KEYNOTE-564 Demonstrates DFS Benefit Of Adjuvant Pembrolizumab In High-Risk RCC

Author: By Hannah Kitt, medwireNews Reporter 

medwireNews: Results from the prespecified interim analysis of the KEYNOTE-564 trial support the use of adjuvant pembrolizumab to treat patients with clear cell renal cell carcinoma (RCC) who have a high risk of relapse following nephrectomy. 

“KEYNOTE-564 is the first positive phase III study of an adjuvant immunotherapy in RCC”, Toni Choueiri, from Dana Farber Cancer Institute in Boston, Massachusetts, USA, told delegates of the 2021 ASCO Annual Meeting. 

He added: “Pembrolizumab is a potential new standard of care for patients with renal cell cancer with risk of disease recurrence after surgery in the adjuvant setting.” 

The double-blind study included 994 patients with histologically confirmed clear cell RCC and an ECOG performance status of 0 or 1 who had undergone nephrectomy within the past 12 months but had not received prior systemic therapy for advanced disease.  

Study participants had intermediate-to-high risk disease (pT2, grade 4 or sarcomatoid, N0 and M0 or pT3, any-grade, N0 and M0), high-risk disease (pT4, any grade, N0 and M0 or any pT, any grade, N+ and M0) or no evidence of disease (M1) after resection of at least one oligometastatic site within a year of nephrectomy.  

The estimated 12-month DFS rates were 85.7% for the 496 patients who were randomly assigned to receive 17 cycles of pembrolizumab 200 mg every 3 weeks, compared with 76.2% for the placebo group, with corresponding 24-month rates of 77.3% and 68.1%.  

Thus, the primary endpoint of investigator-assessed disease-free survival (DFS) was met, with a significant 32% lower risk for recurrence or death among patients taking pembrolizumab versus placebo during the median 24.1 months of follow-up. Median DFS was not reached in either treatment group at the point of data cutoff.  

Overall survival (OS) was a “key secondary endpoint”, according to Toni Choueiri who stressed that “only a quarter of events planned for final OS analysis had occurred at this point and additional analysis is planned.” 

Nevertheless, he explained that “at this early timepoint”, the risk of death was a nonsignificant 46% lower among patients given pembrolizumab versus placebo, with median OS not yet reached.

There were “almost no [OS] events in either arm” prior to month 20 where “the curves begin to clearly separate,” Choueiri commented. Indeed, the 12-month estimated OS rates were 98.6% versus 98.0% for patients taking pembrolizumab and placebo, respectively, but by month 24 the respective rates were 96.6% versus 93.5%.

He added that “pembrolizumab’s safety profile in the adjuvant setting was in line with expectations and no new safety signals were observed.”  

Nearly a third (32.4%) of patients taking pembrolizumab had a grade 3–5 adverse event (AE) compared with 17.7% of patients given placebo and 20.5% versus 11.3% had a serious AE of any cause. In addition, 18.9% versus 1.2% of patients, respectively, had a treatment-related AE of grade 3–5. 

Pembrolizumab was discontinued by 17.6% of patients because of treatment-related AEs after a median of approximately seven cycles of treatment, but no deaths related to pembrolizumab were reported. 

Session discussant Rana McKay, from the University of California, San Diego in La Jolla, USA, described the KEYNOTE-564 study findings as “practice changing”, acknowledging that “the data represent a paradigm shift as the first positive phase III study of adjuvant immunotherapy in RCC.” 

While noting that further follow-up is required to determine OS with adjuvant pembrolizumab, she questioned whether there will be “broad implementation” of this regimen in clear cell RCC patients and wondered if this approach may also benefit non-clear cell RCC patients. 

Rana McKay added: “If recurrence does develop, how does this alter first-line treatment for advanced disease? 

“Ultimately, this is a quantum leap forward for our patients and provides additional options for individual with renal cell carcinoma”, she summarised, adding that she “eagerly awaits” the results for other ongoing adjuvant checkpoint inhibitor trials, IMmotion010, CheckMate 914, Prosper and RAMPART. 

Reference 

Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. J Clin Oncol 2021;39(suppl 15; abstr LBA5). DOI 10.1200/JCO.2021.39.15_suppl.LBA5