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Is There a Role for Adjuvant Immunotherapy in High-Risk Resected Renal Cell Carcinoma?
Patients with renal cell carcinoma (RCC) and high-risk features who undergo partial or radical nephrectomy with curative intent have a significant (40%–50%) chance of systemic failure. Based on findings of improved disease-free survival (DFS) from the KEYNOTE-564 trial, the FDA approved pembrolizumab for adjuvant therapy in patients at intermediate-high or high risk for recurrence.
Now, investigators report findings from CheckMate 914, an industry-sponsored, international, double-blind, phase 3 trial of adjuvant nivolumab plus ipilimumab (nivo/ipi) versus placebo. Following partial or radical nephrectomy, 816 patients without evidence of metastatic disease (stage pT2a [grade III–IV], pT2b, pT3, pT4, pTNIM0 [any grade]) were randomized to receive intravenous (IV) nivolumab (240 mg) every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) every 6 weeks for 4 doses or IV placebo. The primary endpoint was disease-free survival (DFS) assessed by blinded independent review.
Median age was approximately 58 years and 77% had stage pT3 disease. During a median follow-up of 37.0 months, median DFS was not reached in the nivo/ipi arm and was 50.7 months in the placebo arm (hazard ratio, 0.92; P=0.53). Adverse events led to discontinuation of the study drug in 32% of patients in the nivo/ipi arm versus 2% in the placebo arm; there were 4 deaths associated with nivo/ipi.
As editorialists note, although this was a well done clinical trial, there are several considerations: (1) Ipilimumab was administered every 6 weeks, in contrast to an every 3-week regimen in the metastatic setting; (2) Ipilimumab was administered for only 6 months, compared with 1 year of pembrolizumab in KEYNOTE-564; and (3) Tolerance of this regimen was lower in the adjuvant setting than in the metastatic setting, leading to high rates of treatment discontinuation.
A similar negative study of adjuvant atezolizumab, IMmotion010, was recently reported (NEJM JW Oncol Hematol Sep 19 2022 and Lancet 2022 400;1103). We await overall survival data from KEYNOTE-564. Given the current evidence, clinicians and patients need to engage in shared decision making regarding the potential role of adjuvant immune checkpoint therapy.
Motzer RJ et al.
Title: Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): A double-blind, randomised, phase 3 trial.
Source: Lancet 2023 Feb 9; [e-pub]. (Abstract/FREE Full Text)