Phase 3 randomized trial (KEYNOTE-630) of adjuvant pembrolizumab (pembro) versus placebo (pbo) for high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) following surgery and radiation (RT).

Abstract

6000 Background: Patients with high-risk LA cSCC are standardly treated with surgical resection followed by postoperative RT. Up to 30% of pts experience recurrence and/or metastasis. PD-1 inhibitors including pembro are approved in the US for recurrent/metastatic or LA cSCC not curable by surgery or radiation. We present results from the randomized, double-blind, phase 3 KEYNOTE-630 trial (NCT03833167) that evaluated the efficacy and safety of the addition of adjuvant pembro for participants (pts) with high-risk LA cSCC. Methods: Adults with histologically confirmed LA cSCC with ≥1 protocol-defined high-risk feature who underwent complete macroscropic resection and completed adjuvant RT ≥4 and ≤16 weeks from randomization were randomly assigned 1:1 to receive pembro 400 mg or placebo (pbo) IV Q6W for ≤9 cycles. The primary end point was recurrence-free survival (RFS), defined as the time from randomization to the first event of local or regional recurrence of index lesion, distant metastasis, or death due to any cause. Secondary end points included overall survival (OS) and safety. The data cutoff date was June 28, 2024. Results: A total of 450 pts were enrolled (n = 225 in each arm). All pts completed surgery and RT and 224 in each arm received ≥1 dose of adjuvant treatment. Median study follow-up was 28.6 mo (range, 2.0-62.5). The 24-mo RFS rate was 78.3% (95% CI, 71.5-83.7) for pembro vs 68.6% (95% CI, 61.1-75.0) for pbo (HR 0.76 [95% CI, 0.53-1.10] P = 0.07243, which did not cross the p-value boundary of 0.0160 for statistical significance). On subset RFS analysis, pts with extracapsular extension (HR 0.44; 95% CI, 0.24-0.79), pts aged ≥65 years (HR 0.61; 95% CI, 0.41-0.91), and non-smokers (HR 0.58; 95% CI, CI 0.37-0.90) appeared to benefit most from pembro. Locoregional recurrence occurred in 13.8% of pts receiving pembro vs 25.3% receiving pbo; distant metastasis in 4.4% vs 11.6% of pts; and new high-risk primary cSCC in 0% vs 2.7% of pts. The 24-mo OS rate was 87.3% (95% CI, 81.5-91.5) in the pembro arm vs 90.7% (95% CI, 85.2-94.3) in the pbo arm (HR 1.47 [95% CI, 0.87-2.48]). Treatment-related AEs (TRAEs) occurred in 63.8% of pts in the pembro arm and 41.1% in the pbo arm (grade 3-4 in 7.6% and 2.7%). No pts died due to TRAEs. TRAEs led to treatment discontinuation in 5.4% of pts in the pembro arm and in 1.3% in the pbo arm. Conclusions: Pembro did not provide significant benefit in the adjuvant setting for pts with resected, high-risk LA cSCC. The safety profile of adjuvant pembro was consistent with reports from similar studies and there were no treatment-related deaths. The study was stopped for futility as the benefit/risk profile did not support continuing the trial based on recommendations from the data monitoring committee. Clinical trial information: NCT03833167 .