Avutometinib (RAF/MEK clamp) + defactinib (FAK i) with gem/nab-paclitaxel pushes ORR to 83% in first-line metastatic PDAC

Avutometinib and defactinib were combined with standard gemcitabine (800–1000 mg/m)² + nab-paclitaxel (100–125 mg/m²) in the Phase Ib/II RAMP-205 trial (NCT05669482). Among 54 newly diagnosed metastatic PDAC patients (39 efficacy-evaluable ≥6 mo), objective responses spanned 25–100% across five dose levels, peaking at 5/6 (83%) in DL1 and 1/1 (100%) in DL0; disease control remained ≥56–100%. Grade ≥3 toxicities were primarily neutropenia 39%, anemia 20%, fatigue 7%, and the MTD was not reached. Historical gemcitabine + nab-paclitaxel yields ~23% ORR with 38% grade 3/4 neutropenia, while first-line FOLFIRINOX achieves a 32% ORR—highlighting a sizable response lift without added myelotoxicity.