Accelerated FDA Approval Establishes Role of Avutometinib/Defactinib in KRAS-Mutant Recurrent Low-Grade Serous Ovarian Cancer

Rachel Grisham, MD

The FDA accelerated approval of avutometinib in combination with defactinib (Avmapki Fakzynja Co-pack) represents a significant step forward in the treatment of patients with KRAS-mutant recurrent low-grade serous ovarian cancer (LGSOC), according to Rachel Grisham, MD.

On May 8, 2025, the FDA granted accelerated approval to the avutometinib/defactinib combination for adult patients with KRAS-mutated recurrent LGSOC who have received prior systemic therapy.¹ This regulatory decision was supported by data from the phase 2 ENGOT-ov60/GOG-3052/RAMP-201 trial (NCT04625270), which evaluated the efficacy and safety of the regimen in a heavily pretreated population.

Among 57 patients with measurable KRAS-mutated recurrent LGSOC, the confirmed objective response rate (ORR) was 44% (95% CI, 31%-58%), with a median progression-free survival (PFS) of 22 months (95% CI, 11.1-36.6) and a median duration of response (DOR) of 31.1 months (95% CI, 14.8-31.1).^1,2

In an interview with OncLive^®, Grisham discussed the clinical significance of the approval, key design elements of the RAMP-201 trial, and the observed efficacy and safety outcomes associated with the regimen. She also highlighted the importance of somatic tumor testing to identify patients with KRAS mutations who may benefit from this treatment and offered practical guidance for integrating the combination into routine care. Grisham is section head of Ovarian Cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center Westchester in Harrison, New York.

OncLive: What is the clinical significance of the FDA approval of avutometinib in combination with defactinib for this patient population?

Grisham: This is so important for our patients with low-grade serous ovarian cancer, because this is truly the first ever FDA approved treatment, specifically for women with low-grade serous ovarian cancer.

The thing that's been so difficult for our patients with low-grade serous ovarian cancer for decades now is that even though we now understand that it is a distinct disease from high-grade serous ovarian cancer, with a different molecular profile, different histologic appearance, and different clinical characteristics, we've still routinely treated [patients] the same way as [those with] high-grade serous ovarian cancer.

Oftentimes [we’ve] used treatments that have very disappointing response rates for our patients with low-grade serous ovarian cancer. To have a treatment that was developed specifically for patients with low-grade serous ovarian cancer that targets the MAP kinase pathway, the pathway that drives this disease for so many of our patients, is really a game changer.

What key aspects of the RAMP-201 trial design are important to highlight?

RAMP-201 was an interesting phase 2 study that was designed to answer multiple questions. [This] started out as a study where patients were randomized to either treatment with avutometinib as a single agent at a higher dose, or avutometinib in combination with defactinib at the standard dose.

The first question that was answered in the study was whether the combination of avutometinib and defactinib together was more effective than avutometinib as a single agent, even if avutometinib was given at a higher dose.

That initial randomized part of the study did show that the combination of avutometinib with defactinib had a higher response rate and similar [adverse] effects to avutometinib as a single agent, showing us that the combination was superior.

As the study continued, there was an expansion cohort where additional patients [were] enrolled and were treated with the combination of avutometinib and defactinib at the standard dose. Avutometinib is given at 3.2 mg by mouth twice a week, and defactinib is given at 200 mg by mouth twice a day. Both [agents were] given three weeks on, one week off, so that we could learn more about the response rate, progression-free survival, and duration of response for patients treated with this combination.

Then in the dose optimization cohort, a lower dose of avutometinib was [tested] in combination with defactinib, and it was found that a lower starting dose in combination with defactinib was not as effective as the standard dose.

This one study was able to answer three important questions for us. [From this, we learned] that the combination of avutometinib and defactinib is better than avutometinib by itself, that the correct dose of avutometinib and defactinib is the standard dose of 3.2 mg of avutometinib and 200 mg of defactinib twice a day, and that starting at a lower dose can give patients a worse outcome, something that’s really important for us to know [when choosing] where we should start dose wise with a medication.

How did the efficacy differ depending on KRAS mutation status?

Interestingly, patients that were enrolled to this study had recurrent low-grade serous ovarian cancer and had received at least one prior line of chemotherapy. [Patients received a] median of three prior lines of therapy, so [this was] a pretty heavily pretreated population.

[All patients] had to have had somatic tumor testing done ahead of time, [even though] patients did not need to have a KRAS mutation. [Outside of the context of the study] I would consider [somatic tumor testing] to be a standard of care for all patients with ovarian cancer.

This is important because we know that in low-grade serous ovarian cancer, KRAS is something that we can target, but it's also a prognostic indicator, so patients with a KRAS mutation tend to do better [than those without the mutation].

This study looked at the response rate in the overall population, but also in those patients with or without a KRAS mutation. For the overall population, the response rate was 31% which was quite promising. In the patients with a KRAS mutation, the response rate was 44% which is unprecedented for patients with this disease [for whom it’s been] very difficult to elicit meaningful tumor shrinkage.

This was an incredibly impressive response rate for these patients, but the notable [aspect about] these responses [is that they last] a long time. The median DOR was over 31 months, so these patients are responding for years, and many of these patients are still [enrolled] on [the] study now. [The] median PFS for those patients with a KRAS mutation was 22 months.

For the patients that were KRAS wild-type, efficacy was still seen, [with a] response rate of 17% and a median PFS of over 12 months, which is meaningful for these patients that we know have a worse prognosis. However, this being a study where patients were not randomized to standard of care [SOC] therapy, it's hard to know if those responses were meaningfully better than what patients might have had [while receiving] SOC therapy in the KRAS wild-type population.

For those patients that are KRAS wild-type we have an ongoing phase 3 study that's enrolling patients with and without a KRAS mutation, which will hopefully give us more information about how patients that are KRAS wild-type respond to the combination of avutometinib and defactinib vs SOC chemotherapy or endocrine therapy.

What were the key safety findings observed with avutometinib and defactinib in the RAMP-201 trial?

Avutometinib is an oral RAF/MEK clamp therapy, and defactinib is a FAK inhibitor, so both agents are targeted therapies. For MEK inhibitors in general, we oftentimes see the same types of [adverse] effects [AEs].

We see an acneiform rash, particularly on the face and upper chest. We see peripheral edema. We can see gastrointestinal AEs, and then we can also sometimes see ocular toxicity. Now, the thing that's interesting is that with this combination, avutometinib is given twice a week, three weeks on, one week off, and defactinib is given twice a day, three weeks on, one week off.

[This] intermittent dosing and the recovery week out of each cycle allows patients to recover between doses and [avoid] cumulative toxicity.

Another thing that's important with these medications is the use of appropriate prophylaxis to try to prevent toxicity. All patients that were enrolled to [RAMP-201] used prophylactic low-dose antibiotics such as minocycline for the first several months on treatment with the combination to help prevent rash, [while] also [using] appropriate sun protection. Through both this optimized dosing regimen and appropriate use of prophylaxis, we can really make these medications tolerable.

In the RAMP-201 study, only 10% of patients discontinued treatment due to toxicity, which is interesting, because in prior studies of single-agent MEK inhibitors in women with low-grade serous ovarian cancer, it was [closer to] 30% of patients who discontinued [treatment] due to toxicity. Even though this is a combination of two drugs, because of the dosing schedule we oftentimes see less cumulative toxicity than we might see with a single-agent MEK inhibitor.

What steps need to be taken before considering the use of avutometinib and defactinib in routine clinical practice?

I'd like to point out that this accelerated approval for avutometinib and defactinib is specifically for women with recurrent low-grade serous ovarian cancer who have a KRAS mutation. About 30% of women with low-grade serous ovarian cancer will have a somatic KRAS mutation, but the only way to know if someone has a KRAS mutation is to test their tumor, so it's incredibly important [for] all of our patients with ovarian cancer, but here specifically speaking about patients with low-grade serous ovarian cancer, to have that tumor testing done, so they know if they're a candidate to receive these medications.

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 presents positive updated RAMP 201 data for avutometinib and defactinib combination in recurrent low-grade serous ovarian cancer at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting. News release. Verastem Oncology. October 17, 2024. Accessed June 3, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-presents-positive-updated-ramp-201-data