A phase 1/2, open-label study of oral S241656 (BDTX-4933) as monotherapy and in combination with other anti-cancer therapies in patients with KRAS, BRAF and other selected RAS/MAPK mutation positive malignancies.

作者：Ajay Prakash, Michael Offin, Manish R. Sharma, Alexander I. Spira, Sylvia M. Lee, Maria Q. Baggstrom, Agathe Lepissier, Vanessa Seif, Zhaowei Hua, Kabir Mody, Jia Luo, Jiaxin Niu · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.2_suppl.tps857 · 研究领域：Melanoma and MAPK Pathways、Protein Kinase Regulation and GTPase Signaling、Protein Degradation and Inhibitors

TPS857 Background: While the most frequently mutated solid tumor oncogenes, RAS and RAF , function via aberrant RAF dimerization, approved BRAF inhibitors are only active against mutated BRAF monomers and approved KRAS G12C inhibitors are ineffective for patients with RAS non-G12C tumors. There is a high unmet clinical need for RAF inhibitors that target a broad spectrum of mutated RAF and RAS proteins in solid tumor malignancies. S241656 (previously BDTX-4933) is an oral, CNS-penetrant small-molecule inhibitor engineered to suppress oncogenic K/H/NRAS and class I/II/III BRAF signaling, while avoiding paradoxical MAPK activation, thus creating a broad therapeutic window. Pre-clinical studies demonstrated tumor regression in multiple xenograft models, supporting first-in-human evaluation. The objective of this trial is to evaluate the safety, PK and PD parameters, and antitumor efficacy of S241656. Methods: This phase 1/2 dose escalation (DE) (part 1) and dose optimization and expansion (part 2) study (NCT05786924) will enroll patients in several settings who are aged ≥18 years, ECOG 0/1 who meet the following cohort-related criteria. The BOIN method is used for DE. Gastrointestinal (GI) cancers: Patients with relapsed/refractory advanced GI cancers with selected RAS or RAF alterations who have received at least 1 prior line of standard of care therapy will be enrolled into a monotherapy DE cohort and combination DE cohorts with 2nd line gemcitabine/nab-paclitaxel (PDAC patien...