety analysis 
items 
(2) Reason for changes 
The above safety analysis items will be examined exclusively to secure the safety of 
subjects. 
 
18.2 
Changes in the Statistical Analysis Plan from the Statistical Analysis 
Plan version 1.0 
1) 5. General methods 
(1) Changes 
Description of reader adoption for evaluation by IRRC was added. 
(2) Reason for changes 
It needs to clarify how to adopt the reader for evaluation by IRRC. 
2) 6. Reliability of the study 
(1) Changes 
Description of handling data for important protocol deviations was added. 
(2) Reason for changes 
It needs to clarify how to handle important protocol deviations. 
3) 8. Demographics and other baseline characteristics 
(1) Changes 
Description of analytical methods and classification was modified. 
(2) Reason for changes 
It needs to clarify analytical methods. 
4) 9. Primary endpoint 
(1) Changes 


 
 
 
 
65 
 
Description of categories to tabulate the censors was added. 
(2) Reason for changes 
It needs to define the categories to tabulate the censors. 
5) 10. Efficacy secondary endpoint 
(1) Changes 
a) Handling of data about OS was added. 
b) Stratification factors for subgroup analysis were defined. 
c) Exploratory analysis for OS was added. 
(2) Reason for changes 
a) It needs to define the handling of data for last confirmed to be alive. 
b) It needs to define the stratification factors and classification for subgroup analysis. 
c) It needs to evaluate more details of the efficacy especially OS. 
6) 11. Analysis of safety 
(1) Changes 
a) Definition of baseline for safety analysis items except for AEs was added. 
b) Some analyses for time to resolution / resolving were added. 
(2) Reason for changes 
a) It needs to define the baseline for safety analysis items except of AEs. 
b) It needs to evaluate more details of the safety especially Select AEs and IMAEs. 
7) 12. Patient reported outcomes 
(1) Changes 
More details of time windows for QOL evaluations were added. 
(2) Reason for changes 
It needs to make clear the time windows for QOL evaluations. 
8) 14. Interim Statistical Analysis 
(1) Changes 
The 2nd time analysis plan of OS were added. 
(2) Reason for changes 
It needs to evaluate the OS follow-up data. 
9) 15. Blinded Reviews 
(1) Changes 


 
 
 
 
66 
 
Description of analytical methods was modified. 
(2) Reason for changes 
It needs to clarify analytical methods. 
10) 16. Technical matters 
(1) Changes 
Descriptions for SAS programming in analyses and imputation of missing date of the date 
of diagnosis of primary disease were added. 
(2) Reason for changes 
It needs to define the used SAS programming for 10.7 Exploratory Analysis and 
imputation of missing date of the date of diagnosis of primary disease. 
 
 
 
 


 
 
 
 
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19 APPENDIX  
 
Definition of AE and Drug-related AE leading to discontinuation of treatment group / 
investigational product 
 
 AEs and drug-related AEs leading to discontinuation of treatment group 
 Identify the treatment(s) discontinued last in treatment group (investigational product 
and chemotherapy) with their reason of discontinuation for AEs whose action taken is 
"Drug Withdrawn". 
 1. Identify treatment(s)* with last date of withdrawal in treatment group.  
Max (date of withdrawal for investigational product, paclitaxel, carboplatin, 
bevacizumab)  
* There may be more than one treatment. 
 2. Identify AEs with action taken as "Drug Withdrawn" for the treatment(s) 
identified in 1. Corresponding AEs are identified as AEs leading to discontinuation 
of treatment group.  
 3. Identify drug-related AEs with causal relationship to the investigational product 
or chemotherapy as “Related” or missing for the AEs identified in 2. Corresponding 
drug-related AEs are identified as drug-related AEs leading to discontinuation of 
treatment group. 
 
Handling are shown in the following example cases. 
In Case 1, AE1 is identified as the AE leading to discontinuation of treatment group which 
caused discontinuation of investigational product that is the treatment discontinued last in 
treatment group. 
In Case 2, AE1 and AE4 are identified as the AEs leading to discontinuation of treatment group 
which caused discontinuation of investigational product and Bevacizumab that are treatment 
discontinued last in treatment group at the same date. 
In Case 3, all AEs (AE1, AE2 and AE3) are identified as the AEs leading to discontinuation of 
treatment group because all the treatments are discontinued due to expression of AEs (AE1, AE2 
and AE3) at the same date. 
 


 
 
 
 
68 
 
 
 
 AEs and drug-related AEs leading to discontinuation of investigational product 
 AEs leading to discontinuation of investigational product will be defined as any AEs 
with action taken with investigational product = “Drug Withdrawn”. 
 Drug-related AEs leading to discontinuation of investigational product will be defined 
as any AEs leading to discontinuation of investigational product to causal relationship 
with the investigational product assessed as “Related” or missing.