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@NEJM Ask the Authors & Experts: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma & Targeting an Immune Checkpoint or Multiple Kinases

Original Article

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma


Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.


A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.


The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).


Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.)


Renal-Cell Cancer — Targeting an Immune Checkpoint or Multiple Kinases


Therapy for advanced renal-cell cancer has evolved considerably in the past decade, with new agents greeted like “buried treasure,” although these agents come with substantial costs to both patients and the health system. Before 2005, the widely used systemic agents were cytokines — interferon alfa and interleukin-2, which yielded modest efficacy and substantial toxicity. Nevertheless, underlining the immunogenic nature of renal-cell cancer, durable complete responses occur in some patients who receive interleukin-2; these patients are mostly cured.1 After 2005, angiogenesis and mammalian target of rapamycin (mTOR) pathway inhibitors displaced cytokine therapy.2,3 Although the most effective sequence of therapies is not known, most patients with advanced renal-cell cancer receive a vascular endothelial growth factor (VEGF)–receptor (VEGFR) kinase inhibitor up front; at disease progression, options include another type of angiogenesis-targeted therapy or “switching the mechanism of action” to an mTOR inhibitor (e.g., everolimus). For everolimus, the benchmark median progression-free survival is 4.9 months and the median overall survival is 14.8 months; these values are based on a placebo-controlled trial involving patients whose disease progressed during angiogenesis-targeted therapy.4 In previously treated patients, therapy with sorafenib (a VEGFR inhibitor) resulted in better overall survival than did therapy with temsirolimus (an mTOR inhibitor),5 whereas axitinib proved superior to sorafenib with regard to progression-free survival6 (Table 1: Comparison of End Points from Recent Phase 3 Trials Involving Previously Treated Advanced Renal-Cell Cancer).