(UroToday.com) On Sunday, September 11, 2022, in Presidential Symposium II at the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Motzer presented highly awaited results from the CheckMate 914 trial, examining the role of adjuvant nivolumab and ipilimumab in patients treated with nephrectomy for localized renal cell carcinoma (RCC) at a high risk of relapse.
Immunotherapy has become the standard treatment approach in patients with metastatic RCC, with the combination of nivolumab and ipilimumab the first combination regime to show survival benefit as first-lien therapy. This treatment approach was therefore tested in the adjuvant setting in the CheckMate 914 trial (NCT03138512).
CheckMate 914 is a phase III, randomized, double-blind, multicenter, trial which comprises two parts. Part A compares adjuvant nivolumab and ipilimumab vs placebo while Part B compares adjuvant nivolumab monotherapy vs nivolumab and ipilimumab vs placebo in mutually exclusive patients with localized RCC at high risk of post-nephrectomy relapse.
The authors enrolled patients following radical or partial nephrectomy with negative surgical margins > 4 and ≤ 12 weeks before randomization. They had to have predominant clear cell histology; pathological TNM stage T2a (grade [G] 3 or 4) N0M0, T2b (any G) N0M0, T3 (any G) N0M0, T4 (any G) N0M0, or any T (any G) N1M0; and no clinical/radiological evidence of residual disease or distant metastases. In this presentation, Dr. Motzer focused on part A of the trial. Thus, included patients were randomized 1:1 to nivolumab and ipilimumab or placebo. Randomized was stratified according to a number of factors including TNM stage and type of nephrectomy.
Those randomized to intervention received nivolumab 240 mg Q2W (× 12 doses) + ipilimumab 1 mg/kg Q6W (× 4 doses) for 24 weeks or until disease recurrence/unacceptable toxicity.
The primary endpoint was disease-free survival (DFS) per blinded independent central review while overall survival and safety were important secondary endpoints.
The authors randomized 816 patients of whom 405 received nivolumab and ipilimumab and 411 received placebo. The median (Q1, Q3) treatment duration was 5.1 (2.8, 5.3) months and 5.1 (5.1, 5.3) months, respectively.
Over a median follow-up of 37.0 months (range, 15.4–58.0), the primary efficacy endpoint of DFS was not met (HR, 0.92; 95% CI, 0.71–1.19; P = 0.5347). Median DFS was not reached among patients who received nivolumab and ipilimumab and was 50.7 months among those who received placebo. Landmark 2-year DFS was 76.4% and 74.0%, respectively.
Similar results were obtained with investigator-assessed disease-free survival (HR 0.92, 95% CI 0.71-1.20).
Subgroup analyses generally showed consistent results. However, Dr. Motzer made particular note of potential differences in effect due to disease risk per TNM staging and according to the presence of sarcomatoid features.
Any-grade treatment-related adverse events (AEs) were reported in 88.9% vs 56.8% of patients treated with nivolumab and ipilimumab and placebo. Serious (grade ≥ 3) treatment-related AEs were reported in 28.5% vs 2.0% of patients, respectively. Treatment-related AEs led to discontinuation of nivolumab and ipilimumab in 29.0% of patients and of placebo in 1.0% of patients.
Thus, Dr. Motzer concluded that the CheckMate 914 trial of nivolumab and ipilimumab vs placebo as adjuvant therapy in patients with localized RCC at high risk of relapse after nephrectomy did not meet the primary endpoint of DFS. While the safety profile was consistent with its known profile in advanced RCC, the rate of discontinuation due to treatment-related AEs was higher with adjuvant nivolumab and ipilimumab in this trial.
Presented by: Robert J. Motzer, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center
Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 European Society of Medical Oncology (ESMO) Annual Hybrid Meeting, Paris, FR, Fri, Sept 9 – Tues, Sept 13, 2022.