FDA accelerates approval of AVMAPKI combined with FAKZYNJA for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer

In May 2025, biopharmaceutical company Verastem Oncology announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to its AVMAPKI (avutometinib) combination< span>FAKZYNJA(defactinib) for the treatment of adult patients with KRASgene-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. The approval was based on the drug's demonstrated tumor response rate and duration of response in clinical trials. It is important to note that continued approval for this indication is dependent on further confirmation of efficacy in subsequent confirmatory clinical trials. The combination is sold in the United States in the form of a combination package of two oral preparations, called "AVMAPKI FAKZYNJA CO-PACK", and is expected to be officially launched within a week.

Low-grade serous ovarian cancer is a rare and insidious tumor type that is progressive and often fatal. This disease is mainly driven by abnormalities in theRAS/MAPK signaling pathway. It is significantly different from common high-grade serous ovarian cancer, and treatment strategies also need to be treated differently. LGSOCThe response to traditional chemotherapy is poor and the recurrence rate is high. The current standard treatments are mostly hormone therapy and chemotherapy. Previously, there was no FDAFDAKRASmutated recurrentLGSOC pan>approved specific treatment options, therefore the combination of AVMAPKI and FAKZYNJA fills this treatment gap.

AVMAPKIas a MEK kinase inhibitor, can effectively block key links in the MAPK signaling pathway and prevent the RAF protein from compensatory reactivation of MEK. Since blocking RAF or MEK can activate FAK protein,FAK activity is closely related to drug resistance. FAKZYNJA is a FAK inhibitor. The two drugs are used in combination to more comprehensively inhibit tumor growth and drug resistance mechanisms driven by the RAS/MAPK pathway. The pivotal RAMP-201 (Phase 2 clinical) trial enrolled 57 patients with relapsed KRAS mutations in LGSOC, all of whom had received at least one systemic treatment with a platinum-containing regimen. Treatment consists of 3.2 mg of AVMAPKI orally twice weekly and 200 mg of FAKZYNJA twice daily, continued until disease progression or intolerable side effects.

Clinical data showed that the overall response rate of this combination therapy reached 44% under independent blind review, showing a relatively ideal efficacy. The median duration of response ranged from 3.3 to 31.1 months, indicating that some patients can achieve longer disease control. In terms of safety, the more common side effects during treatment include increased creatine phosphokinase, nausea, fatigue, abnormal liver function, rash, and digestive system reactions. The overall tolerance is good. The dosage regimen is AVMAPKI taken orally twice a week (days 1 and 4)3.2 mg, FAKZYNJA200 mg orally twice daily for three weeks until disease progression or unacceptable toxicity.

According to the accelerated approval policy, this approval requires further verification of efficacy and safety in larger phase III clinical trials. The current Phase 3 trial of RAMP-301 will evaluate the combination with standard chemotherapy and hormone therapy in patients with relapsed LGSOC in different KRAS mutation statuses. Verastem Oncology stated that if the phase III trial results are satisfactory, it will not only support the conversion to formal approval, but also potentially expand the indication to all patients with low-grade serous ovarian cancer, regardless of whether they carry KRAS mutations.

To sum up, AVMAPKIjointlyFAKZYNJA isKRASNew treatment hope for patients with mutation-relapsed low-grade serous ovarian cancer fills a long-standing therapeutic gap in the field. In the future, with the further advancement of phase III verification trials, this combination regimen is expected to become an important part of the standard treatment for LGSOC and improve the prognosis and quality of life of patients.

Reference: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.