Frontline Lenvatinib Plus Pembrolizumab Generates Responses But Fails to Produce OS Benefit in HNSCC

Patients recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and a PD-L1 combined positive score (CPS) of at least 1 experienced improved overall response rates (ORR) and progression-free survival (PFS) with frontline lenvatinib (Lenvima) plus pembrolizumab (Keytruda) vs placebo plus pembrolizumab; however, the combination did not elicit an overall survival (OS) benefit, according to findings from the phase 3 LEAP-010 trial (NCT04199104) presented during the 2024 American Society for Radiation Oncology (ASTRO) Multidisciplinary Head and Neck Cancers Symposium.

At the time of the first interim analysis, the ORR by blinded independent central review (BICR) was 46.1% (95% CI, 38.6%-53.7%) with lenvatinib plus pembrolizumab, which included partial responses (PRs) in 31.5% of patients and complete responses (CRs) in 14.6%. Among patients who received placebo plus pembrolizumab, the ORR was 25.4% (95% CI, 19.1%-32.6%), the PR rate was 15.6%, and the CR rate was 9.8%. The difference in ORR between arms was 20.2% (95% CI, 10.5%-29.6%; one-sided P = .0000251).

The ORR at the second interim analysis in the lenvatinib/pembrolizumab and placebo/pembrolizumab arms, respectively, was 46.9% (95% CI, 40.6%-53.2%) and 27.5% (95% CI, 22.1%-33.4%). The median duration of response (DOR) was 10.1 months (range, 1.3+ to 30.9+) and not reached (NR; range, 1.2+ to 32.2+) in each respective arm, and ongoing responses were observed in 41.6% and 62.1% of patients at 12 months.

At the time of the first interim analysis, the median PFS in the lenvatinib and placebo arms, respectively, was 6.2 months (95% CI, 5.1-7.2) vs 2.8 months (95% CI, 2.0-4.0; HR, 0.64; 95% CI, 0.50-0.81; P = .0001040). The 12-month PFS rates were 28.5% vs 19.2% in each respective arm. At the second interim analysis, the median PFS was 7.0 months (95% CI, 5.6-8.0) vs 2.8 months (95% CI, 2.6-4.1) in each respective arm, and the 15-month PFS rates were 25.2% vs 19.5%.

However, the median OS at the time of the second interim analysis was 15.0 months (95% CI, 13.2-17.0) with lenvatinib plus pembrolizumab vs 17.9 months (95% CI, 13.8-21.6) with placebo plus pembrolizumab (HR, 1.15; 95% CI, 0.91-1.45; P = .8820). In each respective arm, the OS rates were 59% vs 59% at 12 months and 36% vs 40% at 24 months.

“First-line pembrolizumab as monotherapy or in combination with chemotherapy remains the standard of care for first-line treatments in patients with recurrent or metastatic [HNSCC],” Lisa Licitra, MD, a medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, said in a presentation on these findings.

In the double-blind LEAP-010 study, patients were randomly assigned 1:1 to receive lenvatinib (n = 256) or placebo (n = 255) at 20 mg orally once a day plus pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles.

Stratification factors included PD-L1 expression status (TPS <50% vs ≥50%), HPV status (positive vs negative) and ECOG performance status (0 vs 1). The trial’s primary end points were ORR and PFS based on RECIST v1.1 criteria per BICR as well as OS. Secondary end points included DOR and safety.

Patients with histologically confirmed recurrent or metastatic HNSCC who were ineligible to receive curative therapy and had measurable disease per RECIST v1.1 guidelines were able to enroll on the trial. Additional eligibility criteria included having no disease progression within 6 months after completing systemic therapy, an ECOG performance status of 0 or 1, a PD-L1 CPS of 1 or higher, and known human papillomavirus (HPV) status.

The median patient age was 65.0 years (range, 36-84) in the lenvatinib arm compared with 63.0 years (range, 29-85) in the placebo arm. Of note, most patients in each respective arm had a PD-L1 tumor proportion score of less than 50% (75.0% vs 74.9%). Additionally, 47.7% and 45.1% of patients in each arm had an ECOG performance status of 0, and 22.3% and 22.7% had HPV–positive status.

Any-grade adverse effects (AEs) at the second interim analysis affected 99% and 97% of patients in the lenvatinib and placebo arms, respectively. Additionally, grade 3/4 AEs occurred in 67% and 38%, AEs resulting in discontinuation of at least 1 study treatment affected 44% and 15%, and AEs leading to death were reported in 16% and 9%. Hypothyroidism and hypertension were the most common AEs in the lenvatinib/pembrolizumab arm.

“The safety profile was consistent with previously reported data; more treatment-related AEs were found in the patients receiving lenvatinib and pembrolizumab,” Licitra said. “However, no [new] safety signals emerged.”

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 (R/M HNSCC): phase 3 LEAP-010 study. Presented at the 2024 American Society for Radiation Oncology Multidisciplinary Head and Neck Cancers Symposium; February 29-March 2, 2024; Phoenix, Arizona. Abstract 1.