Pembrolizumab with or Without Lenvatinib As First-line Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC): Phase 3 LEAP-010 Study

Purpose/Objective(s) The PD-1 inhibitor pembrolizumab (pembro) is approved as first-line monotherapy for patients (pts) with PD-L1-expressing R/M HNSCC (PD-L1 combined positivity score [CPS] ≥1). A phase 1b/2 study of pembro plus the multikinase inhibitor lenvatinib (len) showed promising antitumor activity and manageable toxicity in pts with HNSCC. In LEAP-010, a phase 3, randomized, placebo-controlled, double-blind study, we hypothesized that first-line len + pembro would improve efficacy compared with placebo + pembro, and have a manageable safety profile, in pts with PD-L1 CPS ≥1 R/M HNSCC (NCT04199104). Materials/Methods Eligible pts had R/M HNSCC incurable by local therapy, PD-L1 CPS ≥1 by central laboratory assessment, known HPV status, and ECOG PS 0 or 1. Pts were randomized 1:1 to len 20 mg or placebo orally once daily plus pembro 200 mg IV Q3W for ≤35 cycles given until intolerable toxicity, progression, or withdrawal. Primary end points were ORR and PFS per RECIST 1.1 by BICR and OS; secondary end points were DOR per RECIST 1.1 by BICR and safety. Per the prespecified analysis plan, ORR and PFS are reported from the first interim analysis (IA1) and OS and DOR are reported from IA2. Data cutoff dates were July 6, 2022 for IA1 and May 30, 2023 for IA2. Results 511 pts were randomized to len + pembro (n = 256) or placebo + pembro (n = 255). Median follow-up (ie, time from randomization to data cutoff) was 11.5 months (mo; range, 0.0-27.6) for IA1 and 21.3 mo (range, 9.0-38.4) for IA2. At IA1, median PFS was 6.2 mo (95% CI: 5.1-7.2) for len + pembro vs 2.8 mo (95% CI: 2.0-4.0) for placebo + pembro (HR: 0.64, 95% CI: 0.50-0.81; P=0.0001040). At IA1 and among the 351 pts with ≥6-mo follow-up, ORR was 46.1% (95% CI: 38.6-53.7) for len + pembro vs 25.4% (95% CI: 19.1-32.6) for placebo + pembro (difference 20.2, 95% CI 10.5-29.6, P=0.0000251). At IA2, median DOR was 10.1 mo (range, 1.3-30.9) for len + pembro vs NR (1.2-32.2) for placebo + pembro. At IA2, the median OS was 15.0 mo (95% CI: 13.2-17.0) for len + pembro vs 17.9 mo (95% CI: 13.8-21.6) for placebo + pembro (HR = 1.15, 95% CI: 0.91-1.45; P=0.882), with respective 24-month OS of 35.7% (95% CI: 29.0-42.4) and 40.0% (95% CI: 32.8-47.1). At IA2, 156 (61.4%) pts on len + pembro had grade ≥3 treatment-related adverse events (TRAEs) vs 45 (17.8%) on placebo + pembro, 28% vs 8% pts discontinued any treatment due to TRAEs, and 7 vs 3 pts had treatment-related deaths, respectively. Conclusion In pts with PD-L1 CPS ≥1 R/M HNSCC, first-line len + pembro significantly improved PFS and ORR, but not OS, compared with pembro alone. The safety profile was consistent with previously reported data; more TRAEs were found in pts receiving len + pembro. Further research is needed to identify effective treatment options for these pts.