FDA Grants Priority Review to Avutometinib/Defactinib Combo in KRAS+ Ovarian Cancer

• The FDA accepted and granted priority review to the new drug application (NDA) for avutometinib (VS-6766) plus defactinib (VS-6063) in recurrent low-grade serous ovarian cancer.
• This indication is for adult patients who have received at least 1 prior systemic therapy and harbor a KRAS mutation.
• A target action date of June 30, 2025, under the Prescription Drug User Fee Act, has been assigned to the NDA.

The FDA has accepted an NDA for priority review, seeking approval for the combination of avutometinib (VS-6766) with defactinib (VS-6063) for adult patients with recurrent low-grade serous ovarian cancer who have a KRAS mutation and have undergone at least 1 prior systemic therapy.¹

This NDA is supported by findings from the primary analysis of the phase 2 RAMP 201 trial (NCT04625270). Here, the combination led to durable responses and was generally well tolerated in this patient population.

The PDUFA target action date for this review has been set for June 30, 2025. The FDA does not plan to convene an advisory committee meeting for this 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],” said Dan Paterson, president and chief executive officer of Verastem Oncology, in a press 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.”

Concept of gynecologic cancer: © tom - stock.adobe.com

In addition to the RAMP 201 data, findings from the phase 1 FRAME trial (NCT03875820), the first study conducted with the combination therapy in recurrent low-grade serous ovarian cancer, also supported the NDA.

About the RAMP 201 Trial

RAMP 201, a multicenter, randomized, open-label trial, sought to evaluate the safety and efficacy of avutometinib given alone and in combination with defactinib for the treatment of patients with histologically confirmed low-grade serous ovarian or peritoneal cancer.²

Enrollment was open to those aged 18 years and older with an ECOG performance status of 0 or 1, disease progression or recurrence following 1 or more lines of systemic therapy in the metastatic setting, measurable disease per RECIST 1.1 criteria, and adequate organ function. Further, patients must have fully recovered from toxicities related to previous treatments.

Those enrolled in part A of the study were given either avutometinib as monotherapy or in combination with defactinib, and experts sought to identify the optimal dose for the expansion portion of the trial. Parts B and C gave avutometinib plus defactinib to patients at the optimal dose, which was determined to be 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily.¹ For those enrolled in part D, a lower dose of the regimen was used.

Overall response rate (ORR) per RECIST 1.1 criteria served as the key primary end point of the study, and secondary end points consisted of investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival.

Key Safety and Efficacy Data

According to updated data from the RAMP 201 trial presented at the 2024 International Gynecologic Cancer Society Annual Meeting, at a median follow-up of approximately 12 months, the confirmed ORR with the combination of avutometinib and defactinib was 31% (95% CI, 23%-41%) per blinded independent central review among evaluable patients with measurable disease in the overall population, which consisted of 109 patients.³

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).

With the combination, the confirmed ORR was 44% (95% CI, 31%-58%) for those harboring KRAS mutations (n = 57) and 17% (95% CI, 8%-30%) for those with KRAS wild-type disease (n = 52). In these groups, the median DORs were 31.1 months (95% CI, 14.8-31.1) and 9.2 months (95% CI, 5.5-not evaluable), respectively. In the KRAS-mutated and wild-type populations, the 6-month DCR rates were 70% and 50%, and the median PFS was 22 months (95% CI, 11.1-36.6) vs 12.8 months (95% CI, 7.4-18.4).

Looking at safety, adverse events (AEs) led to treatment discontinuation in 10% of patients, and there were no new safety signals reported. The most common treatment-related AEs of any-grade were nausea (67.0%), diarrhea (58.3%), and increased blood creatine phosphokinase levels (60.0%).

Avutometinib given with defactinib was previously granted breakthrough therapy designation from the FDA in 2021.⁴ Avutometinib as a monotherapy or given in combination with defactinib was also granted FDA orphan drug designation in 2024 for the treatment of patients with low-grade serous ovarian cancer.¹

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://tinyurl.com/dxsv27mu

2. 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

3. 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://tinyurl.com/ywbrxvm4

4. 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://tinyurl.com/t2tcvkuj