Real world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma

Abstract

IntroductionImmunotherapy has revolutionized the prognosis of patients with metastatic melanoma. To date, the most active regimen is the combination of ipilimumab + nivolumab (ipi-nivo) achieving a response rate of nearly 60% and a median survival (OS) of 6 years. However, approximately 40% of patients experience primary resistance, while around 50% experience secondary resistance, highlighting the need for an effective second-line treatment option The recently published results on the use of lenvatinib + pembrolizumab in the advanced line setting led to the adoption of this regimen at our institution. Here we present our experience with this regimen, focusing on efficacy and safety.MethodsElectronic medical records of patients treated at a tertiary referral melanoma center, with at least one cycle of anti PD-1 + lenvatinib from 2020 to 2023 were analyzed for baseline demographic characteristics, disease related characteristics and treatment outcomes.ResultsForty-two patients were identified. The Response rate (RR) was 28% and the disease control rate was 38%. Responses were seen across different melanoma subtypes, including 67% in acral melanoma, 20% in uveal melanoma, and 25% in mucosal melanoma. Patients with a more aggressive disease manifested by elevated lactate dehydrogenase (LDH) achieved a RR of 26%, while patients with active central nervous system (CNS) metastases had a RR of 31%, and an intra-cranial RR of 23%. Responses were seen across lines of treatment, with a 25% RR in the second and third lines, and a 36% RR in the fourth and fifth lines. The median progression free survival was 3 months, and the median survival was 11 months. The treatment was not easily tolerated with 31% of the patients experiencing grade 3-4 toxicity, which was manageable through dose interruptions and reductions. Only 7% of patients discontinued the treatment due to toxicity.ConclusionLenvatinib in combination with anti-PD1 had demonstrated both relative safety and efficacy in patients with metastatic melanoma of all subtypes in the advanced line setting. We are eagerly anticipating the mature results of the LEAP-004 study hoping that this regimen will receive regulatory approval, paving the way for its widespread adoption in daily practice worldwide.

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

“…While these studied showed no survival benefit with Lenvatinib across all skin melanomas, it is important to highlight that acral melanomas were not considered a separate melanoma subtype in these studies. Based on a small cohort study where 4 of 6 acral melanomas responded to second-line Lenvatinib plus ICI 74 and an early clinical study where Anlotinib, another dual FGFR/VEGFR inhibitor, provided a significant survival benefit when used with ICIs 75 , targeting AM with FGFR/VEGFR inhibitors are expected to provide a survival benefit for patients. Based on these studies and our promising preclinical data, we recommend conducting a case series where patients with AM are treated with ICI and Lenvatinib, or another regionally available dual FGFR/VEGFR inhibitor, as a second- or third-line therapy to further establish clinical benefit.…”

“…The only inhibitor identified to promote stable disease or tumor regression across all AM models was Lenvatinib, a multiple receptor tyrosine kinase (RTK) inhibitor that is most potent against the VEGFR and FGFR families 20,21 . While this was a surprising finding considering the poor performance of Lenvatinib against all skin melanomas in the LEAP-003 study results (abstract O-031, 20 th Society Melanoma Research Congress 22 ), it mirrors a small study wherein six AM patients were given the drug as a second-line therapy and four patients (66%) had an objective response 23 . Mechanistically, we demonstrate that Lenvatinib has minimal direct cytotoxicity against transiently cultured AM cells and instead induces tumor regression by remodeling the tumor vasculature.…”

Multidisciplinary approach and treatment of acral and mucosal melanoma

“…Tyrosine kinase inhibitors (TKIs), including sorafenib, lenvatinib, imatinib, sunitinib, pazopanib, and axitinib, are being evaluated in patients with AM and MM. Based on the results discussed above ( 16 , 100 , 101 , 103 , 104 , 111 ), these maybe alternative therapeutic options for patients harboring KIT mutations. Combination therapies have shown the most promise ( 124 , 125 ).…”

“…The ORR and DCR was 24.1% and 82.8%, respectively ( 16 ). A real-world study found a response rate (RR) of 28%, DCR of 38%, median PFS of 3 months, and median survival of 11 months with lenvatinib and pembrolizumab in advanced metastatic melanoma, including 6 MM and 4 AM ( 104 ).…”