Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC).

4514 Background: KEYNOTE-564 (NCT03142334) established pembro monotherapy as the first adjuvant regimen to significantly improve both disease-free survival (DFS) and overall survival (OS) vs placebo (pbo) after surgery for participants (pts) with ccRCC at increased risk of recurrence. We present results from the fourth prespecified interim analysis with a minimum follow-up of 5 yrs. Methods: KEYNOTE-564 is a randomized, double-blind, pbo-controlled, phase 3 study, which enrolled adults with ccRCC with intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0 M0) or high (pT4 any Gr, N0 M0, or any pT and Gr, N+ M0) risk of recurrence or M1 with no evidence of disease (NED) who had nephrectomy and/or metastasectomy ≤12 wks prior to 1:1 randomization to pembro 200 mg or pbo IV Q3W. Treatment continued for ~1 yr (17 cycles) or until recurrence, intolerable AEs, or physician decision to discontinue treatment. The primary endpoint was DFS by investigator; the key secondary endpoint was OS. The study met its DFS and OS objectives at earlier analyses; thus, no subsequent formal statistical testing occurred. AEs were collected for 30-90 days after treatment cessation depending on severity, with serious treatment-related AEs collected regardless of timing. Results: A total of 994 pts were randomized to pembro (n = 496) or pbo (n = 498). The median follow-up time to data cutoff date of 25 Sept 2024 was 69.5 mo (range, 60.2−86.9). All pts completed or discontinued study treatment ≥3 years earlier. 188 DFS events in the pembro group and 241 in the pbo group had occurred. Median DFS was not reached (NR) vs 68.3 mo, respectively (HR 0.71, 95% CI 0.59−0.86); estimated DFS rate at 5 yrs was 60.9% vs 52.2%. 68 OS events in the pembro group and 99 in the pbo group had occurred. Median OS was NR in both arms (HR 0.66, 95% CI 0.48−0.90); estimated OS rate at 5 yrs was 87.7% vs 82.3%, respectively. DFS and OS outcomes were consistent across key subgroups, including by prespecified risk and sarcomatoid features (Table). No new serious treatment-related AEs have been reported for ≥3 years. Conclusions: With ≥5 yrs of follow-up, the benefits observed with adjuvant pembro vs pbo are consistent with prior analyses, including in all subgroups. No new serious treatment-related safety signals occurred. Adjuvant pembro remains a standard-of-care option for patients with ccRCC at increased risk of recurrence. Clinical trial information: NCT03142334 . All pts Prespecified risk subgroups Sarcomatoid features Intermediate-high High M1 NED Present Absent N 994 855 77 57 111 829 DFS events 429 342 49 37 59 339 DFS HR(95% CI) 0.71(0.59−0.86) 0.75 (0.61−0.93) 0.61(0.35−1.08) 0.48(0.25−0.92) 0.56(0.33−0.96) 0.75(0.60−0.92) OS events 167 131 22 13 23 130 OS HR(95% CI) 0.66(0.48−0.90) 0.65(0.46−0.92) 0.86(0.37−1.98) 0.36(0.11−1.18) 0.67(0.29−1.56) 0.64(0.45−0.91)