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

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. 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. Editorial/medical writing support was provided by Darren Chow, MSc, of Meditech Media and was funded by Pfizer. Pfizer, Inc. This trial was sponsored by Pfizer in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.