Avutometinib with defactinib for recurrent KRAS mutant LGSOC completes ongoing new drug application

The ongoing 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 have received treatment at According to the FDA completed at least one prior systemic therapy. The NDA was submitted under the FDA's accelerated approval process. If granted, the exam will be completed within 6 months of the 60-day registration period.¹

Avutometinib is an oral RAF/MEK clamp that induces complexes of MEK with ARAF, BRAF, and CRAF, potentially eliciting a more complete and durable antitumor response through maximal inhibition of the RAS/MAPK signaling pathway. Unlike pure MEK inhibitors, it blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. Defactinib is an oral selective FAK inhibitor.¹ The combination regimen was previously granted orphan drug designation for the treatment of patients with LGSOC regardless of their KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.²

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

NDA submissions were initiated following review of interim and supporting data from the FRAME Phase 1 study. Updated results from the Phase 2 RAMP 201 study (NCT04625270) were presented at a recent oral plenary presentation at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting, held October 16-18 in Dublin, Ireland.¹

RAMP 201 is an adaptive, two-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 KRAF mutation. In part A of the study, patients were selected and given an “advanced” treatment regimen that included the combination of avutometinib and defactinib compared to avutometinib alone, based on overall response rates (ORR). The extension phases of the study – Parts B and C – will assess the safety and effectiveness of the additional treatment regimen (avutometinib 3.2 mg twice per week and defactinib 200 mg twice per week). In addition, Part D will evaluate low dose avutometinib in combination with defactinib to allow individual dose reduction.^1.3

The primary endpoint for all parts of the study is ORR, which is measured from the start of treatment until confirmation of response, i.e. 24 weeks. Secondary endpoints include complete response, duration of response, disease control rate (DCR), progression-free survival (PFS) and OS.³

According to results presented at the IGCS plenary session, patients with KRAS-mutated LGSOC had a confirmed ORR of approximately 44%, a median PFS of 22 months, and a DCR of 70% at 6 months. In addition, the updated data continue to show that avutometinib in combination with defactinib is generally well tolerated, with a 10% discontinuation rate due to adverse events in all patients in both KRAS mutant and KRAS wild type.^1.3

Recruitment is currently underway for RAMP 301, an international phase 3 study that will enroll patients with recurrent LGSOC regardless of KRAS mutation status. The study serves 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-mutated LGSOC,” Dan Paterson, president and CEO of Verastem Oncology, said in a press release. “The completion of our NDA submission is a significant milestone. We plan for possible 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 FDA for Avutometinib Plus Defactinib for the Treatment of KRAS Mutant Recurrent Low-Grade Serous Ovarian Cancer. Press 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-mutated-low-grade-serous-ovarian-cancer

2. McGovern, G. FDA grants orphan drug designation to avutometinib alone or with defactinib in recurrent LGSOC. Pharmacy hours. 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) vs. Avutometinib (VS-6766) + Defactinib in recurrent low-grade serous ovarian cancer with and without KRAS mutation (RAMP 201). ClinicalTrials.gov Identifier: NCT04625270. Updated March 12, 2024. Accessed November 1, 2024.