Adding the multikinase inhibitor lenvatinib to the PD-1 inhibitor pembrolizumab as initial therapy for recurrent or metastatic head and neck squamous cell carcinoma improved response rates and progression-free survival but did not lead to an overall survival advantage over pembrolizumab monotherapy, according to data presented by Licitra et al during the 2024 Multidisciplinary Head and Neck Cancers Symposium (Abstract 1).
Findings from the LEAP-010 study showed an overall response rate of 46.1% vs 25.4% (P < .00001), favoring the combination of lenvatinib and pembrolizumab compared to pembrolizumab alone. Median progression-free survival also more than doubled with the combination of immunotherapy and VEGF inhibition compared with immunotherapy alone (6.2 months vs 2.8 months, hazard ratio [HR] = 0.64, P = .0001). However, no difference was observed in overall survival between the arms (median = 15 months vs 17.9 months, HR = 1.15).
Lisa Licitra, MD,
“These findings reinforce pembrolizumab alone or in combination with chemotherapy as the first-line standard for patients with recurrent metastatic head and neck squamous cell carcinoma,” said lead study author Lisa Licitra, MD, Chief of Head and Neck Cancer Medical Oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, in Italy.
Additional LEAP-010 Details
The open-label trial randomly assigned 511 patients with measurable head and neck squamous cell carcinoma and a PD-L1 combined positive score ≥ 1 to receive lenvatinib at 20 mg daily plus pembrolizumab at 200 mg every 3 weeks or placebo plus pembrolizumab. The primary endpoints were overall response rate, progression-free survival, and overall survival.
The safety profile was consistent with known toxicities of lenvatinib and pembrolizumab, although more treatment-related adverse events, dose interruptions or reductions, and discontinuations occurred with combination therapy.
Study Background
As Dr. Licitra explained, pembrolizumab is considered either alone or in combination with chemotherapy as first-line treatment for patients with PD-L1–expressing recurrent or metastatic head and neck squamous cell carcinoma. Nevertheless, a phase Ib/II study of pembrolizumab plus lenvatinib showed promising antitumor activity and manageable toxicity in heavily pretreated patients with recurrent metastatic head and neck squamous cell carcinoma, according to a report by Taylor et al in the Journal of Clinical Oncology. The overall response rate at 24 weeks was 46%, with a median progression-free survival of 4.7 months.
“These findings reinforce pembrolizumab alone or in combination with chemotherapy as the first-line standard for patients with recurrent or metastatic head and neck squamous cell carcinoma.”— LISA LICITRA, MD
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Based on these findings, Dr. Licitra and colleagues hypothesized that lenvatinib plus pembrolizumab would improve efficacy in the first-line setting. The phase III, randomized, double-blind, LEAP-010 study evaluated lenvatinib plus pembrolizumab vs placebo plus pembrolizumab as first-line therapy in recurrent or metastatic head and neck squamous cell carcinoma.
Implications of the Findings
“Although [the] lenvatinib/pembrolizumab combination showed promising response rates and progression-free survival, it failed to improve overall survival over pembrolizumab monotherapy in the first-line recurrent/metastatic head and neck squamous cell carcinoma setting,” said Dr. Licitra. “Pembrolizumab alone or combined with chemotherapy remains the standard of care.”
According to Dr. Licitra, this trial adds to the body of research showing limited efficacy for lenvatinib/immunotherapy combinations across cancer types. The reasons for the disparity between response rate/progression-free survival and overall survival benefit are still unclear, highlighting the need for further investigation of predictive biomarkers to select patients most likely to achieve durable responses.
“When we look at the results of the LEAP program in other diseases such as non–small cell lung cancer, endometrial cancer, and melanoma, we must consider the fact that this combination is probably not the best way to go.”— LISA LICITRA, MD
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The negative overall survival finding mirrors that of the sister LEAP-007 study evaluating lenvatinib and pembrolizumab in the first-line treatment of metastatic non–small cell lung cancer, published by Yang et al in the Journal of Thoracic Oncology. Given the overall disappointing efficacy signals, said Dr. Licitra, the LEAP clinical program is unlikely to continue expansion in new settings until more data emerge on optimal patient selection.
“When we look at the results of the LEAP program in other diseases such as non–small cell lung cancer, endometrial cancer, and melanoma, we must consider the fact that this combination is probably not the best way to go,” Dr. Licitra concluded.
DISCLOSURE: Dr. Licitra reported financial relationships with AbbVie, Adlai Nortye, ALTIS Omnia Pharma Service, ALX Oncology, AstraZeneca, BMS, Boehringer Ingelheim, Debiopharm, Eisai, Eli Lilly, EMD Serono Research & Development Institute, Exelixis, F. Hoffmann–La Roche, Genmab, Gilead Sciences, GroupH, GSK, Incyte Biosciences, Isa Therapeutics, Janssen Research & Development, Kura Oncology, Merck Healthcare, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics, MSD IT, Nektar Therapeutics, Neutron Therapeutics, Novartis, Regeneron, Roche, Sanofi, Seagen, Sun Pharmaceuticals, Syneos Health, and TAE Life Science.
REFERENCES
1. 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 3 LEAP-010 study. 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 1. Presented February 29, 2024.
2. Taylor MH, Lee CH, Makker V, et al: Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol 38:1154-1163, 2020.
EXPERT POINT OF VIEW
Glenn J. Hanna, MD, Director, Center for Cancer Therapeutic Innovation (Early Drug Development Program), medical oncologist at the Center for Head & Neck Oncology at Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston, told The ASCO Post he was not surprised by the negative outcome of the LEAP-010 trial. This study randomly assigned patients with a PD-L1 combined positive score ≥ 1 to receive pembrolizumab plus lenvatinib vs pembrolizumab plus placebo.
Glenn J. Hanna, MD
“We saw significant toxicity with this combination in an already delicate head and neck cancer population,” said Dr. Hanna, who underscored the lack of survival benefit at the second interim analysis. “Although there is activity associated with this combination, including more responses and some durability, it’s probably not translating into an overall survival signal at least in part due to the safety profile. This combination will not move forward in the first-line setting,” he added.
Dr. Hanna also expressed doubts about the follow-up study, LEAP-009, which is comparing lenvatinib plus pembrolizumab with standard-of-care chemotherapy in the second-line setting. “These patients have already experienced disease progression on immunotherapy with or without chemotherapy, so it’s unlikely a VEGF inhibitor will be able to rescue the immunotherapy without the same toxicity problems,” he explained. “Whether lenvatinib is enough to improve response, durability, and survival remains to be seen, but my concern is toxicity will remain an issue.”
Another Phase III Trial Launches
Finally, Dr. Hanna noted the launch of the phase III STELLAR-305 trial. This study involves a potentially more selective VEGF inhibitor, zanzalintinib (XL092), in combination with pembrolizumab vs pembrolizumab alone.
“Zanzalintinib may have an improved toxicity profile. However, it remains to be seen whether this drug class is more tolerable in combination with immunotherapy in this patient population,” said Dr. Hanna.
DISCLOSURE: Dr. Hanna serves in an advisory role and receives consulting fees from Merck.
