TOPLINE:

Lenvatinib plus pembrolizumab as first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥ 1 significantly improved objective response rate (46.1% vs 25.4%) and progression-free survival (PFS, 6.2 vs 2.8 months) compared with placebo plus pembrolizumab. However, the combination did not improve overall survival (15.0 vs 17.9 months) and was associated with more than 1.7 times the rate of grade 3-4 adverse events.

METHODOLOGY:

• In the KEYNOTE-146 trial, lenvatinib plus pembrolizumab showed promising antitumor activity in metastatic HNSCC with a primary endpoint objective response rate at week 24 of 36% and an overall objective response rate of 46%.
• In the new trial, researchers conducted a randomized, double-blind, placebo-controlled, phase III study at 140 medical centers worldwide, enrolling 511 participants aged ≥ 18 years with PD-L1 CPS ≥ 1 R/M HNSCC deemed incurable by local therapy.
• Participants were randomly assigned 1:1 to receive 20 mg/d lenvatinib orally plus pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 35 cycles (n = 256) or placebo orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 35 cycles (n = 255).
• Primary endpoints were objective response rate and PFS determined using Response Evaluation Criteria in Solid Tumors version 1.1 assessed by blinded independent central review, and overall survival.
• Analysis was performed at the first interim analysis (data cutoff: July 6, 2022) for objective response rate and PFS with a median follow-up of 11.5 months, and at the second interim analysis (data cutoff: May 30, 2023) for overall survival with a median follow-up of 21.3 months.
• Randomization stratification factors included PD-L1 tumor proportion score (< 50% vs ≥ 50%), human papillomavirus status for oropharyngeal cancer determined by p16 immunohistochemistry (positive vs negative), and Eastern Cooperative Oncology Group performance status (0 vs 1).

TAKEAWAY:

• At the first interim analysis, lenvatinib plus pembrolizumab vs placebo plus pembrolizumab demonstrated a statistically significant improvement in objective response rate (46.1% vs 25.4%; difference, P = .0000251).
• Median PFS was significantly prolonged with lenvatinib plus pembrolizumab vs placebo plus pembrolizumab (6.2 months vs 2.8 months; hazard ratio [HR], 0.64; P = .0001040).
• At the second interim analysis, median overall survival showed no significant difference between treatment arms (15.0 months for lenvatinib plus pembrolizumab vs 17.9 months for placebo plus pembrolizumab; HR, 1.15; P = .882).
• Grade 3-4 all-cause adverse events occurred in 170 participants (66.9%) receiving lenvatinib plus pembrolizumab compared with 97 participants (38.3%) receiving placebo plus pembrolizumab at the second interim analysis.

IN PRACTICE:

“First-line pembrolizumab, either as monotherapy or in combination with chemotherapy, remains the standard-of-care treatment for patients with R/M HNSCC,” the authors of the study wrote.

SOURCE:

The study was led by Lisa Licitra, MD, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan in Milan, Italy. It was published online on March 12 in Journal of Clinical Oncology.

LIMITATIONS:

According to the authors, the lack of difference in median overall survival could be driven by the difference in administration of subsequent anticancer therapies as a greater proportion of participants in the placebo plus pembrolizumab arm received subsequent anticancer therapies (44.7%) than those in the lenvatinib plus pembrolizumab arm (35.5%). Conversely, as participants in the lenvatinib plus pembrolizumab arm had longer PFS, fewer participants from this arm had switched to subsequent therapy at data cutoff. The authors noted that while the safety profile for both lenvatinib and pembrolizumab is consistent with previous reports, there were a higher number of participants who discontinued treatment because of adverse events in the lenvatinib plus pembrolizumab arm. The difference in discontinuations was not formally tested, and underlying toxicity or tolerability cannot be ruled out, nor its impact on the results.

DISCLOSURES:

This study received funding from Eisai Inc., Nutley, New Jersey, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co in Rahway, New Jersey. Licitra disclosed receiving honoraria from Merck Serono, MSD IT, Merck KGaA, Bristol Myers Squibb, and ALTIS Omnia Pharma Service Srl; consulting or advisory roles with Merck Serono, GSK, Roche, Genmab, Merck Healthcare KGaA, MSD, Janssen Research & Development, AbbVie, Bicara Therapeutics, Purple Biotech, and multiple other organizations; and research funding from AstraZeneca, Novartis, Roche, MSD, Merck Serono, Exelixis, and other pharmaceutical companies. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.