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

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Overall response rate 24.2% (2 complete responses, 14 partial responses)

• Primary Outcome: Maximum tolerated dose not reached up to 3,600 mg once daily

• Nnt Or Sensitivity: Median progression-free survival: 6.4 months (CRC), 3.5 months (melanoma)

• Confidence Interval: Not reported in abstract

Clinical Application

Oral administration with manageable toxicity profile suitable for outpatient treatment Relevant to Australian oncology practice given established BRAF mutation testing infrastructure and current PBS-listed BRAF inhibitors for melanoma. TGA approval pathway would require phase II/III confirmation Patients with advanced BRAF V600-mutant solid tumors, particularly colorectal cancer and melanoma, including those with prior BRAF inhibitor exposure

Abstract

PURPOSE: 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. PATIENTS AND METHODS: 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). RESULTS: 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). CONCLUSION: 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.

References

1. 1.Vieito, M., Fontana, E., Han, C. H., Castanon, E., Pinato, D. J., Bechter, O., Eefsen, R. L., Moreno, I., Prenen, H., Dummer, R., Plummer, R., Schnetzler, G., Kornacker, M., Pettazzoni, P., Renner, F., About, M., Serrano-Serrano, M. L., Godfried Sie, C., Keelara, A., Roller, A., Dejardin, D., Cinato, E., Fakolade, T., Guarin, E., Flinn, N., Kratochwil, N. A., & Keshelava, N. (2026). 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. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-25-02444