PD-L1 expression has been observed in most clear cell renal cell carcinoma (RCC) and is associated with poorer cancer-specific survival.1 Ipilimumab (IPI), a fully human monoclonal antibody to CTLA-4, has demonstrated preliminary activity and tolerability in metastatic RCC (mRCC).2 Combining nivolumab (NIV), an anti-PD-1 antibody, and IPI has shown encouraging clinical activity and acceptable safety in advanced melanoma.3 To better understand the viability of this combination in mRCC, Hammers and colleagues conducted a phase 1 trial of NIV + IPI in patients with mRCC, including untreated patients and those who relapsed after any number of prior treatments (ASCO 2014; Abstract 4504).
The study enrolled good performance status patients with favorable- and intermediate-risk mRCC based on Memorial Sloan Kettering Cancer Center score. They were randomized to receive either NIV 3 mg/kg and IPI 1 mg/kg (Arm N3I1) or NIV 1 mg/kg and IPI 3 mg/kg (Arm N1I3) every 3 weeks for 4 doses. NIV was then given at a dose of 3 mg/kg intravenously every 2 weeks until disease progression or toxicity. The study’s primary objective was to assess safety and tolerability of the NIV + IPI combination, while the secondary objective was to assess antitumor activity.
A total of 44 patients were randomized to Arm N3I1 (n = 21) and Arm N1I3 (n = 23). Most patients (79%) had received prior systemic therapy for mRCC.
Treatment-related adverse events (AEs) were seen in 76% of patients in Arm N3I1and 100% of patients in Arm N1I3. AEs resulted in discontinuation of the combination in 10% of patients in Arm N3I1 and in 26% in Arm N1I3. Grade 3/4 AEs included increased lipase, increased liver enzymes, increased amylase, diarrhea, and colitis. No grade 3/4 pneumonitis was observed.
After follow-up of at least 35 weeks, the objective response rate to NIV + IPI in these patients with mRCC was 43% in Arm N3I1 and 48% in Arm N1I3. Responses were observed at the first tumor assessment (week 6) in the majority of responding patients in both arms of the study. Only 1 complete response was noted, which occurred in Arm N1I3. Stable disease was documented in 24% of patients in Arm N3I1 and 35% of patients in Arm N1I3 (Table).
Table: Efficacy Outcomes of NIV + IPI in Patients with mRCC (n = 44)
Hammers and colleagues concluded that NIV + IPI showed acceptable safety and encouraging antitumor activity in mRCC, with most responses ongoing. Expansion cohorts at these tested doses, as well as an additional higher-dose cohort (NIV 3 mg/kg + IPI 3 mg/kg) are being assessed.
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