Carbone 2017.

Study characteristics
Methods	Study design: randomised open‐label parallel controlled, phase 3 trial Study setting: multicentre trial, 141 study locations Country: 35 countries: USA, Argentina, Australia, Brazil, Belgium, Canada, Chile, China, Colombia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Mexico, the Netherlands, Peru, Poland, Romania, Russian Federetaion, Saudi Arabia, Spain, others Publication: full‐text paper Study power calculation: yes Study duration: study start date: March 2014, study completion date: October 2018 Ethical approval: yes, by ethics committee at each centre
Participants	Inclusion criteria Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1 Histologically‐confirmed Stage IV, or Recurrent NSCLC with no prior systemic anticancer therapy Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per response evaluation criteria in solid tumour version (RECIST) 1.1 criteria PD‐L1+ (tumour proportional score ≥ 1%) on immunohistochemistry testing performed by central laboratory Men and women, ages ≥ 18 years of age Exclusion criteria Known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy Known anaplastic lymphoma kinase (ALK) translocations Untreated central nervous system (CNS) metastases Previous malignancies Active, known or suspected autoimmune disease
Interventions	Intervention: nivolumab Solution for Injection 3 mg/kg Intravenous every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure Control: investigator's choice chemotherapy administered in 3‐week cycles up to a maximum of 6 cycles of Intravenous injection until disease progression, unacceptable toxicity or completion of the 6 cycles, whichever comes first
Outcomes	Primary outcomes Progression‐free survival in participants with PD‐L1 expression ≥ 5% (time frame: from date of randomisation until date of documented tumour progression (assessed up to August 2016, approximately 28 months) Secondary outcome measures Progression‐free survival in all randomised participants (time frame: from date of randomisation until date of documented tumour progression (assessed up to August 2016, approximately 28 months) Overall survival in participants with PD‐L1 expression ≥ 5% (time frame: from date of randomisation to date of death (assessed up to August 2016, approximately 28 months) Overall survival in all randomised participants (time frame: from date of randomisation to date of death (assessed up to August 2016, approximately 28 months) Overall survival in all randomised participants (time frame: from date of randomisation to date of death (assessed up to August 2016, approximately 28 months) Objective response rate (ORR) in participants with PD‐L1 expression ≥ 5% (time frame: from date of randomisation until date of documented tumour progression or subsequent anti‐cancer therapy, whichever occurs first (assessed up to August 2016, approximately 28 months) Duration of response in participants with PD‐L1 expression ≥ 5% (time frame: from date of first confirmed response to date of tumour progression (assessed up to august 2016, approximately 28 months) Time to response in participants with PD‐L1 expression ≥ 5% (time frame: from date of randomisation to date of first confirmed response (assessed up to August 2016, approximately 18 months) Disease‐related symptom improvement rate by week 12 (time frame: from date of randomizations to week 12) Participants characteristics Enrolled N = 1325 Randomised N = 541 Nivolumab group: N= 271. Age median, range: 63 (32 to 89) years. Age category n (%) ≥ 75: 30 (11). Female n (%): 87 (32). Ethnicity/Region n (%): not reported; ECOG performance n (%): 0 = 85 (31), 1= 183 (68), ≥2: 2(1); smoking status n (%): former smoker: 186 (69), current smoker: 52 (19), never smoked: 30 (11), unknown = 3 (1). Tumour histological type n (%): squamous: 66 (24); non‐squamous 205 (76); PD‐L1 expression level n (%): ≥5%: 208 (77), PD‐L1 expression level n (%) ≥ 50%: 88 (32) Chemotherapy group: N= 270. Age median, range: 65 (29 to 87) years. Age category n(%) ≥75: 32 (12). Female n(%): 122 (45); Ethnicity/Region n (%): not reported; ECOG performance n (%): 0 = 93 (34), 1 = 174 (67), ≥2: 3(1); smoking status n (%): former smoker: 182 (67), current smoker: 55 (20), never smoked: 29 (11), unknown: 4 (1). Tumour histological type n (%): squamous: 64 (24); non‐squamous 206 (76); PD‐L1 expression level n (%): ≥ 5%: 210 (78), PD‐L1 expression level n (%) ≥50%: 126 (47).
Notes	Sponser source: Bristol‐Myers Squibb Author's email: david.carbone@osumc.edu ClinicalTrials.gov Identifier: NCT02041533 Protocol amendments: the study was amended to include as secondary objective the comparison of overall survival upon nivolumab or investigators' choice chemotherapy among all randomised patients with any PD‐L1 positive tumour expression. Other notes Treatment beyond progression allowed in the Nivolumab arm Cross‐over was optional
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants are enrolled using the Interective Voice Response System (IVRS) and randomised when a randomisation call is made into the IVRS
Allocation concealment (selection bias)	Low risk	Central allocation (through a telephone‐based randomisation).
Blinding of participants and personnel (performance bias) All outcomes	High risk	It is an open‐label trial, so not blinded for participants and personnel. The absence of blinding could influence results of primary outcome (progression‐free survival).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The primary outcome (progression‐free survival) is assessed by blinded independent central review
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was a dropout rate of 22% and progression‐free survival was measured on 423 patients instead of 541 randomised patients. However, progression‐free survival in all randomised patients (secondary outcome) confirmed the results observed in 423 patients limiting the risk of attrition bias.
Selective reporting (reporting bias)	Low risk	The study protocol is available and the published reports include all expected outcomes
Other bias	High risk	Some baseline differences in patients characteristics (gender, PD‐L1 expression, liver metastases). Some authors declared conflicts of interest related to the present study or received personal fees from pharmaceutical companies conducting the trial.