Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma

Abstract

BACKGROUND Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Radiotherapy and High-Dose Interleukin-2: Clinical and Immunological Results of a Proof of Principle Study in Metastatic Melanoma and Renal Cell Carcinoma

“…Regarding the therapy, it must be said that ICIs have found an increasingly anticipated application (up to adjuvant therapy) for both melanoma also in association with targeted therapies, and for RCC with antiangiogenics (45)(46)(47)(48). However, these new first line combination therapies and adjuvant applications determine a lack of therapeutic options for progressing patients, so in this scenario HD IL-2 + radiotherapy could play a new role.…”

Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

“…However, this approval was controversial, as the phase 3 trial ASSURE (NCT00326898) showed that sunitinib did not have any survival benefit relative to placebo in the adjuvant setting [106]. Pembrolizumab is the first ICI to provide promising data as an adjuvant therapy, based on the phase 3 trial KEYNOTE-564 (NCT00375674) [107]. In this trial, 994 patients with ccRCC at high risk for recurrence after nephrectomy were randomized to adjuvant pembrolizumab (n = 496) or placebo (n = 498).…”

Adjuvant Systemic Therapies for Patients with Renal Cell Carcinoma: Choosing Treatment Based on Patient-level Characteristics

“…The recent results from KEYNOTE-564 [1] reinvigorated discussions on how to best interpret data from randomized clinical trials (RCTs) to determine which patients are more likely to benefit more from adjuvant therapies. KEYNOTE-564 was a phase 3 RCT that randomized patients with clearcell renal cell carcinoma (ccRCC) to adjuvant pembrolizumab or placebo after nephrectomy.…”

“…KEYNOTE-564 was a phase 3 RCT that randomized patients with clearcell renal cell carcinoma (ccRCC) to adjuvant pembrolizumab or placebo after nephrectomy. The interim analysis noted that pembrolizumab-treated patients experienced significantly better disease-free survival (DFS, the primary endpoint) over placebo-treated patients, whereas data for the key secondary endpoint of overall survival (OS) were immature [1]. This fueled debates on the utility of surrogate endpoints, such as DFS, compared with the more intuitive OS endpoint.…”

“…Figure 1D shows example subgroup HR estimates from our hypothetical RCT of adjuvant systemic therapy for ccRCC. The subgroups and their HR estimates intentionally resemble those seen in recent pivotal adjuvant trials in genitourinary oncology [1,10]. A common error is to conclude that because the confidence intervals for the lymph node-positive (N+) subgroup cross unity, the adjuvant treatment effect is only significant for the lymph node-negative (N0) subgroup.…”