Avutometinib/Defactinib Combo Shows Potential in Recurrent Mesonephric Gynecologic Cancer

Mesonephric Gynecologic Cancer |
Image Credit: © Dr_Microbe
- stock.adobe.com

The combination of avutometinib (VS-6766) and defactinib (VS-6063) has emerged as a potential novel therapeutic approach for patients with advanced or recurrent mesonephric and mesonephric-like gynecologic cancers, according to Rachel N. Grisham, MD.

Findings from the first part of a phase 2, single-institution trial (NCT05787561) evaluating the combination in patients with advanced or recurrent mesonephric and mesonephric-like cancers, which were presented at the 2025 Society of Gynecological Oncology (SGO) Annual Meeting on Women’s Cancer, showed that the regimen exceeded the predefined response threshold to allow for the commencement of part 2 of the trial.1 In part 1, a reduction in target lesions was observed in all patients across primary tumor sites, including the cervix, endometrium, and ovary.

"We found a promising drug combination that's giving us real responses for this rare cancer type, and hopefully we'll continue to see those responses build over time," Grisham explained.

In an interview with OncLive®, Grisham emphasized the importance of increasing clinical trial access for patients with rare gynecologic cancers and the potential for this combination to address a long-standing therapeutic gap. Grisham is chief of the Division of Gynecologic Medical Oncology and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What was the rationale behind conducting this phase 2 study of avutometinib plus defactinib in advanced or recurrent gynecologic mesonephric cancer?

Grisham: Mesonephric cancer is a rare type of cervical cancer which is not associated with human papillomavirus [HPV] that starts from Wolffian duct remnants deep within the cervical walls. Mesonephric-like cancer is histologically similar cancer that instead originates in the endometrium or the ovary.

Both of these types of cancer have a similar histologic appearance. They're usually hormone receptor–negative, and they have similar immunohistochemistry expression patterns. Unfortunately, both mesonephric and mesonephric-like cancer commonly recur and frequently metastasize to the lung. Prior historical data have shown low response rates to systemic therapy in the recurrent setting. There has been a paucity of studies looking at how best to treat mesonephric and mesonephric-like cancer.

At Memorial Sloan Kettering Cancer Center, we performed a retrospective study where we looked at the tumors from our patients with mesonephric and mesonephric-like cancer, and we found that the vast majority of the patients had alterations affecting the MAPK pathway in their tumor tissue, most commonly somatic KRAS mutations, which were present in approximately 77% of patients.

Because of this high rate of KRAS mutations, we were interested how the activity of avutometinib plus defactinib would be in [patients with] mesonephric and mesonephric-like cancer because we've previously seen very high response rates to the combination of avutometinib plus defactinib in another rare type of gynecologic cancer, low-grade serous ovarian cancer, that also commonly has the KRAS mutation present.

What was the design of this phase 2 study?

This was designed as a single-institution, investigator-initiated study for patients who had advanced or recurrent mesonephric or mesonephric-like cancer of gynecologic origin.

Patients [enrolled] onto the study had to have measurable disease, and they could not have received a prior MEK, FAK, or RAF inhibitor. They also had to be able to tolerate oral therapy because these drugs are pills.

What findings were presented from the interim analysis?

The study was designed as a Simon 2-stage study. During stage 1, we accrued 13 patients, and we were required, based on historical data, to have at least 1 response in order to move to stage 2 and accrue an additional 7 patients.

The study was originally planned to accrue a total of 20 patients, with response rate by RECIST 1.1 criteria being the primary end point. At [the 2025 SGO Annual Meeting on Women’s Cancer], we presented the interim results focused on those patients treated in stage 1, [meaning] the first 13 patients that were enrolled to the study.

In the stage 1 [group], there were 2 confirmed and an additional 2 unconfirmed partial responses, exceeding the predefined threshold of 1 response that was needed in order to move to stage 2. The other thing that's quite remarkable is how quickly we were able to enroll to this rare tumor study as a single institution. The study has now actually completed its original planned accrual, and given these promising results, has recently been amended to allow for an expansion phase where an additional 20 patients are being accrued.

What are the primary objectives for this next phase of enrollment, and how could those findings have potential clinical implications?

As we move forward, we plan to present the primary results of the overall study and hopefully continue to show a very promising response rate for these patients with mesonephric and mesonephric-like cancer. This is important because these drugs that are being explored, avutometinib and defactinib, may be FDA approved in the near future in [recurrent, KRAS-mutated], low-grade serous ovarian cancer [based on data from the phase 2 RAMP 201 trial (NCT04625270)].2

Were there any molecular results that were important to mention?

In these interim results from the first 13 patients who were treated during stage 1 of the study, we showed that 10 of them had confirmed KRAS mutations, most commonly KRAS G12V. Out of the 3 patients who did not have KRAS mutations, 1 had an NRAS mutation. One did not have somatic tumor testing performed, and one did not have a MAPK alteration. Of note, all of the 4 patients who had confirmed or unconfirmed partial responses [harbored] KRAS mutations.

What was observed in terms of safety?

Similar to prior studies of avutometinib and defactinib, the most common laboratory toxicity that we saw was elevated blood CPK levels; this is generally asymptomatic, and it's a common [adverse] effect of MEK inhibitors in general, including avutometinib. The most common non-laboratory toxicities that we saw were rash, fatigue, gastrointestinal [adverse] effects; again, this is common to MEK inhibitors and avutometinib. No patients discontinued treatment due to toxicity.

What is the importance of conducting a study like this for patients with a rarer tumor type?

Far too often, these rare cancers are not adequately studied. We need more clinical trial opportunities for our patients with rare cancers like mesonephric and mesonephric-like cancer who are often excluded from larger clinical trials and have a paucity of data about any active drugs for the treatment of the disease.

References

1. 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.
2. Verastem Oncology announces FDA acceptance and priority review of new drug application for avutometinib in combination with defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer.News release. Verastem Oncology. December 30, 2024. Accessed April 2, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-fda-acceptance-and-priority-review