Rizvi 2020.

Study characteristics
Methods	Study design: randomised open‐label parallel controlled, phase 3 trial Study setting: multicentre trial, 167 study locations Country: 17 countries, USA, Canada, Europe, Russia, Australia and parts of Asia, including Japan, Korea, Thailand, Taiwan and Vietnam. Publication: Abstract
Participants	Inclusion criteria Aged at least 18 years Documented evidence of Stage IV NSCLC No sensitising EGFR mutation or ALK rearrangement No prior chemotherapy or any other systemic therapy for recurrent/metastatic NSCLC World Health Organization (WHO) Performance Status of 0 or 1 Exclusion criteria Mixed small‐cell lung cancer and NSCLC histology, sarcomatoid variant Brain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids) Prior exposure to Immunomodulatory therapy (IMT), including, but not limited to, other anti‐cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4), anti‐programmed cell death1 (PD‐1), anti‐programmed cell death ligand 1 (PD‐L1), or anti PD‐L2 antibodies, excluding therapeutic anticancer vaccines Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g., colitis or Crohn's disease) Participants Characterisctics Number randomised: 1118 Durvalumab group (PD‐L1 TPS ≥25%) N = 163. Age median, (range): 64, (32 to 84 years). Male sex n (%): 113 (69.3); ECOG performance n (%): 0: 57 (35); current/former/never smoked 47 (28.8), 92 (56.4), 24 (14.7). Histology: squamous n (%) = 52 (31.9) Durvalumab plus tremelimumab group (PD‐L1 TPS ≥25%) N = 163. Age median, (range): 65, (34 to 87 years), Male sex n (%): 118 (72.4); ECOG performance n (%): 0: 65 (39.9); current/former/never smoked 42 (25.8), 96 (58.9), 25 (15.3). Histology: squamous n (%) = 53 (32.5) Chemotherapy group (PD‐L1 TPS ≥25%) N= 162. Age median, (range): 64.5, (35 to 85 years). Male sex n (%): 106 (65.4); ECOG performance n (%): 0: 70 (43.2); current/former/never smoked 39 (24.1), 102 (63), 22 (13). Histology: squamous n(%) = 52 (32.1)
Interventions	Randomisation ratio: 1:1:1 Intervention1: PD‐L1 monoclonal antibody monotherapy (durvalumab); (20 mg/kg i.v. q4w) Intervention 2 : durvalumab + tremelimumab combination therapy, (D: 20 mg/kg i.v. q4w; T: 1 mg/kg i.v. q4w (up to 4 doses) Control: chemotherapy (intended up to 6 cycles; pemetrexed maintenance permitted in eligible people) until disease progression
Outcomes	Primary outcomes Progression‐free survival (PFS) and Overall survival (OS) in patients with durvalumab and tremelimumab combination compared to chemotherapy in people with PD‐L1 ≥ 25% (time frame: 3 years) Overall survival (OS) with durvalumab compared to chemotherapy in people with PD‐L1 ≥ 25% (time frame: 3 years) Secondary outcomes Objective response rate (ORR) or progression‐free survival (PFS) with durvalumab compared to chemotherapy in people with PD‐L1 ≥ 25% (time frame: 3 years) Objective response rate (ORR) with durvalumab and tremelimumab compared to chemotherapy (in people with PD‐L1 ≥25%, ≥1% and in the overall population) (time frame: 3 years) The safety and tolerability profile of durvalumab + tremelimumab combination therapy and durvalumab monotherapy compared to SoC will be determined using vital signs, laboratory data, electrocardiograms (ECGs), and physical examination (time frame: 3 years)
Notes	Sponsorship source: AstraZeneca AB ClinicalTrials.gov Identifier: NCT02453282 Study protocol: not published Other notes: Cross‐over during the trial was not permitted
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Using the Interactive Voice Response System (IVRS) and integrated web response system (IWRS)
Allocation concealment (selection bias)	Low risk	A blocked randomisation is used and all the centres use the same randomisation list in order to minimize any imbalance in the number of patients assigned to each treatment group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	It is an open‐label study. The absence of blinding could influence results of some primary outcomes (progression‐free survival).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The primary endpoint is progression‐free survival by blinded independent central review assessment
Incomplete outcome data (attrition bias) All outcomes	High risk	The primary analysis population for the study was amended to include only people with PD‐L1 expression ≥25%, therefore only 488 (44%) of 1118 randomised people were included in the analysis of the trial primary outcome
Selective reporting (reporting bias)	Low risk	Outcomes reported for all groups
Other bias	Unclear risk	Some authors declared conflicts of interest related to the present study or received personal fees from pharmaceutical companies conducting the trial.