Abstract 4440
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 BRAFV600 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 BRAFV600-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.
Resources from the same session
3664 - Longitudinal changes in cell-free DNA (cfDNA) methylation levels identify early non-responders to treatment in advanced solid tumors
Presenter: Andrew Davis
Session: Poster Display session 3
Resources:
Abstract
3212 - Multigene panel testing results for hereditary breast cancer in 1325 individuals: implications for gene selection and considerations for guidelines.
Presenter: Georgios Tsaousis
Session: Poster Display session 3
Resources:
Abstract
2591 - PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors
Presenter: Julia Quintanilha
Session: Poster Display session 3
Resources:
Abstract
4377 - ERBB2 mRNA as a predictor in HER2-positive (HER2+)/hormone receptor-positive (HR+) metastatic breast cancer (BC) treated with HER2 blockade in combination with endocrine therapy (ET): a retrospective analysis of the ALTERNATIVE and SOLTI-PAMELA trials.
Presenter: Nuria Chic
Session: Poster Display session 3
Resources:
Abstract
3439 - Early on-treatment vs pre-treatment tumor transcriptomes as predictors of response to neoadjuvant therapy for HER2-positive inflammatory breast cancer
Presenter: Sonia Pernas
Session: Poster Display session 3
Resources:
Abstract
2512 - AXL expression predicts poor prognosis and lack of efficacy of anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents in patients (pts) with RAS wild type (WT) metastatic colorectal cancer (mCRC)
Presenter: Claudia Cardone
Session: Poster Display session 3
Resources:
Abstract
4061 - Prevalence of EGFR mutations and its correlation with Egyptian patients’ human kinetics (PEEK Study)
Presenter: Adel Ibrahim
Session: Poster Display session 3
Resources:
Abstract
2547 - Evaluation of tumor microenvironment identifies immune correlates of response to combination immunotherapy with margetuximab (M) and pembrolizumab (P) in HER2+ gastroesophageal adenocarcinoma (GEA)
Presenter: Sergio Rutella
Session: Poster Display session 3
Resources:
Abstract
4671 - Clinicopathological and molecular criteria assessment for the screening of hypermutated proficient mismatch repair (pMMR) colorectal cancers (CRC) with exonucleasic domain POLE (edPOLE) mutations (mt).
Presenter: Benoit Rousseau
Session: Poster Display session 3
Resources:
Abstract
3862 - Tumor mutation burden and microsatellite instability in colorectal cancer
Presenter: Francesca Fenizia
Session: Poster Display session 3
Resources:
Abstract