Pfizer, Pfizer Exelixis the conduct of the Background— In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (NIVO +IPI) demonstrated superior efficacy over sunitinib (SUN) in patients with previously untreated IMDC intermediate/poor-risk advanced renal cell carcinoma (aRCC) with a manageable safety profile. We assessed efficacy and safety after extended follow-up to inform the long-term clinical value of NIVO+IPI versus SUN in this setting. Methods— In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by IMDC risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label NIVO 3 mg/kg IV plus IPI 1 mg/kg IV every 3 weeks for four doses, followed by NIVO 3 mg/kg IV every 2 weeks; or SUN 50 mg orally once daily for 4 weeks (6-week cycle). Randomisation was done with a block size of four and stratified by risk status and region. Here, we report overall survival (OS), investigator-assessed PFS, the proportion of patients achieving an investigator-assessed objective response per RECIST v1.1, characterisation of response, and safety in all patients (ITT and across risk groups) with extended follow-up. The co-primary endpoints of the trial reported vs 186 [34%] of 546; p=0·02, Δresponse = 7·6% [95% CI 2·0–13·2]) were observed with NIVO +IPI versus SUN, respectively.Of all treated patients (547 NIVO+IPI; 535, SUN), the most common grade 3–4 treatment-related AEs were increased lipase (57 [10%]), amylase (31 [6%], and alanine aminotransferase (28 [5%]) with NIVO+IPI vs hypertension (90 [17%]), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]) with SUN. Eight deaths in the NIVO +IPI arm (one each due to pneumonitis, pneumonia and aplastic anaemia, immune-mediated bronchitis, lower gastrointestinal haemorrhage, hemophagocytic syndrome, sudden death, liver toxic effects, and lung infection) and four deaths in the SUN arm (two cardiac arrests and one each of heart failure and multiple organ failure) were reported as treatment-related. Interpretation— These results suggest that the superior benefit-risk profile of NIVO+IPI over SUN were maintained in intermediate/poor-risk and ITT patients with extended follow-up and demonstrate the long-term benefits of NIVO+IPI in patients with previously untreated aRCC across all risk categories. 0·04 with 90% power for OS) in the primary analysis. A formal comparison of OS in ITT patients was conducted using a two-sided stratified log-rank test at the same alpha level at the time of the final analysis of co-primary endpoints based on a hierarchical testing procedure. Alpha allocations inform the sample size determination to adequately power the study and are no longer relevant in this analysis. We include p-values for descriptive purposes to confirm consistency with primary outcomes as appropriate. Efficacy outcomes were assessed in all randomised patients (ITT population and by risk) and safety outcomes were assessed in all treated patients. The prespecified analyses of OS, PFS, duration of study therapy, and duration of response were estimated per Kaplan-Meier methodology. Stratified Cox proportional HRs and 95% CIs were calculated between treatment arms for OS and PFS, and as an exploratory measure of duration of response. Post-hoc analysis of the effects of clinically relevant baseline features individual of Extended follow-up of first-line combination treatment with NIVO+IPI in patients with aRCC continues to demonstrate impressive antitumour activity over sunitinib in CheckMate 214. Improved OS was maintained with NIVO+IPI versus sunitinib in both the intermediate/poor-risk and the intention-to-treat (ITT) populations, and OS was similar between arms in the smaller favourable-risk subgroup. An improvement was also observed in PFS with NIVO+IPI over sunitinib with longer follow-up, with 28% of ITT patients remaining progression-free at 30 months. Complete and durable responses were observed with NIVO+IPI regardless of IMDC risk–based prognosis. No new safety signals emerged with NIVO+IPI, and the adverse event profile continued to be manageable. These results demonstrate the long-term benefits of NIVO+IPI in patients with previously untreated aRCC, and support future analyses exploring the role for NIVO +IPI in treating novel patient populations and ongoing studies combining NIVO+IPI with novel agents to further improve outcomes for patients with aRCC. u