Phase 1b/2 avutometinib plus defactinib adds RAF/MEK and FAK inhibition to mFOLFIRINOX in pancreatic cancer

This University of Virginia Phase 1b/2, open-label study adds avutometinib, a RAF/MEK pathway inhibitor often described as a RAF/MEK clamp, and defactinib, a focal adhesion kinase inhibitor, to modified FOLFIRINOX in previously untreated pancreatic ductal adenocarcinoma. Verastem Oncology is a collaborator. The oral agents are given for 3 weeks of each 28-day cycle, with protocol-defined combination dosing for up to 6 cycles and an option for maintenance treatment when appropriate.

Part A enrolls metastatic disease and focuses on dose-limiting toxicities. Part B instead enrolls borderline resectable or locally advanced disease that is not eligible for upfront surgery, evaluating response and reassessing operability after cycles 4 and 6. The two parts therefore address different clinical questions: dose feasibility in metastatic disease and response or surgical conversion in initially unresectable localized disease. The study asks whether MAPK inhibition plus FAK-related microenvironment modulation can deepen chemotherapy responses or improve the opportunity for surgery. A single-arm response or conversion-to-resection signal would still need comparison with outcomes from chemotherapy-based care in similarly selected patients.