Conditional survival and long‐term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

Abstract

BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a firstline checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

Setting a new standard for long‐term survival in metastatic kidney cancer

“…[5][6][7][8] These studies clearly demonstrate superior outcomes in the short term, but survival data are immature, leaving in doubt the long-term impact for the majority of the study population.In this issue of Cancer, Motzer and colleagues report a minimum 5 years of follow-up data from the pivotal CheckMate-214 study. 9 The median follow-up for patients in the report was 67.7 months, with 94% to 98% of patients off study treatment. Subsequent systemic therapy was administered to 55% of patients in the intention-to-treat (ITT) group receiving nivolumab plus ipilimumab and to 68% of those receiving sunitinib.…”

“…Survival outcomes (A,B) in CheckMate‐214 and (C) using the International Metastatic Renal‐Cell Carcinoma Database Consortium (IMDC) prognostic model. In CheckMate‐214, (A) the median overall survival (OS) with nivolumab plus ipilimumab (NIVO+IPI) was 43% at 5 years in the intermediate‐risk/poor‐risk group and (B) 63% in the favorable‐risk group; whereas, (C) in the report by Heng et al, 9 using the IMDC model, OS at 5 years ranged from 0% to 20% in the intermediate‐risk/poor‐risk group and was approximately 30% in the favorable‐risk group (C was reprinted from Heng DY, Xie W, Regan MM, et al External validation and comparison with other models of the International Metastatic Renal‐Cell Carcinoma Database Consortium prognostic model: a population‐based study. Lancet Oncol .…”

“…In this issue of Cancer , Motzer and colleagues report a minimum 5 years of follow‐up data from the pivotal CheckMate‐214 study 9 . The median follow‐up for patients in the report was 67.7 months, with 94% to 98% of patients off study treatment.…”

Editorial Comment to Comprehensive assessments of immuno‐oncology drug‐based combination therapies as first‐line treatment for advanced renal cell carcinoma

“…2 Ipilimumab plus nivolumab IO-IO therapy may offer the best chance of durable response or possibly "cure," suggested by the data from the most extended follow-up among all the IO combination therapies currently available in clinical practice. 3 On the other hand, major concerns related to this treatment include initial disease progression risks and severe immune-mediated adverse events. IO-TKI therapies share some characteristics, including a relatively high objective response rate and a low progressive disease rate, suggesting that IO-TKI combination may benefit a larger patient population than IO-IO, at least in the short term.…”

“…have provided an excellent overview of IO‐IO and IO‐TKI therapies 2 . Ipilimumab plus nivolumab IO‐IO therapy may offer the best chance of durable response or possibly “cure,” suggested by the data from the most extended follow‐up among all the IO combination therapies currently available in clinical practice 3 . On the other hand, major concerns related to this treatment include initial disease progression risks and severe immune‐mediated adverse events.…”