Nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced renal cell carcinoma: A randomized phase II trial (PRISM)

Abstract

Background Ipilimumab (IPI) plus nivolumab (N) is a standard first-line treatment for patients (pts) with intermediate and poor-risk advanced renal cell carcinoma (aRCC). Grade 3/4 (G3/4) treatment-related adverse events (trAE) are relatively common during the initial combination period. The aim of this randomized phase II trial was to determine whether modified scheduling of IPI, in combination with N, is associated with improved tolerability, whilst maintaining treatment efficacy in line with previous comparative studies with sunitinib. Methods Pts with untreated clear cell aRCC were randomized 1:2 to receive 4 doses of IPI 1mg/kg Q3W (conventional IPI) or Q12W (modified IPI), in combination with N (3mg/kg), until disease progression or unacceptable toxicity. The primary endpoint was the proportion of pts with a G3/4 trAE within 12 months of initiating treatment (from those who received at least one dose of therapy (modified intention-to-treat)). Secondary endpoints included progression-free survival (PFS) at 12 months and objective response rate (ORR). Results 192 pts (69.8% intermediate/poor-risk) received at least one dose of study drug. G3/4 trAE were significantly lower amongst pts receiving modified IPI compared to conventional IPI (32.8% v 53.1%; OR 0.43 [90% CI: 0.25, 0.72]; p=0.0075). Efficacy endpoints are given in the table and were similar between treatment arms and pre-specified IMDC risk subgroups. Conclusions Giving IPI 12-weekly, instead of 3-weekly, in combination with N, was associated with a clinically significant reduction in rates of G3/4 trAE. Outcome data suggested there was no clear reduction in ORR or PFS with the modified schedule and is in line with previous comparative studies with sunitinib (Table).