4440 - Pembrolizumab (pembro) Plus Lenvatinib (len) for First-Line Treatment of patients (pts) With Advanced Melanoma: Phase 3 LEAP-003 Study

Background

Pembro, a PD-1 inhibitor, has shown effective antitumor activity, durable responses, and survival benefit in pts with advanced melanoma. Len—a potent inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT—plus a PD-1 inhibitor showed superior antitumor efficacy to either agent alone in a murine tumor model. Len + pembro showed antitumor activity and was well tolerated in pts with advanced melanoma in the phase Ib/II KEYNOTE-146 trial. LEAP-003 will compare the efficacy and safety of pembro ± len in advanced melanoma (NCT03820986).

Trial design

Eligibility criteria include ≥18 y, histologically/cytologically confirmed unresectable untreated stage III-IV melanoma, documented BRAF^V600 status, ECOG performance status 0/1, toxicity resolution from most recent therapy, and provision of baseline tumor sample. Prior first-line standard of care targeted therapy allowed only if pt has BRAF^V600-mutant disease. Prior targeted therapy or immunotherapy (as adjuvant/neoadjuvant) allowed if relapse did not occur during treatment or ≤ 6 mo after discontinuation. Pts will be randomized 1:1 to pembro 200 mg every 3 weeks (Q3W) IV plus len 20 mg or placebo QD PO. Randomization will be stratified by BRAF status (mutant/WT), prior adjuvant therapy (PD-1 inhibitor, yes/no), geographic region (China, yes/no). Pembro will continue for up to ∼2 y; len or placebo may continue beyond 2 y in cases of clinical benefit, until progression, unacceptable toxicity, or investigator/pt decision. Response will be assessed per RECIST v1.1 Q9W until wk 54, Q12W until wk 102, and Q24W thereafter. Pts with a CR can discontinue treatment after ≥24 wk of pembro and ≥2 pembro doses after initial CR. Eligible pts can continue treatment beyond initial RECIST-defined PD. AEs will be assessed for ≤90 d and graded per NCI CTCAE v4.0. Survival follow-up will be Q12W. Primary end points are PFS by blinded independent central review (BICR) per modified RECIST v1.1 (max target lesions: 10; 5 per organ) and OS. Secondary end points are ORR and DOR (by BICR per modified RECIST v1.1), safety, and pt-reported health outcomes. Exploratory biomarker and PK analyses of len plus pembro are planned.

Clinical trial identification

NCT03820986; release date: January 29, 2019.

Editorial acknowledgement

Doyel Mitra, PhD, CMPP, and Harleigh E. Willmott, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA).

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

A.M.M. Eggermont: Honoraria (self): Actelion, BMS, GSK, Ellipses, Incyte, IO Biotech, IsaPhamaceuticals, MSD, Novartis, Pfizer, Sanofi, Sellas, SkylineDx; Advisory / Consultancy: Actelion, BMS, GSK, Ellipses, Incyte, IO Biotech, IsaPhamaceuticals, MSD, Novartis, Pfizer, Sanofi, Sellas, SkylineDx; Speaker Bureau / Expert testimony: MSD. M.S. Carlino: Honoraria (self): MSD, BMS; Advisory / Consultancy: MSD, BMS, Novartis, Roche, Merck, Pierre Fabre. A. Hauschild: Honoraria (self): Amgen, BMS, MSD/Merck, Novartis, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme; Honoraria (institution), Support for clinical trials: Amgen, BMS, MerckSerono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme; Advisory / Consultancy: Amgen, BMS, MerckSerono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi-Genzyme, Sun Pharma. P.A. Ascierto: Advisory / Consultancy: BMS, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC; Research grant / Funding (self): BMS, Roche-Genentech, Array; Travel / Accommodation / Expenses: MSD. A. Arance: Advisory / Consultancy: BMS, MSD, Roche, Novartis, Merck; Travel / Accommodation / Expenses: BMS, MSD, Roche, Novartis, Merck. A. Daud: Advisory / Consultancy: Merck, Pfizer, BMS, Genentech, Incyte, Novartis; Shareholder / Stockholder / Stock options: SQZ; Research grant / Funding (self): BMS, Pfizer, Incyte, Checkmate, Merck. S.J. O’Day: Advisory / Consultancy: Biothera, BMS, Merck, RadImmune, ImaginAB; Speaker Bureau / Expert testimony: BMS; Travel / Accommodation / Expenses: Biothera, BMS, Merck, RadImmune, ImaginAB; Research grant / Funding (institution): Amgen, Biothera, Exicure, Genocea, Incyte, Oncothereapeutics, Ultimovacs, Viralytics. M.H. Taylor: Honoraria (self): BMS, Eisai Inc, Array Biopharma, Arqule, Blueprint Medicines, Bayer, Loxo Oncology, Novartis; Advisory / Consultancy: BMS, Eisai Inc, Array Biopharma, Arqule, Blueprint Medicines, Bayer, Loxo Oncology, Novartis; Speaker Bureau / Expert testimony: BMS, Eisai Inc. A. Smith: Full / Part-time employment: Eisai. A. Rodgers: Full / Part-time employment: Merck & Co., Inc. B. Homet Moreno: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. S.J. Diede: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. H. Kluger: Research grant / Funding (institution): Merck, BMS, Apexigen; Honoraria (self): Regeneron, Alexion, Prometheus, Corvus, Nektar, Biodesix, Roche/Genentech, Pfizer, Iovance, Immunocore, Celldex, Array BioPharma.