Avutometinib + defactinib delivers 31% ORR (44% in KRAS‑mut) in recurrent low‑grade serous ovarian cancer (LGSOC)

Avutometinib is an oral “RAF/MEK clamp” that locks MEK in an inactive state while preventing RAF feedback, and defactinib blocks focal‑adhesion kinase; together they target MAPK signaling and stromal crosstalk. In the phase II ENGOT‑OV60/GOG‑3052 (RAMP‑201) primary analysis, 115 women with recurrent LGSOC (median 3 prior lines; 22% prior MEKi) received avutometinib 3.2 mg BID (twice weekly) plus defactinib 200 mg BID. Blinded central review confirmed a 31% ORR (95% CI 23‑41%) with a median DoR of 31 months; efficacy was enriched in KRAS‑mutant tumors (ORR 44%, mPFS 22 mo), expected in ~30% of LGSOC, versus wild‑type (17%, 12.8 mo). Median PFS overall was 12.9 mo. Grade ≥3 AEs were mostly biochemical (creatine phosphokinase 24%), with diarrhea 8% and anemia 5%; 10% discontinued. For context, single‑agent trametinib—the current preferred option—yields a 26% ORR and 13 mo mPFS with 13% grade 3/4 rash and 10% diarrhea.