FDA Grants Priority Review to Avutometinib Plus Defactinib for KRAS+ Recurrent Low-Grade Serous Ovarian Cancer

US FDA

The FDA has accepted and granted priority review to the new drug application (NDA) seeking the approval of avutometinib (VS-6766) in combination with defactinib (VS-6063) for the treatment of adult patients with recurrent low-grade serous ovarian cancer who received at least 1 prior systemic therapy and harbor a KRAS mutation.¹

The NDA has been assigned a target action date of June 30, 2025, under the Prescription Drug User Fee Act. Notably, the FDA does not anticipate holding an advisory committee meeting to discuss the application.

“The FDA filing acceptance and priority review for the combination of avutometinib and defactinib underscores the critical unmet need among patients diagnosed with this rare and insidious disease. We are excited by today’s news and to potentially bring the first ever FDA-approved treatment specifically for recurrent KRAS-mutant low-grade serous ovarian cancer to patients in the [United States],” Dan Paterson, president and chief executive officer of Verastem Oncology, stated in a news release. “With the acceptance of this NDA, we’re taking an important step forward in addressing a condition that has long been overlooked, and we look forward to working with the FDA during its review process and preparing for a commercial launch in mid-2025.”

Findings from the primary analysis of the phase 2 RAMP 201 trial (NCT04625270) supported the NDA. In this study, the RAF/MEK and FAK inhibitor combination generated durable responses and was generally well tolerated in patients with recurrent KRAS-mutant LGSOC.

The filing was also informed by data from the phase 1 FRAME trial (NCT03875820), the first study conducted with the combination therapy in recurrent low-grade serous ovarian cancer. Findings from FRAME also supported the regimen’s prior receipt of breakthrough therapy designation from the FDA for this patient population in 2021.²

Additionally, avutometinib alone or in combination with defactinib was granted orphan drug designation by the FDA in 2024 for the treatment of patients with low-grade serous ovarian cancer.¹

RAMP 201 Overview and Key Data

RAMP 201 was a multicenter, randomized, open-label trial investigating the efficacy and safety of avutometinib alone and in combination with defactinib in patients at least 18 years of age with histologically confirmed low-grade serous ovarian or peritoneal cancer.³ Patients needed to have experienced disease progression or recurrence following 1 or more lines of systemic therapy in the metastatic setting; have measurable disease per RECIST 1.1 criteria; have an ECOG performance status of 0 or 1; have adequate organ function; and recovered from toxicities related to prior treatments.

In part A of the study, patients received either avutometinib as monotherapy or in combination with defactinib to identify the optimal dose for expansion. In parts B and C, avutometinib plus defactinib was administered at the optimal dose, which was determined to be 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily.¹ Notably, a lower dose of the regimen was utilized for patients enrolled in part D.

The study’s primary end point was confirmed overall response rate (ORR) per RECIST 1.1 criteria.³ Key secondary end points included investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival.

Updated data from RAMP 201 presented at the 2024 International Gynecologic Cancer Society Annual Meeting showed that at a median follow-up of approximately 12 months, the confirmed ORR with avutometinib plus defactinib was 31% (95% CI, 23%-41%) per blinded independent central review among evaluable patients with measurable disease in the overall population (n = 109).⁴ Moreover, the median DOR was 3.1 months (95% CI, 14.8-31.1), the 6-month DCR rate was 61%, and the median PFS was 12.9 months (95% CI, 10.9-20.2).

The confirmed ORR with the combination was 44% (95% CI, 31%-58%) for patients harboring KRAS mutations (n = 57) and 17% (95% CI, 8%-30%) in the KRAS wild-type patient population (n = 52). The median DORs for the KRAS-mutated and KRAS wild-type populations were 31.1 months (95% CI, 14.8-31.1) and 9.2 months (95% CI, 5.5-not evaluable), respectively. The 6-month DCR rate was 70% in the KRAS-mutated patient population and 50% in the KRAS wild-type population. The median PFS was 22 months (95% CI, 11.1-36.6) in the KRAS-mutant population and 12.8 months (95% CI, 7.4-18.4) in the KRAS wild-type population.

Updated safety data showed adverse effects (AEs) led to treatment discontinuation in 10% of patients. No new safety signals were reported. Common treatment-related AEs included nausea (any-grade, 67.0%; grade ≥3, 2.6%), diarrhea (58.3%; 7.8%), and increased blood creatine phosphokinase levels (60.0%; 24.3%).

References

1. Verastem Oncology announces FDA acceptance and priority review of new drug application for avutometinib in combination with defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer.News release. Verastem Oncology. December 30, 2024. Accessed January 2, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-fda-acceptance-and-priority-review
2. Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2021. Accessed January 2, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs
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. Updated March 12, 2024. Accessed January 2, 2025. https://clinicaltrials.gov/study/NCT04625270
4. Verastem Oncology presents positive updated RAMP 201 data for avutometinib and defactinib combination in recurrent low-grade serous ovarian cancer at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting. News release. Verastem Oncology. October 17, 2024. Accessed January 2, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-presents-positive-updated-ramp-201-data