Avutometinib/Defactinib Shows Promise in Advanced Mesonephric Gynecologic Cancer

The phase 2 trial is currently accruing additional patients with advanced mesonephric gynecologic cancer for treatment with avutometinib/defactinib.

The use of avutometinib plus defactinib exceeded the response threshold and will advance to stage 2, for patients with advanced or recurrent mesonephric or mesonephric-like gynecologic cancer, according to interim results from a phase 2 trial (NCT05787561) presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).

A reduction in target lesions was noted in all patients. This includes the cervix, endometrium, and ovary. Overall, 12 patients discontinued and with reasons including RECIST progression of disease (n = 9), withdrawal of consent (n = 1), clinical progression of disease (n = 1), and non-compliance (n = 1).

“Avutometinib in combination with defactinib has previously shown activity in patients with low-grade serous ovarian cancer with highest response rates seen in those patients with a KRAS mutation,” Rachel Grisham, MD, section head of Ovarian Cancer, and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center in Westchester, said during the presentation. “The study has reached its original accrual goal and was recently amended to allow for an additional 20 patients.”

The study scheme allowed for 13 patients to be accrued into stage 1 with measurable, advanced or recurrent mesonephric cancer. Patients could advance to stage 2 if 1 or more responses were observed by RECIST v1.1 criteria. Stage 2 would accrue 7 more patients, and if 3 or more responses were observed in the 20 patients, then treatment would be considered active.

Avutometinib was given at 3.2 mg by mouth twice a week plus 200 mg of defactinib by mouth twice daily. Treatment was given for the first 21 days of 28 days of each cycle.

The primary end point is confirmed response rate determined by RECIST v1.1 response. The secondary end points included safety and tolerability, duration of response, clinical benefit rate, progression-free survival, and overall survival.

Patients were included if they were older than 18; had histologic confirmation of mesonephric or mesonephric-like cancer and were eligible if they had mixed histology at the time of recurrence; had measurable disease via RECIST v1.1; or had persistent or recurrent disease.

Patients were excluded if they received systemic anti-cancer therapy other than endocrine therapy within 4 weeks, 1 cycle, or 5 half-lives of the first dose of the study; endocrine therapy could not be given within 1 week of the first dose; if patients received major surgery within 4 weeks, minor surgery within 2 weeks, or palliative radiotherapy within 1 week of induction; having received prior treatment with a MEK, RAF, or FAK inhibitor; or if patients could not swallow oral medication or had an impaired gastrointestinal absorption.

The median patient age was 66 years old, and the tumor site of origin included cervix (38.5%), ovary (38.5%), or endometrium (23.0%). Patients had a median of 3 prior lines of therapy and 77% had prior radiation.

Laboratory toxicities related to treatment noted during stage 1 from grade 1, 2, and 3 were alkaline phosphatase elevation (8%, 0%, 8%), anemia (0% for all 3 grades), aspartate aminotransferase elevation (8%, 0%, 0%), bilirubin increase (46%, 23%, 8%), creatine phosphokinase increase (69%, 38%, 15%), and lymphocyte count decrease (0%, 8%, 0%).

Adverse effects that were related to the treatment of grade 1, 2, and 3 included maculopapular rash (31%, 8%, 8%), diarrhea (62%, 15%, 8%), and edema of the limb (54%, 23%, 8%), and fatigue (63%, 23%, 8%).

The expansion phase of this trial is currently enrolling.

Reference

Grisham RN, Praiss A, Iasonos A, et al. Single arm phase II study of avutometinib and defactinib in advanced or recurrent mesonephric or mesonephric-like (MLA) gynecologic cancer: interim results. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO); Seattle, WA, March 14-17, 2025.