Updated data show survival benefit with adjuvant pembrolizumab in ccRCC

Updated data from the third interim analysis of the phase 3 KEYNOTE-564 trial (NCT03142334) have been published in the New England Journal of Medicine, showing that adjuvant pembrolizumab (Keytruda) extended overall survival (OS) vs placebo in patients with clear cell renal cell carcinoma (ccRCC) at intermediate- or high-risk of recurrence following nephrectomy.¹

At 48-month follow-up, the estimated OS among patients in the pembrolizumab arm was 91.2% compared with 86.0% among patients in the placebo arm.

Previous data from the trial were presented by lead author Toni K. Choueiri, MD, at the 2024 Genitourinary Cancers Symposium in San Francisco, California.²

“This is the first study to show a statistically significant and clinically meaningful survival improvement with any adjuvant therapy in kidney cancer, and this further supports adjuvant pembrolizumab as a standard of care after surgery in this disease setting,” Choueiri noted during the presentation.

Updated data from the trial showed that at 48-month follow-up in the intent-to-treat population, the estimated OS among patients in the pembrolizumab arm was 91.2% (95% CI, 88.3 to 93.4), compared with 86.0% (95% CI, 82.6 to 88.8) among patients in the placebo arm. Overall, the investigators noted a 38% reduction in the risk of death with pembrolizumab vs placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = .005). The OS benefit was consistent across key subgroups.

Further, the disease-free survival (DFS) at 48 months was 64.9% in the pembrolizumab arm, compared with 56.6% in the placebo arm (hazard ratio for recurrence or death, 0.72; 95% CI, 0.59 to 0.87). Among all patients, disease recurrence or death occurred in 174 patients in the pembrolizumab arm and 224 patients in the placebo arm.

In total, 161 patients in the pembrolizumab arm and 210 patients in the placebo arm experienced disease recurrence. Of those in the pembrolizumab arm, 25 (15.5%) had local recurrence and 143 (88.8%) had distant recurrence. Among those in the placebo arm, 43 (20.5%) had local recurrence and 179 (85.2%) had distant recurrence. Subsequent therapy due to recurrence was given to 128 (79.5%) patients in the pembrolizumab group and 171 (81.4%) patients in the placebo group.

Safety data were consistent with previous analyses. Adverse events (AEs) of any cause that led to treatment discontinuation occurred in 21.1% of patients in the pembrolizumab arm and 2.2% of patients in the placebo arm. Treatment-related AEs of any grade occurred in 79.1% and 53.0% of patients in the pembrolizumab and placebo arms, respectively. Grade 3 or 4 treatment related AEs occurred in 18.6% of those who received pembrolizumab and 1.2% of those who received placebo.

Serious AEs of any cause were reported in 20.7% of patients treated with pembrolizumab and 11.5% of those given placebo, leading to discontinuation in 10.0% vs 1.0% of patients, respectively. No treatment-related AEs led to death in either arm.

In total, the double-blind, phase 3 KEYNOTE-564 trial enrolled 994 patients with ccRCC who were at an increased risk of recurrence following nephrectomy. Patients were randomly assigned 1:1 to receive 200 mg pembrolizumab (n = 496) or placebo (n = 498) every 3 weeks for up to 17 cycles or until unacceptable toxicity, recurrence, or withdrawal from the study. The median follow-up was 57.2 months.

The primary end point for the study was DFS, with OS as a key secondary end point. Safety was also a secondary end point.

Additional data

Pre-specified subgroup analyses showed a 48-month OS rate of 92.6% and 87.7% among patients in the pembrolizumab and placebo arms, respectively, who had M0 stage disease an intermediate- to high-risk of recurrence (hazard ratio for death, 0.59; 95% CI, 0.40 to 0.87). Further, among patients who had M0 stage disease and a high risk of recurrence, OS at 48 months was 80.0% in the pembrolizumab arm and 73.0% in the placebo arm (hazard ratio for death, 0.78; 95% CI, 0.32 to 1.93). OS at 48 months among those with M1 NED status was 89.7% in the pembrolizumab arm vs 78.0% in the placebo arm (hazard ratio for death, 0.51; 95% CI, 0.15 to 1.75).

Regarding safety, immune-mediated AEs and infusion reactions occurred in 36.5% of patients who received pembrolizumab vs 7.3% of those who received placebo, as consistent with previous reports. The median time to onset of immune-mediated AEs and infusion reactions was 2.1 (range, 0.03 to 15.3) months and 4.9 (range, 0.03 to 12.0) months in the pembrolizumab and placebo arms, respectively. The median duration of episodes was 2.9 months (range, 0.03 to 70.7) in the pembrolizumab cohort and 1.4 months (range, 0.03 to 66.6) in the placebo cohort. At the time of data cutoff, the episodes at 70.7 months and 66.6 months of duration were ongoing.

Previous data

Previous analyses from the KEYNOTE-564 trial occurred at the median follow-up times of 24.1 months and 30.1 months.

At 24.1-month follow-up, OS in the pembrolizumab arm was 96.6%, vs 93.5% in the placebo arm (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). The estimated DFS at the 24.1-month analysis was 77.3% in the pembrolizumab cohort vs. 68.1% in the placebo cohort (hazard ratio for recurrence or death, 0.68; 95% CI, 0.53 to 0.87; P = .002), which met the trial's primary end point.³

At the 30.1-month median follow-up, OS was 96.2% in the pembrolizumab arm and 93.8% in the placebo arm (hazard ratio for death, 0.52; 95% CI, 0.31 to 0.86). The estimated DFS was 78.3% among those who received pembrolizumab compared with 67.3% among those who received placebo (hazard ratio for recurrence or death, 0.63; 95% CI, 0.50 to 0.80).

References

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695

2. Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359

3. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385:683-694 doi:10.1056/NEJMoa21063