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@article{Vieito:2026:10.1200/JCO-25-02444,
author = {Vieito, M and Fontana, E and Han, CH and Castanon, E and Pinato, DJ and Bechter, O and Eefsen, RL and Moreno, I and Prenen, H and Dummer, R and Plummer, R and Schnetzler, G and Kornacker, M and Pettazzoni, P and Renner, F and About, M and Serrano-Serrano, ML and Godfried, Sie C and Keelara, A and Roller, A and Dejardin, D and Cinato, E and Fakolade, T and Guarin, E and Flinn, N and Kratochwil, NA and Keshelava, N},
doi = {10.1200/JCO-25-02444},
journal = {J Clin Oncol},
pages = {1337--1348},
title = {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.},
url = {http://dx.doi.org/10.1200/JCO-25-02444},
volume = {44},
year = {2026}
}
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TY  - JOUR
AB  - 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-expos
AU  - Vieito,M
AU  - Fontana,E
AU  - Han,CH
AU  - Castanon,E
AU  - Pinato,DJ
AU  - Bechter,O
AU  - Eefsen,RL
AU  - Moreno,I
AU  - Prenen,H
AU  - Dummer,R
AU  - Plummer,R
AU  - Schnetzler,G
AU  - Kornacker,M
AU  - Pettazzoni,P
AU  - Renner,F
AU  - About,M
AU  - Serrano-Serrano,ML
AU  - Godfried,Sie C
AU  - Keelara,A
AU  - Roller,A
AU  - Dejardin,D
AU  - Cinato,E
AU  - Fakolade,T
AU  - Guarin,E
AU  - Flinn,N
AU  - Kratochwil,NA
AU  - Keshelava,N
DO  - 10.1200/JCO-25-02444
EP  - 1348
PY  - 2026///
SP  - 1337
TI  - 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.
T2  - J Clin Oncol
UR  - http://dx.doi.org/10.1200/JCO-25-02444
UR  - https://www.ncbi.nlm.nih.gov/pubmed/41894647
VL  - 44
ER  -
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