Patients with intermediate- or poor-risk clear-cell renal cell carcinoma (RCC) respond better and survive longer with nivolumab combined with ipilimumab than with sunitinib monotherapy, according to results from the phase 3 CheckMate 214 trial published online in the New England Journal of Medicine

Overall survival rates at 18 months were 75% vs 60% in favor of nivolumab plus ipilimumab. The risk for death was 37% lower in recipients of the combination treatment compared with sunitinib-treated patients. In addition, significantly higher proportions of patients receiving the combination therapy experienced objective and complete response: 42% vs 27% and 9% vs 1%, respectively. Median progression-free survival was longer with the combination, albeit insignificantly: 11.6 vs 8.4 months. The combination group also reported greater quality of life.

Patients with favorable-risk disease showed significantly higher objective response rates with sunitinib: 52% vs 29%. Baseline programmed death ligand 1 (PD-L1) expression was lower in these patients.

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For the trial, Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, and collaborators randomly assigned 550 previously untreated patients to nivolumab plus ipilimumab and 546 to standard first-line therapy with sunitinib. Seventy-seven percent of both groups had intermediate- or poor-risk disease and 23% had favorable-risk disease. During the induction phase, nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, was administered intravenously at a dose of 3 mg/kg over 60 minutes followed by ipilimumab, an anti–cytotoxic T-lymphocyte-associated antigen 4 antibody, at 1 mg/kg over 30 minutes, every 3 weeks for 4 doses. For maintenance, nivolumab monotherapy was given at 3 mg/kg every 2 weeks. Sunitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, was administered orally at 50 mg once daily for 4 weeks of each 6-week cycle. Dose delays for adverse events were allowed, but not dose reductions.

Adverse events occurred in 93% of the nivolumab-plus-ipilimumab group and 97% of the sunitinib group. Grade 3 or 4 events were reported in 46% and 63% of the groups, respectively. Discontinuation of therapy due to adverse events occurred in 22% and 12%, respectively.

In an accompanying editorial, Brendan D. Curti, MD, of the Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon, commented: “The goal of future immunotherapy development should be not just transient response or tumor control, but rather cure in a higher proportion of patients. The combination of ipilimumab and nivolumab is a step in the right direction.”

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical, which produce nivolumab (Opdivo) and ipilimumab (Yervoy).

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Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. DOI: 10.1056/NEJMoa1712126 [Published online March 21, 2018]

Curti BD. Immunotherapy in advanced renal cancer — Is cure possible? New Engl J Med. DOI: 10.1056/NEJMe1801682 [Published online March 21, 2018]