Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM)

Abstract

Purpose: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile.

Methods: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy.

Results: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively.

Conclusion: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

FIG 1.

CONSORT flow diagram.

FIG 2.

Key trAEs by severity. CTCAE, Common Terminology Criteria for Adverse Events; trAE, treatment-related adverse event.

FIG 3.

(A) PFS and (B) OS by treatment allocation among the mITT population. mITT, modified intention-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 4.

(A) PFS and (B) OS by treatment allocation among the IMDC intermediate-/poor-risk population. IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 5.

Summaries of mean (A) QLQ-C30 global health status, (B) FKSI-19 total score, and (C) EQ-5D VAS over time, by randomized allocation. EQ-5D, EuroQol 5-dimension; FKSI, Functional assessment of cancer-therapy Kidney Symptom Index; QLQ-C30, Quality of Life Questionnaire-C30; QoL, quality of life; VAS, visual analogue scale.