Dr Grisham on the Safety of Avutometinib Plus Defactinib in Gynecologic Mesonephric Cancer

“The most common non-laboratory toxicities we saw were rash, fatigue, gastrointestinal [adverse] effects. [These are] common [with] MEK inhibitors. With avutometinib, no patients discontinued treatment due to toxicity.”

Rachel Grisham, MD, section head of Ovarian Cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center Westchester, discussed safety findings from a phase 2 study (NCT05787561), which evaluated the combination of avutometinib (VS-6766) and defactinib (VS-6063) in patients with advanced or recurrent gynecologic mesonephric or mesonephric-like carcinoma.

Grisham explained that the study enrolled patients with these rare and molecularly distinct forms of gynecologic cancer, explaining that these patients are often excluded from larger histology-driven trials and lack standard systemic treatment options. The combination regimen was chosen based on prior evidence supporting the synergistic activity of dual RAF/MEK and FAK inhibition.

Findings showed the study met its response threshold to commence enrollment in part 2 of the trial. The safety profile of avutometinib plus defactinib was consistent with previous reports in other tumor types. Elevated blood creatine phosphokinase (CPK) levels was the most commonly reported laboratory abnormality. These CPK elevations were generally asymptomatic and did not lead to treatment interruption or dose modification. Grisham noted that such elevations are a known class effect of MEK inhibition and have been previously observed with avutometinib.

The most common non-laboratory adverse effects (AEs) included rash, fatigue, and gastrointestinal AEs, particularly nausea and diarrhea. These toxicities were low-grade, manageable with supportive care, and consistent with established MEK inhibitor–associated toxicities. Importantly, no patients discontinued treatment due to toxicity, and no dose-limiting toxicities were reported.

Grisham emphasized the significance of these findings in the context of limited therapeutic options for patients with mesonephric carcinoma. Although rare, this histologic subtype poses a considerable treatment challenge due to the paucity of clinical trial data and the lack of effective targeted therapies. The favorable tolerability of the combination supports its further evaluation, particularly given the early signs of clinical activity previously reported in this population.

The study underscores the importance of expanding clinical trial access for patients with rare gynecologic malignancies. Grisham noted that continued development of targeted agents in this space is critical to improving outcomes.