CheckMate 025: A randomized, open-label, phase III study of nivolumab versus everolimus in advanced renal cell carcinoma Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Li-An Xu, Ian M. Waxman, Robert J. Motzer, on behalf of the CheckMate 025 investigators

Introduction Each year, an estimated 338,000 new cases of renal-cell carcinoma are diagnosed worldwide, and approximately 30% of patients present with metastatic disease at the time of diagnosis A number of targeted therapies have been approved for the treatment of advanced or metastatic RCC based on PFS Current therapies provide limited OS benefit in patients who have been previously treated, highlighting a significant unmet medical need This phase III study compared nivolumab, a PD-1 immune checkpoint inhibitor, versus everolimus in patients with mRCC after prior systemic therapy RCC, renal cell carcinoma; PFS, progression-free survival; OS, overall survival; PD-1, programmed death-1.

Study design and endpoints Randomized, open-labeled phase III study to compare nivolumab with everolimus in patients with advanced RCC after prior systemic therapy (NCT01668784) Enrolled patients Previously treated advanced or metastatic clear-cell RCC 1 or 2 prior anti- angiogenic treatments Randomize 1:1 Nivolumab (N = 410) 3 mg/kg every 2 weeks intravenous Everolimus (N = 411) 10 mg/day oral Treat until progression or intolerable toxicity Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted Disease assessments Every 8 weeks from randomization through 12 months Then every 12 weeks until progression or treatment discontinuation Primary endpoint Overall survival (OS)

Overall survival Median OS, months (95% CI) Nivolumab (N = 410) 25.0 (21.8–NE) Everolimus (N = 411) 19.6 (17.6–23.1) 3 6 12 9 15 18 21 24 27 30 33 0.0 0.3 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Overall Survival (Probability) Nivolumab Everolimus HR (98.5% CI), 0.73 (0.57–0.93) P = 0.0018 Months The risk of death was reduced by 27% in patients in the nivolumab treatment group compared with those in the everolimus group Study stopped after planned interim analysis (398 deaths) because assessment by an independent data monitoring committee concluded that the study met its primary endpoint, demonstrating superior OS for nivolumab This means that patients are more likely to live when treated with nivolumab versus everolimus HR, hazard ratio; NE, not estimable.

Objective response rate Patients on nivolumab treatment had a significantly better objective response rate than those on everolimus treatment This means that more patients responded to treatment with nivolumab than to treatment with everolimus

Treatment-related AEs Grade 3 or 4 treatment-related AEs were less frequent with nivolumab than with everolimus and treatment-related adverse events leading to discontinuation were experienced by fewer patients treated with nivolumab The most common treatment-related AEs of any grade reported in the nivolumab arm were fatigue (33%), nausea (14%), and pruritus (14%), and in the everolimus arm, fatigue (34%), stomatitis (29%), and anemia (24%) There were no treatment-related deaths in the nivolumab treatment arm This suggests that nivolumab has a favorable safety profile in patients with mRCC AE, adverse event; mRCC, metastatic renal cell carcinoma.

Key conclusions CheckMate 025 met its primary endpoint, demonstrating OS superiority with nivolumab versus everolimus This is the only phase III trial to demonstrate a survival advantage in previously-treated patients with mRCC versus standard therapy Nivolumab was associated with a greater number of objective responses than everolimus The survival improvement and favorable safety profile demonstrated in this phase III trial provides evidence for nivolumab as a potential new treatment option for previously treated patients with mRCC Based on the positive results of this trial, nivolumab was granted a breakthrough therapy designation from the FDA for advanced RCC, reinforcing the importance of these results in a patient population with large unmet medical need