LEAP-010 Trial Falls Short on OS in HNSCC Despite PFS, ORR Gains

According to findings from the phase 3 LEAP-010 trial (NCT04199104), the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda), improved both progression-free survival (PFS) and objective response rate (ORR) vs pembrolizumab and placebo, in patients with recurrent or metastatic headn and neck squamous cell carcinoma (HNSCC). However, the improvement did not extend to overall survival (OS), the trial’s third primary end point.

A Discordant Survival Outcome

The data were presented from 2 prespecified interim analyses. At the first interim analysis, with a median follow up of 11.5 months, the median PFS was 6.2 months in the lenvatinib plus pembrolizumab arm compared with 2.8 months in the placebo plus pembrolizumab arm (HR, 0.64; 95% CI, 0.50-0.81; P =.0001040).

The objective response rate was also significantly higher with the addition of lenvatinib, at 46.1% versus 25.4% for the control arm.

Despite these gains, the OS analysis from the second interim analysis told a different story. At a median follow up of 21.3 months, median OS was 15.0 months for patients receiving lenvatinib plus pembrolizumab compared with 17.9 months for those receiving placebo plus pembrolizumab (HR, 1.15; 95% CI, 0.91-1.45; P =.882).

Trial Schema and Methodology

LEAP 010 was a phase 3 study designed to evaluate first-line treatment in patients with recurrent or metastatic HNSCC. Eligible participants were 18 years or older with disease deemed incurable by local therapy and a PD-L1 combined positive score of 1 or higher.

Participants were randomly assigned in a 1:1 fashion to 1 of 2 treatment arms. Patients in the experimental arm received 20 mg of lenvatinib orally once daily plus 200 mg pembrolizumab intravenously once every 3 weeks. Patients in the control arm received placebo orally once daily plus 200 mg pembrolizumab intravenously once every 3 weeks. Pembrolizumab was administered for up to 35 cycles in both groups.

End Points and Analysis Plan

The trial had 3 primary end points: ORR, PFS, and OS. According to the prespecified analysis plan, ORR and PFS were reported from the first interim analysis, with a data cutoff date of July 6, 2022. OSwas reported from the second interim analysis, with a data cutoff date of May 30, 2023.

Patient Demographics

A total of 511 participants were enrolled in the study, with 256 assigned to the treatment arm and 255 assigned to the control arm. The median time from random assignment to data cutoff was 11.5 months for the first interim analysis and 21.3 months for the second interim analysis.

Safety Profile

The safety analysis from the second interim analysis showed a higher incidence of grade 3 to 4 all cause adverse events in the lenvatinib-containing arm. Among participants receiving lenvatinib plus pembrolizumab, 170 patients, representing 66.9% of the arm, experienced grade 3 to 4 adverse events. In the placebo plus pembrolizumab arm, 97 patients, or 38.3%, experienced events of this severity.

The investigators concluded that “first-line lenvatinib plus pembrolizumab significantly improved ORR and PFS, but not OS, compared with placebo plus pembrolizumab.” They noted that the safety profile observed in the trial was consistent with previously published data for the combination.

REFERENCE

Licitra L, Tahara M, Harrington K, et al. Pembrolizumab with or without lenvatinib as first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma: Phase III LEAP-010 Study. J Clin Oncol. doi:10.1200/JCO-25-00570