Avutometinib Plus Defactinib Generates Responses in Recurrent Low-Grade Serous Ovarian Cancer

The combination of avutometinib (VS-6766) and defactinib (VS-6063) elicited responses in patients with recurrent low-grade serous ovarian cancer, according to data from a planned interim analysis of the registration-directed phase 2 RAMP-201 trial (NCT04625270).¹

Response-evaluable patients who received the combination (n = 29) achieved a confirmed objective response rate (ORR) of 28% per blinded independent central review (BICR). Additionally, those with KRAS-mutated disease (n = 15) experienced a confirmed ORR of 27%, and those with KRAS wild-type disease (n = 14) had a confirmed ORR of 29%. Three additional patients with KRAS-mutant low-grade serous ovarian cancer had unconfirmed partial responses. The overall disease control rate (DRC) for patients treated with the combination was 93%. At a minimum follow-up of 5 months, 62% of evaluable patients were still on study treatment.

Patients treated with avutometinib monotherapy (n = 30) experienced a confirmed ORR of 7% per BICR. In this group, the overall DCR was 90%.

Target enrollment for the combination arm in RAMP-201 has been achieved, and findings from the trial are expected to be presented at a scientific conference in the middle of 2023.

In a meeting with the FDA to discuss the results, the combination was selected vs the monotherapy as the go-forward treatment for analysis in all patients with recurrent low-grade serous ovarian cancer, irrespective of KRAS status.

Additionally, Verastem Oncology intends to include mature data from RAMP-201 and the phase 1 FRAME trial (NCT03875820) to potentially support filing for accelerated approval for avutometinib plus defactinib in this patient population.

“The interim data from the ongoing phase 2 RAMP 201 trial show that the combination of avutometinib with defactinib yields encouraging response rates with a well-tolerated safety profile in women with heavily pretreated recurrent low-grade serous ovarian cancer,” Susana Banerjee, MBBS, MA, PhD, FRCP, global lead investigator of the study, 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, stated in a press release. “[With] the contribution of [avutometinib and] defactinib, rates of tumor shrinkage in both KRAS-mutant and KRAS wild-type low-grade serous ovarian cancer and [the] high DCR seen so far are important initial findings leading to the decision to move forward with the combination regimen. We look forward to the final analysis.”

Avutometinib is a RAF/MEK clamp that elicits inactive complexes of MEK with ARAF, BRAF and CRAF to potentially create a more complete and durable antitumor response through maximal RAS pathway inhibition.

RAMP-201 is an ongoing, adaptive, 2-part, multicenter, parallel cohort, randomized, open-label trial that is evaluating the safety and efficacy of avutometinib alone and in combination with defactinib in patients with recurrent low-grade serous ovarian cancer. Part A of the study was designed to determine the optimal regimen of either the monotherapy or the combination. Treatment in the expansion phase is based on ORRs reported from part A of the research.

The trial is enrolling patients with histologically proven low-grade serous ovarian cancer.² In part A, patients were required to harbor a KRAS mutation or KRAS wild-type disease. Other inclusion criteria include progression or recurrence of low-grade serous ovarian cancer after at least 1 prior systemic therapy for metastatic disease, measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and adequate recovery from toxicities related to prior treatments.

Key exclusion criteria include having received any systemic anticancer therapy within 4 weeks of the first dose of study therapy, co-existing high-grade ovarian cancer or another histology, history of prior malignancy with recurrence less than 3 years from the time of enrollment, major surgery within 4 weeks of enrollment, or symptomatic brain metastases requiring steroids or other interventions. Patient with prior exposure to a MEK inhibitor could not have experienced a prior grade 4 toxicity determined to be related to the MEK inhibitor.

In part A, patients were randomly assigned 1:1 to receive avutometinib with or without defactinib. Patients enrolled to part B will receive the combination of avutometinib and defactinib. The primary end point of part B is the efficacy of the optimal regimen determined in part A. Secondary end points consist of ORR, duration of response, DCR, progression-free survival, and overall survival.

Regarding safety, no additional signals were observed in the combination or monotherapy arms. The most common treatment-related adverse effects (AEs) experienced with the combination in all treated patients included diarrhea, nausea, increased blood creatine phosphokinase, blurred vision, dermatitis acneiform and rash, fatigue, and peripheral edema, most of which were mild to moderate.

Nine percent of patients discontinued treatment due to AEs.

References

1. Verastem Oncology announces positive data and regulatory update from planned interim analysis of registration-directed phase 2 RAMP-201 trial of avutometinib and defactinib in recurrent low-grade serous ovarian cancer. News release. January 24, 2023. Accessed January 25, 2023. https://investor.verastem.com
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 December 30, 2022. Accessed January 25, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04625270