Verastem Oncology Begins Rolling NDA Submission to FDA for Accelerated Approval of Avutometinib & Defactinib for Recurrent KRAS Mutant Low-Grade Serous Ovarian Cancer

Verastem Oncology, a biopharmaceutical firm focused on developing cancer treatments, has begun the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). This submission seeks accelerated approval for the combination of avutometinib, a RAF/MEK clamp, and defactinib, a FAK inhibitor, for treating adult patients with recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC) who've had at least one prior systemic therapy.

The rolling review process, which allows for the submission of completed sections for FDA review before the entire application is complete, will initially include nonclinical and quality sections. Verastem has an agreement with the FDA to submit a primary efficacy analysis based on the RAMP 201 study, which involves 12 months of follow-up. If Verastem provides data showing significant improvement over current therapies in the KRAS wild-type population, the proposed indication for final submission can be expanded.

Previously, the FDA granted Breakthrough Therapy Designation (BTD) for this combination treatment for patients with recurrent LGSOC regardless of KRAS status and Orphan Drug Designation (ODD) for certain LGSOC indications. Verastem plans to request a priority review of the NDA. Currently, no FDA-approved treatments specifically target recurrent LGSOC.

Dan Paterson, President and CEO of Verastem Oncology, emphasized the significance of the rolling NDA submission, stating that it is a crucial step toward addressing the unmet needs of patients with KRAS mutant low-grade serous ovarian cancer. He highlighted that the ongoing RAMP 201 trial continues to show promising results and expects to complete the NDA submission with mature data from the trial in the second half of 2024. Additionally, Verastem aims to present this mature dataset at a medical conference during the same period.

The RAMP 201 trial is a Phase 2, registration-directed study evaluating the combination of avutometinib and defactinib in patients with recurrent LGSOC. Enrollment in the trial is complete, with 115 patients receiving the recommended Phase 2 dose. Verastem plans to finalize the NDA submission after obtaining mature safety and efficacy data, including 12 months of follow-up, projected for the second half of 2024. The company will also discuss the KRAS wild-type data with the FDA to determine the potential path forward for this patient group.

As of February 2024, interim data has shown robust overall response rates and durable responses with low discontinuation rates due to adverse events in patients from RAMP 201 Parts A, B, and C. This investigational combination received Breakthrough Therapy Designation from the FDA in May 2021 for treating all patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. The combination also received Orphan Drug Designation from the FDA for LGSOC treatment in March 2024.

LGSOC is a rare and recurrent form of ovarian cancer that is distinct from high-grade serous ovarian cancer and requires different treatment. Patients with LGSOC face significant challenges, including a high recurrence rate and limited sensitivity to chemotherapy. The current standard of care includes hormone therapy and chemotherapy, but no FDA-approved treatments specifically target LGSOC.

Verastem is also conducting the RAMP 301 international Phase 3 trial, which compares the combination of avutometinib and defactinib to standard chemotherapy or hormonal therapy in patients with recurrent LGSOC. The primary endpoint of this trial is progression-free survival, with secondary endpoints including overall response rate, duration of response, disease control rate, safety and tolerability, patient-reported outcomes, and overall survival.

Verastem's investigational combination of avutometinib and defactinib aims to address the significant unmet needs of patients with recurrent low-grade serous ovarian cancer, with the potential to become a new standard of care pending FDA approval.