Lenvatinib (len) plus pembrolizumab (pembro) in patients with advanced melanoma that progressed on anti–PD-(L)1 therapy: Over 4 years of follow-up from the phase 2 LEAP-004 study.
Authors: Arance Ana Maria , O'Day Steven J. , de la Cruz-Merino Luis , Petrella Teresa M. , Jamal Rahima , Ny Lars , Carneiro Ana , Berrocal-Jaime Alfonso , Marquez-Rodas Ivan , Spreafico Anna , Atkinson Victoria , Svedman Fernanda Costa , Okpara Chinyere E , Lawlor Kevin , Diede Scott J. , Neff Tobias , Long Georgina V. 
Published: July 2024

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Background: PD-1 inhibitors such as pembro are a standard-of-care option for advanced melanoma, and effective treatments are needed for disease that progresses on anti–PD-(L)1–based therapy. Previous results from the single-arm, open-label, phase 2 LEAP-004 study (NCT03776136) showed that len + pembro had antitumor activity in patients (pts) with advanced melanoma that progressed on prior anti–PD-(L)1–based therapy. With a median follow-up of 15.3 mo, the ORR was 21.4% and median DOR was 8.3 mo. Results from LEAP-004 led to the inclusion of len + pembro in treatment guidelines for pts with advanced melanoma and confirmed progression on a PD-(L)1 inhibitor. Here, we present results from LEAP-004 with over 4 years of follow-up. Methods: Eligible pts were aged ≥18 years, had unresectable stage III or IV melanoma, had ≥1 measurable lesion, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had confirmed disease progression within 12 weeks of the last dose of anti–PD-(L)1 therapy given alone or in combination for ≥2 doses. All pts received len 20 mg PO QD + ≤35 doses of pembro 200 mg IV Q3W. The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Results: 103 pts were enrolled and received treatment. Median time from first dose to data cutoff (Oct 11, 2023) was 52.0 months (range, 48.8-55.7). ORR in the overall population was 24.3% (95% CI, 16.4-33.7), with 5 pts (4.9%) having a complete response and 20 (19.4%) a partial response. In key subgroups, ORR was 33.3% (10/30; 95% CI, 17.3-52.8) in pts with progression on prior anti–PD-1 + anti–CTLA-4 therapy and 10.7% (3/28; 95% CI, 2.3-28.2) in pts with BRAF-mutant tumors who received prior BRAF/MEK-directed therapy for metastatic disease. Median DOR in the overall population was 8.5 mo (range, 3.2-40.8) and an estimated 35% of responders remained in response at ≥12 mo. Median PFS was 4.2 mo (95% CI, 3.5-6.3); 24-mo PFS rate was 10.1%. Median OS was 14.0 mo (95% CI, 10.8-18.3); 24-mo OS rate was 29.7%. Efficacy outcomes in pts with mucosal (n = 11) and acral lentiginous (n = 8) melanoma were consistent with the overall population. Any-grade treatment-related AEs occurred in 99 pts (96.1%). Grade 3-5 treatment-related AEs occurred in 51 pts (49.5%). No new treatment-related deaths occurred since prior analysis (1 pt had died because of treatment-related decreased platelet count). Conclusions: With over 4 years of follow up, len + pembrocontinued to show antitumor activity in pts with advanced melanoma and confirmed progression after ≥2 doses of anti–PD-(L)1-based therapy. Safety remained consistent with previous reports, with no new or unexpected safety signals. These results support len + pembro as a potential treatment option for advanced melanoma after anti–PD-(L)1-based therapy. Clinical trial information: NCT03776136 .