Advanced Melanoma: Lenvatinib Plus Pembrolizumab After Disease Progression on Anti–PD-1 Therapy

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Checkpoint inhibitors can be lifesaving for many patients with advanced melanoma, but those who experience disease progression currently have few treatment options. The combination of a tyrosine kinase inhibitor and an anti–PD-1 agent may offer some hope in this setting, according to a study of lenvatinib plus pembrolizumab presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1

In the open-label, single-arm LEAP-004 trial, patients who experienced disease progression on anti–PD-1 agents, given alone or in combination and then received pembrolizumab plus lenvatinib had a median overall survival of nearly 14 months, reported Ana Arance, MD, PhD, of Hospital Clinic de Barcelona in Spain.

Ana Arance, MD, PhD

Ana Arance, MD, PhD

“These results are encouraging, given the stringent definition of disease progression on prior anti–PD-1-based therapy and the enrollment of a tough to treat population of patients,” Dr. Arance said. Noting there is no approved regimen for patients with metastatic melanoma who have progressed on or after anti-PD-1 alone or anti-PD-1 plus anti-CTLA-4 and BRAF/MEK therapies, she said the LEAP-004 data support lenvatinib plus pembrolizumab as a potential treatment regimen “for this population of high unmet medical need.”

Lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and it has demonstrated immunomodulatory activity in the tumor microenvironment. Since resistance to immunotherapy is multifactorial, its use in a combination regimen may be effective in patients who experience disease progression on anti-PD-1 therapy given alone or in combination with anti-CTLA-4 agents, a population specially difficult to treat, she said.

LEAP-004 enrolled 103 patients (median age of 63) with unresectable stage III or IV melanoma whose disease progressed on or after treatment with a PD-L1 inhibitor alone or with a CTLA-4 inhibitor. Patients received pembrolizumab at 200 mg intravenously for up to 35 cycles plus lenvatinib at 20 mg daily until disease progression, unacceptable toxicity, or patient or physician decision. The primary endpoint was objective response rate by blinded independent review.

According to Dr. Arance, the definition of progressive disease was stringent. Patients had to have confirmed disease progression per immune Response Evaluation Criteria in Solid Tumors on or within 12 weeks of the last dose of anti–PD-1 given alone or in combination, for at least two doses. Progressive disease was confirmed by at least two radiologic assessments at least 4 weeks apart. In addition there was no limit in the number, type, or sequence of previous systemic therapies.

This study focused on a high-risk patient population: 20% had lactate dehydrogenase levels twice the upper limit of normal, 15% had brain metastases, and the medium sum of target lesions was 100 mm. A BRAF V600 mutation was identified in 37% of patients, and 64% of all patients had PD-L1–positive disease.

Encouraging Outcomes

At a median follow-up of 12 months, the overall response rate to lenvatinib plus pembrolizumab was 21.4%, and 43.7% achieved stable disease, translating into a clinical benefit rate of 65%. Responses were observed across subgroups and were increased to 31% among 29 patients who had previously been treated with an anti–CTLA-4 plus an anti–PD-1/PD-L1 doublet, reported Dr. Arance.

The median duration of response by blinded independent review was 6.3 months, with 72.6% of patients still responding at 6 months. Median progression-free survival was 4.2 months, with progression-free rates of 41.7% at 6 months and 26.2% at 9 months. Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months, and 65.4% alive at 9 months, she stated.


  • LEAP-004 evaluated lenvatinib plus pembrolizumab in patients with advanced melanoma whose disease progressed after treatment with an anti–PD-1/PD-L1-based therapy.
  • In this open-label, single-arm study, 21.4% of patients experienced an objective response by blinded independent review, and median overall survival was 13.9 months.
  • This is but one of many studies pairing checkpoint inhibitors with novel agents in patients with advanced melanoma who develop treatment resistance.

Although almost all patients experienced at least one treatment-related adverse event, for 44.7% these events were grade ≥ 3, leading to treatment discontinuation in 7.8%. The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34.0%), and hypothyroidism (33.0%), although in the vast majority of cases, they were grade 1 or 2. 

DISCLOSURE: The study was funded by Merck. Dr. Arance has reported financial ties to Merck, Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre-Fabre, Sanofi, and Roche.


1. 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.

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