Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study

Abstract

Purpose Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab plus ipilimumab in combination, and nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the nivolumab plus ipilimumab arms of the study are presented. Patients and Methods Patients with mRCC received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). Results All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively. Conclusion Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.

Fig 1.

Time to response, duration of response, and time during therapy (weeks) by treatment arm. N1I3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; N3I1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg; NR, not reached.

Fig 2.

(A) Tumor burden over time on the basis of percent change in target lesion size from baseline for the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg arm. (B) Tumor burden over time on the basis of percent change in target lesion from baseline for the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg arm. Dashed lines denote a 20% increase (progression) or 30% decrease indicative of response.

Fig 3.

Kaplan-Meier plot of overall survival by treatment arm. N1I3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; N3I1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg; NR, not reached.

Fig A1.

Patient distribution. (*) Data are not presented in this article. (†) All patients in the nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) arm (n = 6) were censored at the time of analysis. AE, adverse event; N3I1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg; N1I3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg.

Fig A2.

Best percent change from baseline in target lesion tumor burden up to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) progression. Dashed lines denote 30% decrease and 20% increase in tumor burden. Patients whose target lesion resolved 100% may have had concurrent progression of nontarget lesions. N1I3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; N3I1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.

Fig A3.

Kaplan-Meier plot of progression-free survival by treatment arm. N1I3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; N3I1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.