1180TiP - Randomized phase II trial (PORTSIDE) evaluating encorafenib (enco) and binimetinib (bini) plus pembrolizumab (pembro) versus nivolumab (nivo) and ipilimumab (ipi) for the treatment of advanced BRAF-mutant melanoma

Background

Anti–PD-1 therapy (eg, pembro, nivo) in the adjuvant setting is one of the standard-of-care regimens for patients with BRAF-mutant metastatic melanoma. However, a significant proportion of patients have a limited or no response to anti–PD-1 therapy. Therefore, there is an unmet need to determine the optimal treatment sequence in patients resistant to anti–PD-1 therapy. BRAF + MEK inhibitors (eg, enco + bini) are also treatment options for BRAF-mutant metastatic melanoma. This phase II trial will evaluate the combination of enco + bini + pembro vs nivo + ipi in participants (pts) with advanced BRAF-mutant melanoma who progressed during or after anti–PD-1 therapy.

Trial design

PORTSIDE is an international open-label trial recruiting approximately 150 pts. Pts will be randomized 1:1 to receive either enco 450 mg (QD, PO), bini 45 mg (BID, PO), and pembro 200 mg (Q3W, IV) in 21-day cycles or 4 cycles of induction with nivo 1 mg/kg (Q3W, IV) and ipi 3 mg/kg (Q3W, IV) followed by maintenance with nivo 480 mg (Q4W, IV). Pts will be stratified by type of PD-1 resistance (primary vs secondary) and baseline lactate dehydrogenase level (above vs below the upper limit of normal). Pts must be ≥18 years old with histologically confirmed unresectable locally advanced or metastatic cutaneous BRAF V600E/K-mutant melanoma (per AJCC 8th edition) with ≥1 measurable lesion per RECIST v1.1. Pts must have received only 1 prior line of systemic therapy for melanoma and have confirmed disease progression per RECIST v1.1, either during or after receipt of an anti-PD1 therapy. Pts must have an ECOG PS of 0 or 1 and adequate organ function. Pts who discontinued prior anti–PD-1 therapy due to toxicity or who may not tolerate combination therapy are not eligible. Pts must not have previously participated in the STARBOARD study (NCT04657991) or received prior treatment with BRAF and/or MEK inhibitors, ipi, combined immunotherapy with anti-PD1/L1 treatment, or any other anticancer agents. The primary endpoint is objective response rate; key secondary endpoints are progression-free and overall survival.

Clinical trial identification

Editorial acknowledgement

Editorial/medical writing support was provided by Darren Chow, MSc, of Meditech Media and was funded by Pfizer.

Legal entity responsible for the study

Pfizer, Inc.

Funding

This trial was sponsored by Pfizer in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi, Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi-Regeneron, Pfizer, Philogen, Neracare; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, MSD, Pierre Fabre, Sanofi, Philogen; Financial Interests, Institutional, Research Grant: BMS, MSD; Non-Financial Interests, Member of Board of Directors: EORTC-MG. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer, Simcere. A. Ribas: Financial Interests, Personal, Advisory Board, Honoraria for consulting: Amgen, AstraZeneca, Merck, Novartis, Jazz; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: Apricity, Appia, Arcus, Compugen, Immpact, Lutris, MapKure, Merus, PACT Pharma, Synthekine, Tango; Financial Interests, Personal, Member of Board of Directors, Member of the Board of Directors: Arcus, Lutris, PACT Pharma; Financial Interests, Personal, Stocks/Shares, Stock ownership: 4C Biomed, Apricity, Appia, Arcus, Compugen, Highlight, ImaginAb, Immpact, ImmuneSensor, Inspirna, Isoplexis, Lutris, MapKure, Merus, Pluto, Synthekine, PACT Pharma, Tango, Advaxis, CytomX, RAPT, Kite-Gilead; Financial Interests, Personal, Invited Speaker: Arsenal Bio; Financial Interests, Institutional, Funding: Agilent, Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Member of the scientific advisory board: Highlight, ImmuneSensor, Inspirna, Pluto. C. Robert: Financial Interests, Personal, Other, Consultancy fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, AstraZeneca, Pfizer. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, OncoSec, Pfizer, Replimune, Marengo; Financial Interests, Personal, Royalties: Up-To-Date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Invited Speaker: GSK, Pfizer, Sanofi, Moderna, Roche-Genentech, BioMed Valley Discoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Simcha Therapeutics, OnKure, Marengo, Synthekine. A. King: Other, Institutional, Full or part-time Employment: Pfizer, Inc. A. Polli: Financial Interests, Institutional, Full or part-time Employment: Pfizer, Inc. A. di Pietro: Other, Institutional, Full or part-time Employment: Pfizer, Inc. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant and Advisory Role, Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: iTeos; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role. Travel support: Replimune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Institutional, Funding, Clinical Trial: Pfizer/Array, Roche Genentech, Sanofi; Financial Interests, Personal, Advisory Board: Erasca; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, SMR, AIOM.