Updated RAMP 201 Data to Support NDA Submission for Avutometinib/Defactinib Combo in Recurrent KRAS+ Ovarian Cancer

Following a Type A meeting with the FDA, Verastem Oncology intends to complete a new drug application (NDA) in October 2024 seeking the approval of the combination of avutometinib (VS-6766) and defactinib (VS-6063) for the treatment of adult patients with recurrent low-grade serous ovarian cancer harboring KRAS mutations who have received at least 1 prior line of systemic therapy.¹

The NDA will be supported by data from the phase 2 RAMP 201 trial (NCT04625270). Updated findings from the study announced by Verastem Oncology and presented at the 2024 International Gynecologic Cancer Society Annual Meeting showed that at a median follow-up of approximately 12 months, evaluable patients with measurable disease in the overall population (n = 109) experienced a confirmed overall response rate (ORR) of 31% (95% CI, 23%-41%) per blinded independent central review (BICR). The median duration of response (DOR) was 31.1 months (95% CI, 14.8-31.1). The disease control rate (DCR) at 6 months or more was 61%, and the median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2).

In patients harboring KRAS mutations (n = 57), avutometinib plus defactinib elicited a confirmed ORR of 44% (95% CI, 31%-58%). In those with KRAS wild-type disease (n = 52), the confirmed ORR was 17% (95% CI, 8%-30%). The respective 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). The DCR rate at 6 months or more was 70% in the KRAS-mutated population and 50% in the KRAS wild-type population. The median PFS was 22 months (95% CI, 11.1-36.6) in the KRAS-mutated population and 12.8 months (95% CI, 7.4-18.4) in the KRAS wild-type population.

“The notable ORRs and low [treatment] discontinuation rate seen with the combination of avutometinib and defactinib are significant. These updated results confirm the potential of this new combination therapy to change practice and be the new standard for care for recurrent low-grade serous ovarian cancer, which previously had limited effective treatment options,” Susana Banerjee, MBBS, MA, PhD, FRCP, global lead investigator of RAMP 201, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust, and team leader in Women’s Cancers at The Institute of Cancer Research in London, United Kingdom, stated in a news release.

The multicenter, randomized, open-label RAMP 201 trial enrolled patients at least 18 years of age with histologically proven low-grade serous ovarian or peritoneal cancer who experienced disease progression or recurrence after at least 1 line of prior systemic therapy in the metastatic setting.² Key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and recovery from toxicities related to prior treatments.

Patients were excluded if they had received systemic anticancer therapy within 4 weeks of the first study treatment; had co-existing high-grade ovarian cancer or another histology; had a history of prior malignancy with recurrence less than 3 years prior to enrollment; had undergone major surgery within 4 weeks of enrollment; or had symptomatic brain metastases requiring steroids or other treatment. Patients who received prior treatment with a MEK-directed therapy were not allowed to have grade 4 toxicities related to the MEK inhibitor.

In part A of the study, patients received either avutometinib alone or in combination with defactinib to identify the optimal dose for expansion. In parts B and C, patients were administered avutometinib plus defactinib at the optimal dose; those enrolled in part D received a lower dose of the combination.

Confirmed ORR per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included investigator-assessed ORR, DOR, DCR, PFS, and overall survival.

Updated safety data showed that avutometinib plus defactinib was generally well tolerated.¹ Adverse effects (AEs) led to treatment discontinuation in 10% of patients, and no new safety signals were reported.

The most 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%).

“Now that we have the mature data from the RAMP 201 trial, we are on track to complete our NDA submission for recurrent KRAS-mutant low-grade serous ovarian cancer in October,” Dan Paterson, president and chief executive officer of Verastem Oncology, added in a news release. “We look forward to working with the FDA to potentially bring the first and only FDA-approved treatment specifically for patients with recurrent KRAS-mutant low-grade serous ovarian cancer to the United States market in 2025.”

References

1. 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 October 17, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-presents-positive-updated-ramp-201-data
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 October 17, 2024. https://clinicaltrials.gov/study/NCT04625270