Phase 1b study of a brain-penetrant MEK inhibitor, PF-07799544, plus next-generation BRAF dimer inhibitor, PF-07799933, in advanced BRAF -mutant melanoma.

9512 Background: Treatment of BRAF -mutant (mut) melanoma has been transformed by targeted inhibition of MEK and BRAF kinases. However, duration of clinical benefit has been limited by de novo and acquired resistance through RAF-kinases signaling as dimers, poor activity in brain metastases (BMs), and paradoxical activation adverse events (AEs) negatively impacting tolerability. PF-07799544 is an oral, brain-penetrant, reversible MEK inhibitor (MEKi). PF-07799933 is an oral, brain-penetrant, selective BRAF dimer inhibitor (BRAFi) with activity against BRAF V600 and non-V600 muts. We report initial results of this next-generation BRAFi/MEKi combination from ongoing phase 1 study. Methods: This platform study (NCT05538130) is evaluating PF-07799544 as monotherapy or combined with other targeted therapy for BRAF -mut melanoma and other solid tumors. Substudy B is an open-label, multicenter study assessing safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and clinical activity of PF-07799544 + PF-07799933. Dose escalation (DE) enrolled into 4 dose levels patients (pts) with BRAF -mut advanced melanoma who had progressed on standard therapy, including pts with BMs. Randomized dose optimization (DO) enrolled pts with BRAF V600 -mut advanced melanoma previously treated with 1-2 immunotherapy (IO) lines and ≤1 BRAFi ± MEKi line; pts with BMs were eligible if asymptomatic. We report pooled baseline characteristics and safety and separate efficacy. Results: As of Nov 12, 2025, 60 pts received ≥1 dose of study treatment. At baseline: median age, 54.5 years; female, 50%; White, 95%; ECOG PS of 0, 63%; adrenal insufficiency, 25%; BMs, 53%; and BRAF V600 mutation, 95%; 77% received ≥3 prior systemic anticancer therapies, 100% received prior IO, 100% of pts with BRAF V600 mutation received prior BRAFi ± MEKi, and 73% received BRAFi ± MEKi <6 months before beginning study treatment. Any-grade treatment-emergent AEs (TEAEs) occurred in 95%; most common (≥20%) were rash (40%), fatigue (37%), diarrhea (32%), and peripheral edema (22%). Grade ≥3 TEAEs occurred in 67%; most common (≥5%) were rash (7%), disease progression (7%), anemia (5%), and fall (5%). Dose modifications due to TEAEs (any-causality, treatment-related) included reductions (13%, 13%), interruptions (53%, 33%), and discontinuations (10%, 3%). Objective response rate (ORR; including unconfirmed) by investigator was 27% in 41 DE pts and 32% in 19 DO pts. In pts with baseline BMs, intracranial (IC) ORR was 30% in 23 DE pts and 22% in 9 DO pts. PK showed BRAFi/MEKi exposures consistent with preclinical exposures which showed antitumor activity supporting selected DO doses. Conclusions: PF-07799544 + PF-07799933 showed manageable safety and promising systemic and IC antitumor activity in heavily pretreated BRAF -mut advanced melanoma. Evaluation of dose expansion cohorts is ongoing. Clinical trial information: NCT05538130 .