LBA44 - Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004

Background

Identification of safe and effective treatment options for MEL that progressed on anti–PD-1-based therapy is a large unmet need. The open-label, single-arm, phase 2 LEAP-004 study (NCT03776136) evaluates the combination of len (multikinase inhibitor) and pembro (anti–PD-1) in this population.

Methods

Eligible pts had unresectable stage III-IV MEL, PD confirmed per iRECIST within 12 wk of the last dose of a PD-1/L1 inhibitor given alone or with anti–CTLA-4 or other therapies for ≥2 doses, measurable disease, and ECOG PS 0/1. Pts received len 20 mg/d PO QD + ≤35 doses of pembro 200 mg IV Q3W until PD or unacceptable toxicity; eligible pts could be treated beyond PD. Imaging is done Q9W through wk 54, Q12W through wk 102, and Q24W thereafter. Primary end point is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety.

Results

From Feb to Sep 2019, 103 pts were enrolled and treated; median age was 63 y, 67.0% had stage M1c/M1d disease, 55.3% had LDH >ULN (20.4% ≥2 × ULN), and 36.9% had BRAFV600 mutation. 61.2% received ≥2 prior therapies for MEL, 32.0% received prior BRAF ± MEK inhibition, and 28.2% had PD on prior anti–PD-1/L1 + anti–CTLA-4. Median study follow-up was 12.0 mo (range 8.7-15.6). Confirmed ORR by BICR was 21.4% (95% CI 13.9-30.5; 2 CRs, 20 PRs) overall and 31.0% (15.3-50.8; 1 CR, 8 PRs) for pts with PD on prior anti–PD-1/L1 + anti–CTLA-4. DCR was 65.0%. Median DOR was 6.3 mo (range 2.1+-11.1+); KM estimate of DOR ≥6 mo was 72.6%. Median (95% CI) PFS and OS were 4.2 mo (3.5-6.3) and 13.9 mo (95% CI 10.8-NR). 9-mo PFS and OS estimates were 26.2% and 65.4%. Most common treatment-related AEs (TRAEs) were hypertension (56.3%), diarrhea (35.9%), and nausea (34.0%). TRAEs were gr 3-5 in 44.7%, gr 5 in 1.0%, and led to discontinuation of len and/or pembro in 7.8%.

Conclusions

The combination of len and pembro has activity in pts with advanced MEL with confirmed progression on a PD-1/L1 inhibitor, including those with PD on combined anti–PD-1/L1 + anti–CTLA-4. The safety profile was consistent with prior studies. These data support len + pembro as a potential regimen for this population of high unmet need.

Clinical trial identification

NCT03776136, originally posted on December 14, 2018.

Editorial acknowledgement

Melanie Leiby of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, 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. Arance Fernandez: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre-Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Eisai Ltd. S.J. O'Day: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Research grant/Funding (institution): Eisai Ltd.; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Agenus; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Biothera; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: ImaginAb; Honoraria (self), Advisory/Consultancy: RadImmune; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Exicure; Research grant/Funding (institution): Genocea; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Oncotherapeutics; Research grant/Funding (institution): Ultimovacs; Research grant/Funding (institution): Viralytics; Travel/Accommodation/Expenses: Caris MPI. L. de la Cruz Merino: Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Amgen; Research grant/Funding (institution): Eisai Ltd.; Research grant/Funding (institution): Celgene. T. Petrella: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Pfizer; Research grant/Funding (self): Roche; Research grant/Funding (institution): Eisai Ltd. R. Jamal: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers Squibb; Advisory/Consultancy, unpaid: Merck; Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Research grant/Funding (institution): Eisai Ltd.; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Evelo Biosciences; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Non-remunerated activity/ies: Conferences and advisory/consultancy. L. Ny: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Pierre-Fabré; Advisory/Consultancy: Sanofi; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Leo Pharma; Research grant/Funding (institution): Syndax Pharmaceuticals; Research grant/Funding (institution): Eisai Ltd. A. Carneiro: Research grant/Funding (institution): MSD; Research grant/Funding (institution): Eisai Ltd. A. Berrocal: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Research grant/Funding (institution): Eisai Ltd. I. Márquez-Rodas: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy: GSK; Advisory/Consultancy: Amgen; Advisory/Consultancy: Incyte; Advisory/Consultancy: Regeneron; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Bioncotech; Research grant/Funding (institution): Eisai Ltd. A. Spreafico: Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Oncorus; Advisory/Consultancy: Janssen; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): AstraZeneca/MedImmune; Research grant/Funding (institution): Surface Oncology; Research grant/Funding (institution): Eisai Ltd.; Research grant/Funding (institution): Northern Biologics; Research grant/Funding (institution): Janssen Oncology/Johnson & Johnson; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Alkermes; Research grant/Funding (institution): Array Biopharma; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Bayer. V. Victoria Atkinson: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Nektar; Research grant/Funding (institution): Eisai Ltd. F. Costa Svedman: Research grant/Funding (institution): MSD; Research grant/Funding (institution): Eisai Ltd. A.D. Smith: Full/Part-time employment: Eisai Ltd. K. Chen: Full/Part-time employment: Merck & Co., Inc. S.J. Diede, C. Krepler: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck & Co., Inc. G.V. Long: Advisory/Consultancy: Aduro; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Highlight Therapeutics S.L.; Advisory/Consultancy: Mass-Array; Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: OncoSec Medical; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Roche; Advisory/Consultancy: QBiotics; Advisory/Consultancy: Skyline DX; Advisory/Consultancy: Sandoz; Research grant/Funding (institution): Eisai Ltd.