Longer follow-up of the LEAP-004 trial in metastatic melanoma upheld the benefit seen with the VEGF kinase inhibitor lenvatinib plus the PD-1 inhibitor pembrolizumab for patients experiencing disease progression on prior checkpoint blockade, investigators reported at the 2021 ASCO Annual Meeting.1
“With additional follow-up, lenvatinib plus pembrolizumab continues to show clinically meaningful, durable responses in patients with advanced melanoma with confirmed disease progression on a PD-1 or PD-1 plus CTLA-4 inhibitor, an expanding population with very limited options.”— Ana Arance, MD, PhD
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“With additional follow-up, lenvatinib plus pembrolizumab continues to show clinically meaningful, durable responses in patients with advanced melanoma with confirmed disease progression on a PD-1 or PD-1 plus CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitor, an expanding population with very limited options,” said Ana Arance, MD, PhD, of Hospital Clinic de Barcelona. “The data continue to support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”
LEAP-004 enrolled 103 patients with unresectable stage III or IV melanoma who developed progressive disease while on treatment or within 12 weeks of their last dose of a PD-1 inhibitor given alone or with an anti–CTLA-4 or other therapy. Patients received 20 mg of lenvatinib daily plus pembrolizumab at 200 mg every 3 weeks for a maximum of 35 doses. The primary endpoint of the study was objective response assessed by Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent review.
At a median study follow-up of 15.3 months, when 18 patients were still on study treatment, the objective response rate remained essentially the same (21.4%) as reported in a previous analysis.2 One additional patient achieved a complete response, and one more was confirmed for stable disease (66%; Table 1).
“Median duration of response, compared with the previous analysis, increased from 6.3 months to 8.3 months. With that, 38.6% of the responses are ongoing at 9 months,” Dr. Arance reported. Median progression-free survival and overall survival remained unchanged at 4.2 months and 14.0 months, respectively. At 12 months, 18.5% of patients were progression-free, and 54.5% were alive.
Primary and Secondary Resistance
Responses were analyzed according to primary and secondary resistance. Among 103 enrolled patients, 62 (60.2%) had primary resistance in the metastatic setting (nonresponse or disease progression on prior anti–PD-1 therapy). Responses were comparable among patients with primary (22.6%) and secondary (22.7%) resistance to prior anti–PD-1–based therapy, according to Dr Arance. Response to lenvatinib/pembrolizumab was 18.2% in patients who experienced primary resistance in the adjuvant setting (n = 11).
Treatment-related adverse events were comparable to previous analyses and consistent with the known safety profile of the combination of lenvatinib and pembrolizumab. Grade 3 to 5 adverse events were observed in 46% of patients. Lenvatinib dose interruptions or reductions were required in almost 60%, although less than 8% discontinued treatment.
DISCLOSURE: Dr. Arance has served as a consultant or advisor to; participated in a speaker’s bureau for; and been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi.
1. Arance AM, de la Cruz-Merino L, Petrella TM, et al: Lenvatinib plus pembrolizumab for patients with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004. 2021 ASCO Annual Meeting. Abstract 9504. Presented June 6, 2021.
2. Arance Fernandez AM, O’Day SJ, de la Cruz Merino L, et al: Lenvatinib plus pembrolizumab for advanced melanoma that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004. ESMO Virtual Congress 2020. Abstract LBA44. Presented September 19, 2020.
Jason J. Luke, MD
The invited discussant of LEAP-004, Jason J. Luke, MD, Associate Professor of Medicine and Director of the Cancer Immunotherapeutics Center, University of Pittsburgh Hillman Cancer Center, said the investigators of LEAP-0041 deserve credit for designing a study with a...