As reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, the phase III CheckMate 214 trial has shown an overall survival advantage with nivolumab (Opdivo) plus ipilimumab (Yervoy) vs sunitinib (Sutent) in patients with previously untreated advanced renal cell carcinoma.¹

Study Details

In the open-label trial, 1,096 patients with advanced clear cell renal cell carcinoma from 175 sites in 28 countries were randomized between October 2014 and February 2016 to receive nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg every 2 weeks (n = 550) or oral sunitinib at 50 mg once daily for 4 weeks in 6-week cycles (n =

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.

— Robert J. Motzer, MD and colleagues

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546). Among patients in the nivolumab/ipilimumab group, 425 had intermediate- (n = 334) or poor-risk (n = 91) disease; among the patients in the sunitinib group, 422 had intermediate- (n = 333) or poor-risk (n = 89) disease. The coprimary 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 an intermediate or poor prognostic risk.

Outcomes in Intermediate- or Poor-Risk Patients

Median follow-up was 25.2 months among intermediate- or poor-risk patients. Overall survival in the nivolumab/ipilimumab group vs the 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 a complete response in 9% vs 1%. Median progression-free survival was 11.6 months vs 8.4 months (HR = 0.82, P = .03), with the difference not being statistically significant due to not meeting the prespecified 0.009 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 an analysis among all patients, including the 125 who received nivolumab/ipilimumab and the 124 who received sunitinib with a 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). The objective response rate was 39% vs 32% (P = .02, not significant per the prespecified 0.001 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 the 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 patients (29%) in the sunitinib group had ≥ 1% PD-L1 expression. In an 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 both groups (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 adverse events in the nivolumab/ipilimumab group were increased lipase levels (10%), diarrhea (4%), and fatigue (4%), and the most common adverse events in the sunitinib group were hypertension (16%), palmar-plantar erythrodysesthesia (9%), and increased lipase levels (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 eight patients in the nivolumab/ipilimumab group (one 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 four patients in the sunitinib group (two due to cardiac arrest and one 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.”

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. ■

DISCLOSURE: The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.