The following article features coverage from the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

In patients with advanced melanoma and confirmed progression on a programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, lenvatinib plus pembrolizumab demonstrated clinically meaningful, durable responses, according to researchers. These findings were part of the results of the LEAP-004 study presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting by lead author Ana Maria Arance, MD, PhD, Hospital Clinic Barcelona in Spain. The benefit, she stated in a virtual oral presentation, was observed among patients who had progressed on anti–PD-1 plus anticytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy regardless of primary or secondary resistance to prior anti-PD-L1 therapy.

In an earlier presentation of findings from the open-label, single-arm, phase 2, LEAP-004 study (Clinical identifier: NCT03776136), the objective response rate (ORR) in patients with unresectable stage III-IV melanoma and confirmed progressive disease on a PD-L1 inhibitor given alone or in combination was 21.4%, with a 6.3-month median duration of response (DOR). Among the patients with progressive disease who were on prior anti-PD-1 + anti-CTLA-4 therapy, the ORR was 31.0%.

The current presentation added 3 months of follow-up and additional subgroup analyses. It evaluated patients whose confirmed disease progression occurred within 12 weeks of the last PD-L1 inhibitor dose given alone or with anti-CTLA-4 or other therapies for 2 or more doses. Patients had received lenvatinib (20 mg once daily plus ≤35 doses of pembrolizumab 200 mg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoints, by blinded independent central review, were ORR, overall survival (OS), and safety.

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Investigators enrolled 103 patients (median age 63 years), 68.0% of whom had stage M1c/M1d melanoma, 55.3% had lactate dehydrogenase (LDH) above the  upper limit of normal (ULN; 20.4% ≥2 × ULN), and 58.3% had received 2 or more prior treatments. Among those receiving treatment for metastatic disease, 91.3% had received immunotherapy, with 82.5% receiving anti-PD-1/L1, 26.2% receiving treatment with an anti-CTLA-4 plus anti-PD-1/L1, and 32.0% receiving BRAF with or without MEK inhibition.

With median study follow-up of 15.3 months (range, 12.1-19.0), 17.5% of patients were still receiving the study drug. The ORR remained  at 21.4% (95% CI, 13.9-30.5), although the number of complete responses increased from 2 to 3, and the disease control rate increased from 65.0% to 66.0%. Ongoing response rates increased from 77.3% at 6 months to 38.6% at 9 months. Compared with the initial analysis, median DOR increased from 6.3 months to 8.3 months (3.2-15.9+). Median OS in the total population was 14.0 months (95% CI, 10.8-NR) and the 12-month OS estimate was 54.5%.

Treatment-related adverse events rates were 96.1% (any grade), 45.6% (grade 3-4), and 1.0% (grade 5, decreased platelet count). These led to discontinuation of lenvatinib and/or pembrolizumab in 7.8%, and to lenvatinib dose reduction in 56.3%. The safety profile, Dr Arance noted, was consistent with prior studies of lenvatinib plus pembrolizumab.

“With additional follow-up, lenvatinib plus pembrolizumab continues to show clinically meaningful, durable responses in patients with advanced melanoma with confirmed progression on a PD-1 or PD-L1 inhibitor given alone or in combination,” Dr Arance concluded. “These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.”

Disclosure: This research was supported by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Read more of Cancer Therapy Advisor’s coverage of the 2021 ASCO Annual Meeting by visiting the conference page.


Arance AM, de la Cruz-Merino L, Petrella TM, et al. Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004. J Clin Oncol. 2021;39:(suppl 15; abstr 9504). doi:10.1200/JCO.2021.39.15_suppl.9504