Dr Grisham on the Efficacy/Tolerability of Avutometinib Plus Defactinib in KRAS+ Serous Ovarian Cancer

“It's important for any treatment that a patient is going to be on for a long time that they're able to tolerate therapy. Prior studies of single-agent MEK inhibitors like binimetinib and trametinib showed that more than 30% of patients discontinued treatment due to toxicity. Thus far in the RAMP 201 study, only 10% of patients have discontinued treatment due to toxicity."

Rachel N. Grisham, MD, an associate attending physician at Memorial Sloan Kettering Cancer Center; section head of Ovarian Cancer; and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center Westchester, discussed efficacy and tolerability data from a the phase 2 RAMP 201 trial (NCT04625270), which evaluated avutometinib (VS-6766) with or without defactinib (VS-6063) in patients with recurrent low-grade serous ovarian cancer.

Updated findings from the study presented at the 2025 Society of Gynecological Oncology Annual Meeting on Women’s Cancer demonstrated that patients in the overall population treated with avutometinib at 3.2 mg and defactinib at 200 mg (n = 109) achieved a confirmed overall response rate (ORR) of 31%. The ORR was 44% in patients with KRAS-mutant tumors (n = 57). These results build upon prior evidence supporting the clinical activity of dual RAF/MEK and FAK inhibition in molecularly selected subgroups of low-grade serous ovarian cancer, a disease subtype with historically limited systemic treatment options.

Previously reported findings from RAMP 201 supported the submission of a new drug application (NDA) seeking the approval of the combination for the treatment of adult patients with recurrent low-grade serous ovarian cancer who received at least 1 prior systemic therapy and harbor a KRAS mutation. The FDA granted priority review to the NDA in January 2025 and assigned a target action date of June 30, 2025, under the Prescription Drug User Fee Act.

Grisham emphasized that the prolonged duration of therapy underscores the need for a well-tolerated regimen. In contrast to prior trials with single-agent MEK inhibitors—such as binimetinib (Mektovi) and trametinib (Mekinist)—which have been associated with high rates of treatment disconinuation, the RAMP 201 study showed a notably lower discontinuation rate of 10%. This improvement in tolerability suggests that the combination regimen may be better suited for long-term administration.

Grisham noted that response rates were particularly compelling in the KRAS-mutant subgroup, aligning with the mechanistic rationale of targeting MAPK pathway alterations. She further highlighted the need for ongoing biomarker-driven research to refine patient selection.