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.

Abstract

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 patients) and with 2nd line investigator choice 5FU doublet and anti-EGFR therapy (cetuximab or panitumumab) (CRC patients). After selection of a dose, monotherapy dose expansion cohorts will enroll patients with (a) PDAC; (b) CRC; and (c) biliary tract cancer. NSCLC: Patients with relapsed/refractory advanced NSCLC with RAS or RAF alterations who have received at least one prior line of standard of care therapy will be enrolled into monotherapy DE cohorts. After selection of a dose in DE and/or dose optimization, expansion arms will enroll patients with (a) KRAS non-G12C alterations; (b) BRAF alterations (all classes); (c) KRAS G12C alterations post-progression on G12C targeted therapy; and (d) active CNS metastasis. Other Solid Tumors: Patients with relapsed/refractory advanced other non-NSCLC or non-GI solid tumors with 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. All patients will provide blood and FFPE tumor samples for correlative analyses. The primary objective is safety and tolerability. Secondary endpoints include anti-tumor efficacy, PK studies, and ctDNA analysis. As of September 2025, 23 patients are enrolled. Enrollment is ongoing and the trial is opening more sites in the US, Australia, EU, UK, China, and Japan. Clinical trial information: NCT05786924 .