Avutometinib/Defactinib Expands Treatment Options for KRAS-Mutant Low-Grade Serous Ovarian Cancer

Bradley Monk, MD, FACOG, FACS

The FDA accelerated approval of avutometinib in combination with defactinib (Avmapki Fakzynja Co-pack) represents a meaningful therapeutic development for patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC), a rare and historically treatment-resistant subtype, according to Bradley Monk, MD, FACOG, FACS.

On May 8, 2025, the FDA granted accelerated approval to the avutometinib/defactinib combination for adult patients with KRAS-mutated recurrent LGSOC following at least 1 prior systemic therapy.1 This approval was based on findings from the phase 2 ENGOT-ov60/RAMP-201/GOG-3052 trial (NCT04625270), which demonstrated a confirmed objective response rate (ORR) of 44% (95% CI, 31%–58%) and a duration of response ranging from 3.3 to 31.1 months with the combination among 57 patients with measurable, KRAS-mutated, recurrent LGSOC.

“Congratulations to the investigators, and most importantly, congratulations to the patients,” Monk said in an interview with OncLive®. “We have to educate each other, and we have to educate our patients about this new opportunity.”

Monk is a gynecologic oncologist and medical director of the Late-Stage Clinical Research Program at Florida Cancer Specialists & Research Institute in Palm Beach, Florida.

OncLive: What is the clinical significance of the FDA’s accelerated approval of avutometinib plus defactinib for patients with KRAS-mutated recurrent serous ovarian cancer?

Monk: This is the first time we have ever had an FDA approval for LGSOC, a rare variant of ovarian cancer. Generally, we think of ovarian cancer as being high grade serous, but low-grade serous cancer is a [disease subtype] where 70% of the tumors are driven by RAS and [are] part of the MAPK pathway. [Approximately] 30% of those tumors are KRAS mutant, [and] there are other mutations—including NRAS, BRAF, NF1, and other RAS pathway–associated gene mutations. However KRAS mutations are particularly important, and this accelerated approval is [for agents targeting] tumors with KRAS mutations.

This [approval] was based on an international collaboration between the Gynecologic Oncology Group and The European Network for Gynaecological Oncological Trial groups in the RAMP-201 study. We leverage all the best practices in drug development. [In March 2021, the FDA granted] breakthrough therapy designation to avutometinib plus defactinib for LGSOC based on [findings from] the investigator-initiated phase 1 FRAME trial [NCT03875820].2 Over [the past approximately 4] years, we’ve been working in this rare tumor type—including in the approximately 30% [of these tumors] that are KRAS mutated—for [dose optimization].

[We needed] to optimize the dose [of this combination], and we did that. [Additionally, to receive] accelerated approval, [we needed to] have the phase 3 trial [of this combination] substantially enrolled, and we [also] did that. That trial is RAMP 301 [NCT06072781]. The RAMP 201 [study findings are planned to] be published in a high-impact clinical oncology journal.

How does the mechanism of action of this RAF/MEK and FAK inhibitor combination address the biologic complexity of KRAS-mutated serous ovarian cancer?

This medication combination can improve outcomes in women with this rare tumor type. This combination [includes] oral avutometinib, which is a RAF/ MEK clamp that potentially inhibits MEK, as well as the oral selective FAK inhibitor defactinib.

This combination is active, with an ORR of 44% of tumors, and [we have seen] long-term safety and efficacy data. We can [use this regimen] immediately. [When designing RAMP-201], we already knew about MEK inhibition, but an escape mechanism is FAK, and the idea was, if we could inhibit both MEK and FAK, we could overcome the inherent resistance that MEK [inhibition] develops intrinsically.

What is the dosing schedule of the combination regimen?

Patients are administered 3.2 mg of oral avutometinib twice weekly, on days 1 and 4 [of each week]. They also receive 200 mg of oral defactinib twice daily. [The combination is given for] 3 out of 4 weeks [in each cycle], so that further complicates it.

What is the safety profile of avutometinib plus defactinib?

In addition to enthusiasm about the [regimen’s] activity, we have to be familiar with the most common adverse [effects (AEs)]. [This regimen consists of] kinase inhibitors, [and the dosing schedule] is idiosyncratic. [The combination is] oral, and it's taken for a long time. [Common AEs include] fatigue, some pain, edema, and importantly, skin changes. However, there’s an aggressive mitigation strategy to treat and prevent the acne-like rash.

What is your advice about the use of this combination in clinical practice?

It all starts with identifying LGSOC as a unique subtype. This is not a BRCA-associated tumor. This is a MAPK-associated disease. Once you have identified [LGSOC], there’s a role for systemic therapy. Once the patient has [progressed on] first-line therapy, they are eligible [for avutometinib plus defactinib] if they have a KRAS mutation.

The phase 3 trial will continue to enroll [patients with] KRAS-mutated or wild-type tumors here in the United States, as well as around the world. My advice to oncologists [focuses on] education [regarding this combination].

References

1. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. FDA. May 8, 2025. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low
2. Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem, Inc. May 24, 2021. Accessed May 9, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs