Avutometinib Combo Produces Responses in Low-Grade Serous Ovarian Cancer

Avutometinib (VS-6766) and defactinib combination therapy garnered positive responses in patients with recurrent low-grade serous ovarian cancer, according to a press release on findings from the part A interim analysis of the phase 2 RAMP-201 trial (NCT04625270).¹

Investigators reported an objective response rate (ORR) of 28% in 29 evaluable patients treated with avutometinib and defactinib by blinded independent central review. Additionally, among patients with KRAS mutant low-grade serous ovarian cancer the ORR was 27% and 29% in those with KRAS wild-type disease. Three patients with KRAS-mutant disease had an unconfirmed partial response.

"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 pre-treated recurrent low-grade serous ovarian cancer," according to an expert from the Royal Marsden NHS Foundation Trust.

The overall disease control rate (DCR) among patients treated with the combination was 93%, and 62% of evaluable patients were still on treatment at the time of data cut-off with a minimum follow-up of 5 months.

Among 30 evaluable patients receiving avutometinib monotherapy, the ORR and DCR was 7% and 90%, respectively.

Investigators of the RAMP-201 trial will discuss the regulatory path forward for avutometinib and defactinib combination therapy with the FDA following encouraging data from the interim analysis. The intent is to eventually file for accelerated approval based on mature data from the RAMP 201 study.

“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 pre-treated recurrent low-grade serous ovarian cancer,” global lead investigator Susana Banerjee, MBBS, MA, PhD, FRCP, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London, said in the press release.

In part A of the phase 2 RAMP-201 trial, investigators aimed to determine the optimal go forward regimen for avutometinib monotherapy or avutometinib plus defactinib; part B was the expansion phase of the trial. Investigators randomly assigned patients with recurrent low-grade serous ovarian cancer, including those with KRAS mutant or KRAS wild-type disease, to receive avutometinib monotherapy (n = 33) or avutometinib plus defactinib (n = 31). Data from the part A interim analysis informed the decision to use avutometinib and defactinib as the go forward treatment regimen based on higher ORRs.

The primary end point of the study is ORR for part A and determination of optimal regimen in part B. Secondary end points included ORR by investigator assessment, duration of response, DCR, progression-free survival, and overall survival.

Patients 18 years and older with histologically confirmed low-grade serous ovarian cancer that had progressed after at least 1 prior systemic therapy for metastatic disease were eligible to enroll on the trial. Additional inclusion criteria included having 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.

Patients receiving avutometinib plus defactinib in the RAMP-201 trial had a mean of 4 prior systemic therapies, including platinum-based chemotherapy, endocrine therapy, and bevacizumab (Avastin) among most patients; approximately 20% of patients previously received a MEK inhibitor.

Avutometinib did not produce any new safety signals and demonstrated safety alone and in combination with defactinib. The most common adverse effects (AEs) related to the combination therapy included diarrhea, nausea, blood creatine phosphokinase increases, blurry vision, rash, fatigue, and peripheral edema. There was a 9% treatment discontinuation rate due to AEs.

Investigators previously reported an update from an interim analysis of the RAMP-201 trial in June 2022.² The initial findings were “encouraging,” with investigators reporting independently confirmed responses in patients who were KRAS mutant and wild type. Avutometinib and defactinib previously received breakthrough therapy designation from the FDA for all patients with recurrent low-grade serous ovarian cancer regardless of KRAS status.³

“The interim positive data from RAMP 201 are encouraging and indicate the combination of avutometinib and defactinib remains a promising approach for treating patients with recurrent [low-grade serious ovarian cancer],” study investigator Rachel N. Grisham, MD, section head of Ovarian Cancer and director of Westchester Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center in New York, concluded.¹

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. Verastem Oncology. January 24, 2023. Accessed January 25, 2023. bwnews.pr/3kLELFq
2. Verastem Oncology provides update on RAMP 201 study evaluating VS-6766 ± defactinib in low-grade serous ovarian cancer. News release. Verastem Oncology. June 6, 2022. Accessed January 25, 2023. bwnews.pr/3jbkR61
3. Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem, Inc. May 24, 2021. Accessed January 25, 2023. https://bit.ly/2QLO5dx