Phase I Study of Mosperafenib, a Novel Paradox Breaker B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) Inhibitor, in Patients With BRAF V600-Mutant Solid Tumors.

BRAF V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity. This phase Ia/b study was conducted in patients with advanced solid tumors harboring a BRAF V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and/or recommended phase II dose(s). Eighty patients (60% BRAFi-exposed)-63 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors-received ≥1 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition ≥90%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day). Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-naïve and BRAFi-exposed patients.