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

Susana Banerjee, MBBS, MA, PhD, FRCP

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

Patients with an evaluable response who received the combination (n = 29) achieved a confirmed objective response rate (ORR) of 28% by blinded independent central review (BICR). Furthermore, those with KRAS-mutant 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 KRASSevere low-grade mutant ovarian cancer showed unconfirmed partial responses. The overall disease control (CKD) rate 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) had a confirmed ORR of 7% by BICR. In this group, the overall DCR was 90%.

The enrollment target for the combination arm in RAMP-201 has been met, and the study results are expected to be presented at a scientific conference in mid-2023.

In a meeting with the FDA to discuss the results, the combination was selected versus monotherapy as the initial treatment for analysis in all patients with severe recurrent low-grade ovarian cancer, regardless of KRAS status.

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

“Interim data from the ongoing phase 2 RAMP 201 study show that the combination of avutometinib with defactinib produces encouraging response rates with a well-tolerated safety profile in women with heavily pre-treated low-grade recurrent serous ovarian cancer,” Susana Banerjee, MBBS, MA, PhD, FRCP, global principal investigator of the study, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and team leader in female cancers at the Institute of Cancer Research in London, said in a press release. “[With] the contribution of [avutometinib and] defactinib, tumor shrinkage rates in both KRAS-mutant and KRAS severe low-grade wild-type ovarian cancer and [the] the high DCR observed so far are important initial findings that led to the decision to proceed with the combined regimen. We look forward to the final analysis.”

Avutometinib is an RAF/MEK hairpin that causes inactive MEK complexes with ARAF, BRAF and CRAF to potentially create a more complete and durable anti-tumor response through maximal inhibition of the RAS pathway.

RAMP-201 is an ongoing, adaptive, 2-part, multicenter, parallel cohort, randomized, open-label study 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 is designed to determine the optimal monotherapy or combination regimen. Treatment in the expansion phase is based on the ORRs reported in part A of the survey.

The study is enrolling patients with histologically proven severe low-grade ovarian cancer.two In part A, patients were required to harbor a KRAS mutation or KRAS wild-type disease. Other inclusion criteria include progression or recurrence of severe low-grade ovarian cancer after at least 1 prior systemic therapy for metastatic disease, measurable disease according to RECIST v1.1 criteria, ECOG performance status of 0 or 1, adequate function of the organ and adequate recovery due to toxicities related to previous 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 other histology, history of previous malignancy with recurrence less than 3 years from the time of enrollment, surgery within 4 weeks of enrollment, or symptomatic brain metastases requiring steroids or other interventions. The patient with prior exposure to a MEK inhibitor could not have experienced 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 in Part B will receive the combination of avutometinib and defactinib. The primary endpoint of part B is the effectiveness of the optimal regimen determined in part A. The secondary endpoints consist of ORR, duration of response, DCR, progression-free survival, and overall survival.

Regarding safety, no additional signs 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, acneiform dermatitis and rash, fatigue, and peripheral edema, most of which light to moderate .

Nine percent of patients discontinued treatment due to AEs.


  1. Verastem Oncology announces positive data and regulatory update from the planned interim analysis of the registry-driven phase 2 study RAMP-201 of avutometinib and defactinib in recurrent low-grade serous ovarian cancer. Press 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 (RAMP-201) mutation. ClinicalTrials.gov. Updated December 30, 2022. Accessed January 25, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04625270
Avutometinib Plus Defactinib Generates Responses in Recurrent Low-Serous Ovarian Cancer

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