KEYNOTE-564: First positive phase 3 results with adjuvant checkpoint inhibition in RCC

KEYNOTE-564 is the first positive phase 3 study with adjuvant immunotherapy in patients with renal cell carcinoma (RCC). These results support the use of pembrolizumab as a potential new standard of care for patients with RCC in the adjuvant setting.

Nephrectomy is the standard of care for the treatment of locoregional RCC. Nearly half of patients eventually experience disease recurrence after surgery. Patients with M1 stage and no evidence of disease (NED) after resection of oligometastatic sites are also at high risk of relapse. Relapse after surgery for high-risk clear-cell RCC (ccRCC) is associated with shortened survival. To reduce the relapse risk, effective perioperative treatments are needed, and adjuvant immune therapy might offer an attractive potential strategy for these patients.

The phase 3, double-blind, multicentre KEYNOTE-564 trial (NCT03142334) investigates pembrolizumab versus placebo in patients with ccRCC [1]. Patients with histologically confirmed ccRCC (n=994) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ~1 year. Patients were in one of the following risk groups:

• pT2, grade 4 or sarcomatoid, N0, M0;
• pT3 or pT4 any grade, N0, M0;
• pT4 any grade, N0, M0;
• pT any stage, any grade, N+, M0; or
• M1 with NED after surgery of primary tumour and resection of oligometastatic lesions.

Prof. Thomas Powles (Barts Cancer Centre, London, UK) shared the results of the study.

After a median follow-up of 24.1 months, the primary endpoint of disease-free survival (DFS) was met. Median DFS was not reached for both arms. The estimated DFS rate at 24 months was 77.3% with pembrolizumab versus 68.1% with placebo (HR 0.68; 95% CI 0.53–0.87; P=0.0010; see Figure). Overall, DFS benefit was consistent across risk subgroups.

Figure: DFS by investigator in the intention-to-treat population [1]



Figure kindly provided by Prof. Powles.

The key secondary endpoint was overall survival (OS). Interim results demonstrated an estimated OS rate at 24 months of 96.6% with pembrolizumab versus 93.5% with placebo. Median OS was not reached for both arms (HR 0.54; 95% CI 0.30–0.96; P=0.0164). Due to a prespecified p-value boundary, these results were not significant.

Safety results were in line with expectations; no new safety signals were observed. Grade 3–5 all-cause adverse events occurred in 32.4% with pembrolizumab and in 17.7% with placebo. No treatment-related deaths occurred with pembrolizumab.

Adjuvant pembrolizumab after nephrectomy demonstrated a statistically significant and clinically meaningful improvement in DFS compared with placebo in patients with intermediate-high, high-risk, or M1 NED ccRCC. The benefit was consistent across subgroups, including the M1 NED population, potentially extending the use of pembrolizumab to these patients. Although the number of participants who had partial nephrectomy was small, DFS benefit was consistent in this population. Additional follow-up is planned for the key secondary endpoint of OS.

1. Powles T. Pembrolizumab (pembro) vs. placebo as post nephrectomy adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): randomized, double-blind, phase 3 KEYNOTE-564 study. Game changing session 4. EAU21 Virtual, 8–12 July 2021.

 

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Posted on 31 August 2021