1. Amongst patients with advanced renal-cell carcinoma and an intermediate or poor prognosis, nivolumab plus ipilimumab was superior to sunitinib alone in improving overall survival.
2. Though not statistically compared, there was a lower incidence of grade three or four adverse events with nivolumab plus ipilimumab, although more patients in the combination therapy arm stopped treatment due to side effects.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Advanced renal cell carcinoma carries high morbidity and mortality. The current standard of care involves treatment with sunitinib, a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor. The combination of nivolumab plus ipilimumab, a programmed death 1 immune checkpoint inhibitor antibody and anti-cytotoxic T-lymphocyte associated antigen 4 antibody, respectivly, has shown efficacy in treatment of melanoma, and showed efficacy for treatment of renal cell carcinoma in pilot studies. This phase three trial randomized patients with previously treated advanced renal cell-carcinoma of either intermediate or poor prognosis to either sunitinib or nivolumab plus ipilimumab and compared overall survival, objective response rate, and progression-free survival. Combination therapy was superior to sunitinib in extending overall survival and achieving objective response, but combination therapy did not have a statistically significant effect on progression-free survival.
Strengths of this study include its randomized study design and the use of overall survival as a primary outcome. Generalization of results is limited to patients with poor and intermediate risk advanced renal cell, although these patients do constitute many advanced renal cell cases.
In-Depth [randomized controlled trial]: This was a phase three, multicenter randomized controlled trial that assigned 1096 patients to either nivolumab plus ipilimumab (n = 550) or sunitinib (n = 546). Patients were eligible if they had untreated advanced renal cell carcinoma that was either determined to be intermediate or poor prognostic risk. The Karnofsky score, a measure of functional status, had to be greater than 70. Combination therapy was administered in an induction and maintenance phase. The coprimary endpoints were overall survival, objective response rate, and progression-free survival. Quality of life was also investigated as a secondary outcome.
Median follow-up was 25.2 months. The 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with combination therapy and 60% (95% CI, 55 to 65) with sunitinib (hazard ratio [HR] 0.63, 95% CI, 0.44 to 0.89; p < 0.001). The objective response rate was greater in the combination therapy group (42% vs. 27%, p < 0.001). No statistically significant difference was seen in median progression-free survival (p = 0.03, prespecified threshold of 0.009). There was generally a lower incidence of grade three or four adverse events with combination therapy, although more patients in combination therapy stopped treatment due to side effects, though no statistical analysis was performed. The mean change from baseline in the quality of life score in the combination therapy group was greater in the combination therapy group than the sunitinib group (p < 0.001).
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