Avutometinib With Defactinib for Recurrent KRAS Mutant LGSOC Completes Rolling New Drug Application

The rolling new drug application (NDA) for the investigational combination of avutometinib (VS-6766; Verastem Oncology) and defactinib (VS-6063; Verastem Oncology) for adults with recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC) who received at least 1 prior systemic therapy has been completed, according to the FDA. The NDA was submitted under the FDA’s accelerated approval pathway, and if granted, the review will be completed within 6 months following the 60-day filing period.¹

Avutometinib is an oral RAF/MEK clamp that induces complexes of MEK with ARAF, BRAF, and CRAF, potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. It blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK, unlike MEK-only inhibitors. Defactinib is an oral selective FAK inhibitor.¹ The combination treatment was previously granted an orphan drug designation for the treatment of patients with LGSOC regardless of their KRAS status following 1 or more prior lines of therapy, including platinum-based chemotherapies.²

LGSOC is a rare ovarian cancer that is persistent and ultimately fatal. It is distinct and different from high-grade serous ovarian cancer and requires different treatments. The disease is highly recurrent and less sensitive to chemotherapy, and it tends to affect younger women who bimodal peaks of diagnosis at ages 20 to 30 years and 50 to 60 years, with a median overall survival (OS) of about 10 years. Current standard of care includes hormone therapy and chemotherapy, but there are no FDA-approved treatments specifically for LGSOC.¹

The NDA submissions was initiated following the review of preliminary data and supportive data from the FRAME phase 1 trial. Updated results from the phase 2 RAMP 201 study (NCT04625270) were presented at a late-breaking oral plenary presentation at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting, which was held in Dublin, Ireland from October 16 to 18.¹

RAMP 201 is an adaptive, 2-part multicenter, randomized, open-label phase 2 study (NCT04625270) to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC with or without a KRAF mutation. In part A of the study, selection of patients was determined and were administered a “go forward” treatment regimen, which included the combination of avutometinib and defactinib compared with avutometinib alone, based on overall response rates (ORR). The expansion phases of the trial—parts B and C—evaluate the safety and efficacy of the go forward regimen (3.2 mg of avutometinib twice per week and 200 mg of defactinib twice per week). Additionally, part D evaluates a low dose of avutometinib in combination with defactinib to inform individualized dose reduction.^1,3

The primary end point for all parts of the study is ORR, which is measured from the start of treatment to confirmation of response, or 24 weeks. Secondary end points include complete response, duration of response, disease control rate (DCR), progression-free survival (PFS), and OS.³

According to the findings presented at the IGCS plenary session, patients with KRAS mutant LGSOC had a confirmed ORR of about 44%, a median PFS of 22 months, and a DCR of 70% at the 6-month point. In addition, the updated data continue to show that avutometinib combined with defactinib is generally well-tolerated, with a 10% discontinuation rate because of adverse events across all patients, both KRAS mutant and KRAS wild-type.^1,3

Currently, enrollment is ongoing for RAMP 301, an international phase 3 trial which will include patients with recurrent LGSOC regardless of KRAS mutation status. The trial will serve as a confirmatory study for the initial indication and has the potential to support an expanded indication regardless of KRAS mutation status.¹

“We believe that avutometinib in combination with defactinib has the potential to change the treatment paradigm for patients with recurrent KRAS mutant LGSOC,” said Dan Paterson, president and CEO of Verastem Oncology, in a news release. “Completing our NDA submission is a significant milestone…we plan for potential FDA approval in mid-2025, but also for patients as there are no FDA-approved treatments specifically for this rare ovarian cancer.”¹

REFERENCES

1. Businesswire. Verastem Oncology Completes Rolling NDA Submission to the FDA for Avutometinib Plus Defactinib as a Treatment for Recurrent KRAS Mutant Low-Grade Serous Ovarian Cancer. News release. October 31, 2024. Accessed November 1, 2024. https://www.businesswire.com/news/home/20241031747822/en/Verastem-Oncology-Completes-Rolling-NDA-Submission-to-the-FDA-for-Avutometinib-Plus-Defactinib-as-a-Treatment-for-Recurrent-KRAS-Mutant-Low-Grade-Serous-Ovarian-Cancer

2. McGovern, G. FDA Grants Orphan Drug Designation for Avutometinib Alone or With Defactinib in Recurrent LGSOC. Pharmacy Times. March 7, 2024. Accessed November 1, 2024. https://www.pharmacytimes.com/view/fda-grants-orphan-drug-designation-for-avutometinib-alone-or-with-defactinib-in-recurrent-lgsoc

3. A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation (RAMP 201). ClinicalTrials.gov identifier: NCT04625270. Updated March 12, 2024. Accessed November 1, 2024. https://clinicaltrials.gov/study/NCT04625270