By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has granted accelerated approval for a combination of two kinase inhibitors, avutometinib and defactinib, for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy, including a platinum-based regimen.1 Avotometinib inhibits mitogen-activated protein kinase 1 (MEK1 kinase) activity, while defactinib is a focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2) inhibitor. The combination works synergistically to provide antitumor activity. This combination was granted priority review and breakthrough and orphan drug designations.1 It is distributed by Verastem, Inc. as Avmapki Fakzynja CO-PACK.
Indications
Avutometinib-defactinib is indicated for the treatment of adult patients with KRAS-mutated recurrent LGSOC who have received systemic therapy.2 The accelerated approval was based on tumor response, and continued approval may be contingent upon verification of description of clinical benefit in a confirmatory trial.2
Dosage
Avutometinib (3.2 mg [four capsules]) is administered orally twice weekly (day 1 and day 4) for the first three weeks of each four-week cycle.2 Defactinib (200 mg) is administered twice daily for the first three weeks of each four-week cycle. Dose modifications/reduction are recommended based on the severity of adverse reactions.2 Avutometinib is available as 0.8-mg capsules, and defactinib is available in the form of 200-mg tablets.
Potential Advantages
Avutometinib-defactinib is the first FDA-approved, albeit conditionally, treatment for LGSOC. Avutometinib is a first-in-class oral dual inhibitor of rapidly accelerated fibrosarcoma (RAF) and MEK kinases on consecutive steps along the RAS-RAF/MEK/ERK signaling pathway (i.e., RAF/MEK clamp). Defactinib is the first FAK inhibitor approved which acts on another signaling pathway involving FAK and Pyk2, the two members of the focal adhesion kinase family of non-receptor protein kinases.2 The combination has been shown to enhance inhibition of cell proliferation in vitro and in mouse tumor models, including LGSOC.2
Potential Disadvantages
The following adverse reactions occur with a high frequency: ocular (visual impairment and vitreoretinal disorder [68%]), serious skin toxicities (94%), hepatotoxicity (increased aspartate aminotransferase, alanine transaminase, bilirubin, alkaline phosphatase [46% to 73%]), and an increase in creatine phosphokinase (75%).2 Rhabdomyolysis has occurred in one study participant treated with avutometinib-defactinib.
Avutometinib-defactinib can cause fetal harm. Female patients of reproductive age should use effective contraception during treatment and for one month after the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for four months after the last dose. Other adverse reactions include nausea/diarrhea, fatigue, edema, musculoskeletal pain, decreased albumin, and decreased hemoglobin.2 Defactinib is a substrate of CYP3A4, so concomitant use with strong or moderate CYP3A4 inhibitors and inducers should be avoided.2
Comments
RAS-RAF/MEK/ERK is an important pathway that relays signals from receptors on the cell surface to the nucleus. This regulates gene expression and cellular processes. Dysregulation of this pathway can lead to uncontrolled cell proliferation. The KRAS mutation is common in lower-grade, low-stage ovarian cancer. The FAK pathway regulates cell proliferation and survival and frequently is up-regulated in various cancers. The efficacy of avutometinib-defactinib was evaluated in an open-label study in adult participants with measurable KRAS-mutated recurrent LGSOC who have received at least one prior systemic therapy, including a platinum-based regimen.2 Participants had a median age of 60 years, 75% were white, and 40% had received more than three prior lines of systemic therapy (i.e., platinium-based chemotherapy, hormonal therapy, bevaciumab, prior MEK inhibitor). Eighty-eight percent had KRAS mutation (G12V [53%] or G12D [35%]). Treatment was continued until disease progression or unacceptable toxicity. Efficacy outcome was the overall response rate assessed by a blinded independent review committee according to tumor response (Response Evaluation Criteria in Solid Tumors [RECIST, version 1.1]). Response was assessed every eight weeks for the first 72 weeks and every 12 weeks thereafter. The overall response rate was 44%, 95% confidence interval (31, 58), with another 44% showing partial responses. The range of duration of response was 3.3 to 31.1 months. The responders all had KRAS mutations.1
Clinical Implications
LGSOC is a rare cancer that represents 2% to 5% of ovarian carcinomas and 5% to 10% of serous ovarian carcinomas and is a separate entity from high-grade carcinomas.3 It is characterized by a younger age of diagnosis, indolent progression, relative chemo-resistance, and long-term survival.3,4 KRAS G12D may be associated with disease progression and shorter survival.3 There were no approved treatments for LGSOC until the accelerated approval of avutometinib plus defactinib. A Phase III trial (approximately 270 participants) comparing avutometinib-defactinib to investigator’s choice of treatment of LGSOC (KRAS-mutated or wild-type) is expected to be completed in 2031.4 The cost for avutometinib-defactinib is $48,500 for each four-week cycle.
References
- Verastem. Aymapki Fakzynja CO-PACK prescribing information. Revised May 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219616s000lbl.pdf
- U.S. Food and Drug Administration. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low
- Babaier A, Mal H, Alselwi W, Ghatage P. Low-grade serous carcinoma of the ovary: The current status. Diagnostics (Basel). 2022;12(2):458.
- Grisham R, Monk BJ, Nieuwenhuysen EV, et al. GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: A phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer. Int J Gynecol Cancer. 2025; Jan 6:ijgc-2024-005919. doi: 10.1136/ijgc-2024-005919. [Online ahead of print].
The U.S. Food and Drug Administration has granted accelerated approval for a combination of two kinase inhibitors, avutometinib and defactinib, for the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer who have received prior systemic therapy, including a platinum-based regimen.
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