ESMO 2021: Nivolumab in Combination With Alternatively Scheduled Ipilimumab in First-Line Treatment of Patients With Advanced RCC: A Randomized Phase II Trial (PRISM)

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 virtual annual meeting’s non-prostate cancer proffered paper session included a presentation by Dr. Naveen Vasudev discussing results of the phase II PRISM trial assessing nivolumab combination with alternatively scheduled ipilimumab in first-line treatment of advanced renal cell carcinoma (RCC). Ipilimumab plus nivolumab is a standard first-line treatment for patients with intermediate and poor-risk advanced RCC based on data from the CheckMate 214 trial.1 Grade 3/4 treatment-related adverse events are relatively common during the initial combination period, including 47% of patients experiencing a grade 3/4 treatment-related adverse event and 22% of patients discontinuing treatment due to treatment-related adverse events in the CheckMate 214 trial. The aim of this randomized phase II trial was to determine whether modified scheduling of ipilimumab, in combination with nivolumab, is associated with improved tolerability, while maintaining treatment efficacy in line with previous comparative studies with sunitinib.

Patients with untreated clear cell advanced RCC were randomized 1:2 to receive 4 doses of ipilimumab 1mg/kg Q3W (conventional ipilimumab) or Q12W (modified ipilimumab), in combination with nivolumab (3mg/kg), until disease progression or unacceptable toxicity. The study design for PRISM is as follows:

 

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As follows is a summary of the treatment schedule in PRISM:

 

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The primary endpoint was the proportion of patients with a grade 3/4 treatment-related adverse events 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 tested against the historical PFS associated with sunitinib and objective response rate (ORR).

 There were 192 patients (69.8% intermediate/poor-risk), including 128 patients in the modified ipilimumab arm and 64 patients in the standard ipilimumab arm, that received at least one dose of study drug. The median follow-up for the cohort was 19.7 months IQR: 15.9-23.6 months). Grade 3/4 treatment-related adverse events were significantly lower amongst patients receiving modified ipilimumab compared to conventional ipilimumab (32.8% versus 53.1%; OR 0.43, 90% CI 0.25, 0.72):

 

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The most common grade 3/4 adverse events in the modified ipilimumab group was diarrhea (5.5%) and ALT increase (4.7%), whereas the most common grade 3/4 adverse events in the standard ipilimumab arm was arthralgia (7.8%), and diarrhea (4.7%). 12-month PFS rate was 46.1% (90% CI 38.6-53.2%) in the modified ipilimumab compared to the sunitinib historical rate of 39.7%; median PFS in the modified ipilimumab arm was 10.8 months (95% CI 8.2-14.2) compared to 9.8 months (95% CI 9.8-13.3) in the standard ipilimumab arm. Median PFS in the IMDC intermediate/poor risk group was 10.5 months for the modified ipilimumab arm (90% 7.0-14.2) compared to 8.6 months (90% 6.0-16.3) in the standard ipilimumab arm. In the intention-to-treat analysis, the ORR in for the modified ipilimumab arm was 45.3% (95% CI 36.7-53.9) compared to 35.9% (95% CI 24.2-47.7) in the standard ipilimumab. As follows is the summary of the treatment responses:

 

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Although with limited follow-up, the median OS in either arm was not reached, however the 12-month landmark OS rate was 88.3% for the modified ipilimumab arm compared to 83.7% in the standard ipilimumab arm.

 

Dr. Vasudev concluded his presentation of the PRISM trial with the following take-home messages:

  • Giving ipilimumab 12-weekly, instead of 3-weekly, in combination with nivolumab, was associated with a clinically significant reduction in rates of grade 3/4 treatment-related adverse events (33% versus 53%)
  • The lower limit of the confidence interval for 12 month PFS observed with modified ipilimumab failed to exclude the rate associated with historical control data (sunitinib)
  • However, median PFS, ORR, duration of response and 12-month landmark OS results were comparable between treatment arms
  • This positive phase 2 trial supports further exploration of different nivolumab/ipilimumab regimes

 

Presented by: Naveen S. Vasudev, PhD, MRCP, MBChB, BMSc (Hons), Medical Oncology Department, St. James's University Hospital Leeds, Leeds, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter  during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.

References:

  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.

 

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