Motzer 2015a

Methods	Study design: 2‐arm, parallel‐group, open‐label RCT. Study dates: randomization October 2012 to March 2014, data cutoff: June 2015, minimal follow‐up of 14 months. Setting: multicentre (146 centres), international, phase III. Countries: North America (US, Canada), Western Europe (Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Norway, Poland, Romania, Spain, Sweden, UK), South America (Argentina, Brazil) and Asia (Israel, Japan).
Participants	Inclusion criteria: people with histologically confirmed advanced or mRCC with a clear‐cell component, aged ≥ 18 years, measurable disease, prior treatment with 1 or 2 antiangiogenic therapies, ≤ 3 previous systemic therapies with cytokines and cytotoxic drugs and disease progression during or > 1 treatment regimen within 6 months before study enrolment, KPS ≥ 70. Exclusion criteria: central nervous system metastasis, previous treatment with an mTOR inhibitor, condition requiring treatment with glucocorticoids (equivalent to > 10 mg of prednisone > 10 mg daily). Sample size:821. Age (years, median with range): group 1: 62 (23‐88); group 0: 62 (18‐86). Sex (M/F, %): group 1: 77/23; group 0: 74/26. Prognostic factors: performance status (KPS < 70/70/80/90/100, %): 1/6/28/34/32; prior nephrectomy (%): 88; prior systemic therapies for advanced RCC (1/2, %): 72/28; prior systemic therapies for mRCC (sunitinib/pazopanib/axitinib, %): 59/30/10; risk prognosis (MSKCC favourable/intermediate/poor, %): 36/49/15.
Interventions	Group 1 (n = 410): nivolumab Nivolumab 3 mg/kg IV every 2 weeks, no dose modifications permitted). Group 0 (n = 411): everolimus Everolimus 10 mg orally, every day, dose modifications permitted. Cointerventions (standard‐of‐care according to local practice): not specified.
Outcomes	OS (primary endpoint) How measured: time from randomization to the date of death. Time points measured: every 8 weeks for the first year, and then every 12 weeks until disease progression or discontinuation of treatment, after discontinuation of treatment, participants followed every 3 months for assessment of survival and subsequent anticancer therapy. Time points reported: Kaplan‐Meier survival curves over up to 30 months, median with 95% CI, unstratified HR with 98.5% CI. Subgroups: MSKCC prognostic score, previous antiangiogenic regimens, region, age, gender. AEs, grade ≥ 3 (secondary endpoint) How measured: NCI‐CTC AE V4.0. Time points measured: at each clinic visit. Time points reported: overall frequency of all and most common treatment‐related AEs (fatigue, pruritus, stomatitis, anaemia) and AEs grade 3/4 including treatment‐related deaths. Subgroups: not reported. QoL (secondary endpoint) How measured: health‐related QoL assessments with FACT FKSI‐DRS and a resulting summary score and EQ‐5D. Time points measured: baseline, after randomization but before cycle 1 of therapy, on day 1 of each cycle, at the first 2 follow‐up visits (each assessment before physician contact, treatment doses and any procedures), about 30 and 100 days after last dose, EQ‐5D: additional at each of the 10 survival follow‐ups visits (every 3 months). Time points reported: FKSI‐DRS and EQ‐5D (utility index and VAS) with completion rates at baseline, mean change from baseline to weeks 4 to 104, clinically important improvements, time to improvement (Cella 2016). Subgroups: not reported. PFS (secondary endpoint) How measured: time from randomization to first documented RECIST‐defined tumour progression or death from any cause. Time points measured: CT and MRI at baseline, every 8 weeks for the first year and then every 12 weeks until disease progression or discontinuation of treatment. Time points reported: Kaplan‐Meier survival curves over up to 30 months, median. Subgroups: not reported. Tumour remission (secondary endpoint) How measured: evaluated by the investigator (RECIST 1.1), number of randomized participants with a complete or partial response. Time points measured: CT and MRI at baseline, every 8 weeks for the first year and then every 12 weeks until disease progression or discontinuation of treatment. Time points reported: overall response. Subgroups: not reported.
Funding sources	Bristol Myers Squibb.
Declarations of interest	RJM: honoraria from Bayer, Pfizer, Novartis and GlaxoSmithKline. SG: fees for consulting and serving on advisory boards from Bristol‐Myers Squibb, Novartis, Bayer, Sanofi‐Aventis, Astellas, Xcenda and Onclive; grant support from Bristol‐Myers Squibb, Novartis, Bayer, Pfizer, Acceleron, Merck and Agensys. HJH: grant support from Pfizer, Newlink Genetics, GlaxoSmithKline and SFJ Pharmaceuticals. SST: fees for serving on advisory boards from Prometheus; consulting fees from Amgen; grant support through his institution from Prometheus, Argos Therapeutics, Immatics Biotechnologies, Novartis and Exelixis. GP: fees for serving on advisory boards from Janssen and Novartis; lecture fees from Astellas and Pfizer; grant support from Bayer. ERP: fees for serving on advisory boards from Merck, Dendreon, GlaxoSmithKline, Pfizer, Astellas, Novartis and Genentech; grant support from AstraZeneca, Eli Lilly, Merck, Dendreon, GlaxoSmithKline, Acceleron and Pfizer. TKC: fees for consulting and for serving on advisory boards from GlaxoSmithKline, Novartis, Pfizer, Merck, AstraZeneca, Bayer and Prometheus; grant support through his institution from Bristol‐Myers Squibb, GlaxoSmithKline, Novartis, Exelixis, Pfizer, Merck, Roche, AstraZeneca, TRACON Pharmaceuticals and Peloton. HG: fees for serving on advisory boards from Novartis, Bayer, Sanofi‐Aventis, Astellas and Pfizer. FD: grant support from Novartis, Pfizer and GlaxoSmithKline. PB: honoraria from GlaxoSmithKline, Pfizer and Orion. JW: fees for serving on advisory boards, paid to his institution, from Bristol‐Myers Squibb, Novartis, GlaxoSmithKline, Roche and Amgen. YT: fees for serving on advisory boards from ONO Pharmaceuticals and Pfizer; honoraria and grant support from ONO Pharmaceuticals, Novartis and Pfizer. TCG: fees for consulting and serving on advisory boards from Boehringer Ingelheim, Merck Serono, Novartis, Pfizer, GlaxoSmithKline, Merck Sharp & Dohme, Bayer HealthCare, Roche, Bristol‐Myers Squibb, Eli Lilly and Janssen‐Cilag; honoraria from Boehringer Ingelheim, Merck Serono, Novartis, Pfizer, GlaxoSmithKline, Bayer, Roche, Eli Lilly, Janssen‐Cilag, Sanofi‐Aventis; travel support from Boehringer Ingelheim, Merck Serono, Pfizer, Roche and Eli Lilly; owning stock in Bayer. FAS: fees for serving on advisory boards from Pfizer, GlaxoSmithKline and Novartis; lecture fees from GlaxoSmithKline. CK: fees for serving on advisory boards from Pfizer, Novartis, Sanofi‐Aventis, Bayer and Seattle Genetics; lecture fees from Pfizer and Novartis. AR: lecture fees from Merck Sharp & Dohme. JSS, LAX, IMW: employees of and hold stock in Bristol‐Myers Squibb. PS: reports receiving consulting fees from Jounce Therapeutics, Amgen, Bristol‐Myers Squibb, GlaxoSmithKline and AstraZeneca/MedImmune; also founder of and holds stock in Jounce Therapeutics.
Notes	Registration: NCT01668784 (CheckMate025). Study was stopped early due to the results of a planned interim analysis by the independent data monitoring committee showing significant benefit for OS.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Low risk of selection bias assumed due to block randomization, stratified by region, MSKCC prognostic risk group and the number of previous antiangiogenic therapy regimens (1 or 2) for advanced RCC.
Allocation concealment (selection bias)	Low risk	Central randomization.
Blinding of participants and personnel (performance bias) Subjective outcomes	High risk	Open‐label study.
Blinding of participants and personnel (performance bias) Objective outcomes	Low risk	No performance bias on OS assumed.
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	No detection bias on OS assumed.
Incomplete outcome data (attrition bias) (OS and PFS)	Low risk	Low risk of attrition bias assumed, high completeness of follow‐up with similar censoring in between treatment groups.
Incomplete outcome data (attrition bias) (safety)	Low risk	Low risk of attrition bias assumed, safety analysis bases on all treated participants.
Incomplete outcome data (attrition bias) (tumour remission)	High risk	High risk of bias on attrition bias for tumour remission assumed due to different numbers of non‐evaluated participants (6% with nivolumab vs 12% with everolimus).
Incomplete outcome data (attrition bias) (QoL)	Low risk	High completion rates (≥ 80% in the first year) with no differences between treatment groups.
Selective reporting (reporting bias)	Low risk	All preplanned outcomes from the protocol reported.
Other bias	High risk	Stopped early for benefit in OS, subsequent systematic therapies (group 1: 55%; group 0: 63%) with cross‐over (25% from group 1 to group 0; 1.7% from group 0 to group 1).