Lenvatinib Plus Pembrolizumab for Advanced Melanoma Progressing on PD-1/PD-L1 Inhibitor Therapy

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In the phase II LEAP-004 trial reported in Journal of Clinical Oncology, Arance et al found that the combination of lenvatinib and pembrolizumab was active in patients with advanced melanoma with confirmed progression on PD-1/PD-L1 inhibitors as monotherapy or in combination with other agents.

As stated by the investigators, “Evidence suggests the multikinase inhibitor lenvatinib helps shift the tumor microenvironment to an immune-stimulatory state by inhibiting vascular endothelial growth factor receptor and fibroblast growth factor receptor.”

Study Details

In the international trial, 103 patients with unresectable stage III or stage IV melanoma with progressive disease within 12 weeks of the last dose of a PD-1/PD-L1 inhibitor given alone or with other therapies, including CTLA-4 inhibitors, were enrolled between February 2019 and September 2019. Treatment consisted of lenvatinib at 20 mg once daily and ≤ 35 doses of pembrolizumab at 200 mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on Response Evaluation Criteria in Solid Tumors, version 1.1, on independent central review.


As of data cutoff (in September 2020), median study follow-up was 15.3 months (range = 12.1–19.0 months). An objective response was observed in 22 patients (21.4%, 95% confidence interval [CI] = 13.9%–30.5%), with a complete response in 3 (2.9%). An additional 46 patients (44.7%) had stable disease.


  • Objective response was observed in 21% of patients, including 33% of those with disease progression on combined PD-1 and CTLA-4 inhibitor therapy.
  • Median response duration was 8.3 months (range = 3.2-15.91 months).

The median duration of response was 8.3 months (range = 3.2–15.91 months), and the median duration of stable disease was 5.75 months. An objective response was observed in 10 (33.3%) of 30 patients whose disease progressed on combination PD-1 inhibitor and CTLA-4 inhibitor therapy.

Median progression-free survival was 4.2 months (95% CI = 3.8-7.1 months). Median overall survival was 14.0 months (95% CI = 10.8 months to not reached).  

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 47 patients (45.6%), most commonly hypertension (21.4%), diarrhea (4.9%), and increased lipase (3.9%). Treatment-related serious adverse events occurred in 18.4% of patients. Treatment-related adverse events led to discontinuation of either component of study treatment in 7.8%. Potential immune-related adverse events of any grade occurred in 42.7% of patients (most commonly hypothyroidism), with grade 3 events (no grade 4 or 5 events observed) occurring in three patients (2.9%). One treatment-related death was reported, due to decreased platelet count.

The investigators concluded: “Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed [progressive disease] on prior PD-1/PD-L1 inhibitor–based therapy, including those with [progressive disease] on anti–PD-1 plus anti–CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.”

Ana Arance, MD, PhD, Department of Medical Oncology, Hospital Clínic Barcelona, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Eisai Inc and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.