FDA Priority Review of Avutometinib and Defactinib – Low-Grade Serous Ovarian Cancer

Low-grade serous ovarian cancer (LGSOC, low-grade serous ovarian cancer) is a rare but treatment-resistant type of ovarian cancer, with low response rates and a high risk of recurrence. Patients with a KRAS mutation are a notable group within this subtype. Recently, the combination of avutometinib and defactinib , developed by Verastem Oncology, has attracted attention as a promising option for recurrent LGSOC.

The US Food and Drug Administration (FDA) has granted priority review to the application for a new treatment combining avutometinib and defactinib for patients with a KRAS mutation who have previously received at least one systemic therapy. The FDA is expected to announce whether it will approve this treatment on 30 June 2025.

A New Player in Cancer Treatment: FAK Inhibitors

Defactinib is a focal adhesion kinase (FAK) inhibitor that works by suppressing the activity of the FAK protein.

FAK is a tyrosine kinase involved in communication between cells, cellular sensing of environmental signals, and cell migration. FAK signaling in tumor cells plays an important role in the development of metastasis and drug resistance mechanisms.

Defactinib:

• By inhibiting FAK activity , it reduces tumor cells' ability to adhere and move.
• By regulating the immune response in the tumor microenvironment, it may enhance the immune system's ability to fight the tumor.
• By preventing cancer stem cell survival, it may prevent cancer spread and drug resistance.

To date, no FAK inhibitor has been approved by the FDA.

However, FDA-approved RAF/MEK inhibitors are available. RAF/MEK inhibitors are targeted drugs used in cancer treatment, particularly for melanoma, lung cancer , and certain other solid tumors.

• RAF (BRAF) inhibitors: vemurafenib (Zelboraf), dabrafenib (Tafinlar), encorafenib (Braftovi).
• MEK inhibitors: trametinib (Mekinist), cobimetinib (Cotellic), binimetinib (Mektovi).

Avutometinib is also an oral RAF/MEK inhibitor, but it has not yet received FDA approval for ovarian cancer or any other cancer.

RAMP 201 Phase 2 Clinical Study

The new drug application is supported by data from the phase 2 clinical study called RAMP 201. This study evaluated the efficacy and safety of the combination of avutometinib (an oral RAF/MEK inhibitor) and defactinib (an oral FAK inhibitor) in patients with recurrent LGSOC.

Dosing:

• Avutometinib: 3.2 mg twice weekly
• Defactinib: 200 mg twice daily

Results

All Patients

• Overall Response Rate (ORR): 31%
• Median Response Duration: 31.1 months

Patients with a KRAS Mutation

• Response Rate: 44%
• Median Response Duration: 31.3 months

KRAS Wild-Type Patients

• Response Rate: 17%
• Median Response Duration: 9.2 months

Progression-Free Survival:

• Median progression-free survival (PFS) for all patients: 12.9 months
• Patients with a KRAS mutation: 22 months
• KRAS wild-type patients: 12.8 months

Treatment Tolerability

The combination treatment was generally well tolerated. The most common treatment-related adverse effects were:

• Nausea
• Diarrhea
• Increased creatine kinase levels

Treatment interruptions or dose reductions due to adverse effects were rare.

RAMP 301 Phase 3 Trial

Verastem Oncology stated that enrollment was ongoing in the RAMP 301 phase 3 study, which includes patients with recurrent LGSOC regardless of KRAS mutation status. This study aims to confirm the reliability of the phase 2 results.

Are Avutometinib and Defactinib Available?

The combination of avutometinib and defactinib has not yet received FDA approval and is not commercially available. This treatment is currently being evaluated in clinical trials, and the FDA's final approval decision is awaited.

Conclusion and Commentary

The combination of avutometinib and defactinib offers the potential for an important advance for patients with KRAS-mutant LGSOC. The FDA's priority review decision reflects the treatment's promising efficacy data.

If approved, it could establish a new standard in an area with very few treatment options for LGSOC. The FDA's decision date has been set for 30 June 2025, and patients and clinicians are eagerly awaiting the outcome.