With encouraging response rates and a well-tolerated safety profile seen in RAMP-201, experts are hopeful for the accelerated approval of avutometinib plus defactinib for low-grade serous ovarian cancer.
The combination of avutometinib (VS-6766) with defactinib (VS-6063), as well as avutometinib alone, was well-tolerated and elicited encouraging response rates in patients with recurrent low-grade serous ovarian cancer (LGSOC), according to positive interim data from part A of the ongoing phase 2 RAMP-201 (NCT04625270; ENGOTov60/GOG3052) study.1
Twenty-nine patients in the combination arm of avutometinib and defactinib were evaluable for response by blinded independent central review (BICR). Among these patients, the confirmed objective response rate (ORR) was 28% in all patients, 27% in patients with KRAS mutations (n = 15), and 29% in patients with KRAS wild-type (n = 14) LGSOC, respectively.
For evaluable patients in the monotherapy arm (n = 30), the confirmed ORR by BICR was 7%, and the overall disease control rate (DCR) by BICR was 90%. Regarding safety, no additional safety signals have been reported in either the combination or monotherapy arm and each have shown there to be a favorable safety and tolerability profile.
Additionally, an FDA meeting was recently held which discussed the positive results from RAMP-201. A regulatory path forward was discussed, and it was announced that the combination of avutometinib and defactinib was selected compared with the monotherapy as the phase 2 treatment regimen for all patients with recurrent LGSOC, regardless of KRAS status. The company now plans to file for an accelerated approval of the combination to the FDA.
“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,” said Susana Banerjee, MD, MBBS, MA, PhD, FRCP, global lead investigator of the study, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and team leader in women’s cancers at The Institute of Cancer Research, London, in the press release. “The contribution of defactinib, rates of tumor shrinkage in both KRAS mutant and KRAS wild-type LGSOC and a high disease control rate 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.”
RAMP-201 study is an open-label, multicenter, randomized, phase 2 study where investigators will evaluate the safety, tolerability, and preliminary efficacy of avutometinib alone vs avutometinib combined with defactinib in patients with LGSOC.2
Part A of the study is the selection phase which aims to determine the optimal regimen of avutometinib monotherapy or in combination with defactinib. Then, part B is the expansion phase which would determine the efficacy of the regimen identified from the selection phase. Efficacy was assessed in patients with KRAS-mutant and KRAS-wild type LGSOC.
Eligible patients enrolled in part A were randomized to receive avutometinib monotherapy (n = 33) or the combination of avutometinib and defactinib (n = 31). In the combination arm of the study, patients were heavily pretreated and had an average of 4 prior systemic regimens but could receive up to 11. These include prior platinum-based chemotherapy, endocrine therapy, and bevacizumab in most patients and prior MEK inhibitor therapy in about 20% of patients.
Overall, the study showed an ORR of 28% in the combination arm and 7% in the monotherapy arm. ORR rates in the combination arm were 27% vs 29% for patients with KRAS mutant and KRAS wild-type LGSOC. Then, 3 additional patients with KRAS-mutated LGSOC had an unconfirmed partial response.
Tumor regression was observed in most patients and the overall DCR for patients in the combination arm was 93% vs 90% in the monotherapy arm. A majority of the evaluable patients (62%) continued to receive treatment with the combination at the time of the data cut with a minimum follow-up of 5 months.
Regarding safety, the most common treatment-related adverse events (TRAEs) in the combination arm included diarrhea, nausea, increased blood creatine phosphokinase, blurred vision, dermatitis acneiform and rash, fatigue, and peripheral edema. Most of these TRAEs were mild to moderate, and there was a 9% discontinuation rate due to AEs.
Now that the combination arm of the RAMP-201 study has achieved target enrollment, the Company plans to present data at an upcoming scientific conference.
“We appreciate the productive and ongoing discussions with the FDA regarding the progress of our LGSOC program, including the alignment around key next steps as part of our breakthrough therapy designation,” said Brian Stuglik, chief executive officer of Verastem Oncology, in the press release. “With the encouraging results of the RAMP-201-part A interim analysis and the FRAME study [NCT03875820], we will work expeditiously to prepare to file for an accelerated approval that encompasses the totality of the data from both trials as well as progress on the confirmatory study.”