Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer.

TPS505 Background: Diffuse-type gastric cancer (DGC) accounts for approximately one third of gastric cancer diagnoses. DGC is characterized by poor differentiation, discohesive growth, frequent peritoneal spread, chemoresistance, and inferior survival compared to intestinal-type gastric cancer. Moreover, DGC is commonly genomically stable and often lacks clinically actionable targets such as ERBB2 amplification. Alterations enriched in DGC including loss-of-function CDH1 mutations and gain-of-function RHOA mutations can facilitate increased focal adhesion kinase (FAK) signaling that drives tumor proliferation, invasiveness, and metastasis. Recent preclinical studies demonstrated that the FAK inhibitor defactinib can inhibitor DGC growth in vitro and in vivo . FAK inhibitor monotherapy leads to compensatory mitogen-activated protein kinase (MAPK) pathway upregulation, which can be overcome with combined FAK and MEK inhibition. In preclinical DGC xenograft models, defactinib plus the RAF/MEK clamp avutometinib led to deep tumor regressions, suggesting synergistic activity of the combination. The goal of this study is to investigate the efficacy and tolerability of avutometinib plus defactinib in patients with advanced DGC refractory to standard therapy. Methods: This investigator-initiated, multicenter phase 2 trial will enroll 27 patients with metastatic/unresectable gastric or gastroesophageal junction carcinoma classified as diffuse, poorly cohesive, signet ring cell, or mixed type with progression on at least one line of therapy including platinum/fluorouracil chemotherapy. Patients with known pathogenic CDH1 and/or RHOA alterations regardless of histology are also eligible. Patients must have ECOG PS 0/1 and can have either measurable or evaluable non-measurable disease per RECIST 1.1 criteria. Avutometinib is given 3.2 mg orally twice weekly and defactinib is given 200 mg orally twice a day, both for 3 weeks on/1 week off for each 28-day cycle. The primary endpoint is 6-month PFS rate, with secondary endpoints including ORR, OS, DOR, and tolerability. Exploratory studies will interrogate FAK/MAPK pathway activation, ctDNA dynamics, and the impact of the combination of avutometinib/defactinib on the tumor microenvironment from pre- and on-treatment biopsies. The trial was opened for enrollment in August 2024. Clinical trial information: NCT06487221 .