Nivolumab Plus Ipilimumab vs Sunitinib in Previously Untreated Advanced RCC
As reported in The New England Journal of Medicine by Motzer et al, the phase III CheckMate 214 trial has shown an overall survival advantage with nivolumab plus ipilimumab vs sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC).
Study Details
In the open-label trial, 1,096 patients with advanced clear cell RCC from 175 sites in 28 countries were randomized between October 2014 and February 2016 to receive nivolumab (Opdivo) at 3 mg/kg plus ipilimumab (Yervoy) at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks (n = 550) or oral sunitinib (Sutent) at 50 mg once daily for 4 weeks in 6-week cycles (n = 546). Among patients in the nivolumab/ipilimumab group, 425 had intermediate-risk (n = 334) or poor-risk (n = 91) disease; among the patients in the sunitinib group, 422 had intermediate-risk (n = 333) or poor-risk (n = 89) disease.
The co-primary endpoints were overall survival (alpha level = 0.04), objective response rate (alpha level = 0.001), and progression-free survival (alpha level = 0.009) among patients with intermediate or poor prognostic risk.
Outcomes by Risk Group
Median follow-up was 25.2 months among patients with intermediate- or poor-risk disease. Overall survival in the nivolumab/ipilimumab group vs sunitinib group was 80% vs 72% at 1 year and 75% vs 60% at 18 months, with median overall survival not reached vs 26.0 months (hazard ratio [HR] = 0.63, P < .001). The objective response rate was 42% vs 27% (P < .001), with complete response in 9% vs 1%.
Median progression-free survival was 11.6 vs 8.4 months (HR = 0.82, P = .03), with the difference not being statistically significant as it did not meet the prespecified .009 threshold. Hazard ratios were 0.66 (95% confidence interval [CI] = 0.50–0.87) among patients with intermediate risk and 0.57 (95% CI = 0.39–0.82) among those with poor risk.
Outcomes in All Patients
In analysis among all patients, including the 125 nivolumab/ipilimumab recipients and 124 sunitinib recipients with favorable risk, overall survival was 83% vs 77% at 12 months and 78% vs 68% at 18 months. Median overall survival was not reached vs 32.9 months (HR = 0.68, P < .001). Objective response rates were 39% vs 32% (P = .02, not significant per the prespecified .001 threshold). Median progression-free survival was 12.4 months vs 12.3 months (HR = 0.98, P = .85). Among favorable-risk patients alone, overall survival was 94% vs 96% at 12 months and 88% vs 93% at 18 months, with the hazard ratio nonsignificantly favoring sunitinib (HR = 1.45, P = .27).
Overall, 39% of the nivolumab/ipilimumab group and 54% of the sunitinib group received subsequent systemic therapy, with the most common being sunitinib (20%) and pazopanib (Votrient, 13%) in the nivolumab/ipilimumab group and nivolumab (27%) and axitinib (Inlyta, 19%) in the sunitinib group.
Outcome by PD-L1 Expression Status
Among 776 intermediate- and poor-risk patients with quantifiable programmed cell death ligand 1 (PD-L1) expression, 100 of 384 patients (26%) in the nivolumab/ipilimumab group and 114 of 392 (29%) in the sunitinib group had ≥ 1% PD-L1 expression. In exploratory analysis, overall survival was 86% vs 66% at 12 months and 81% vs 53% at 18 months, with median survival not reached vs 19.6 months (HR = 0.45, 95% CI = 0.29–0.71) among patients with PD-L1 expression ≥ 1%. Overall survival was 80% vs 75% at 12 months and 74% vs 64% at 18 months, with median survival not reached in either group (HR = 0.73, 95% CI = 0.56–0.96) among patients with PD-L1 expression < 1%.
Adverse Events
Grade 3 or 4 adverse events occurred in 46% of patients in the nivolumab/ipilimumab group vs 63% in the sunitinib group. The most common in the nivolumab/ipilimumab group were increased lipase (10%), diarrhea (4%), and fatigue (4%), and the most common in the sunitinib group were hypertension (16%), palmar-plantar erythrodysesthesia (9%), and increased lipase (7%).
Treatment-related immune-related adverse events of any grade occurred in 80% of patients in the nivolumab/ipilimumab group; among these patients, 35% received high-dose corticosteroids. Treatment-related adverse events led to discontinuation of treatment in 22% of the nivolumab/ipilimumab group and 12% of the sunitinib group. Treatment-related adverse events led to death in 8 patients in the nivolumab-ipilimumab group (1 each due to pneumonitis; pneumonia and aplastic anemia; immune-mediated bronchitis; lower gastrointestinal hemorrhage; hemophagocytic syndrome; sudden death; liver toxicity; and lung infection) and in 4 patients in the sunitinib group (2 due to cardiac arrest and 1 each due to heart failure and multiple organ failure).
The investigators concluded, “Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal cell carcinoma.”
The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical.
Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, Hans J. Hammers, MD, PhD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and Bernard Escudier, MD, of Institut Gustave Roussy, contributed equally to the New England Journal of Medicine article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
