Avutometinib/Defactinib Display Safety, Efficacy in Ovarian Cancer Subtype

Among patients treated with the combination therapy, the median progression-free survival was 12.9 months.

Avutometinib in combination with defactinib (Avmapki Fakzynja Co-Pack) exhibited a tolerable safety profile and enhanced efficacy vs avutometinib alone in patients with recurrent low-grade serous ovarian cancer (LGSOC), according to findings from the phase 2 RAMP 201 (NCT04625270) trial published in the Journal of Clinical Oncology.¹

Efficacy data revealed that the objective response rate (ORR) among patients treated with the combination was 31% vs 17% among those treated with avutometinib monotherapy. Furthermore, 29% achieved a partial response (PR) and 2% achieved a complete response (CR) in the combination arm vs 16% and 1%, respectively, in the avutometinib monotherapy arm.

The median time to confirmed response in the combination arm was 3.7 months (range, 1.7-19.2), with a median duration of response (DOR) of 31.1 months (95% CI, 14.8 to 31.1). Furthermore, among responders in the combination arm, 81% (95% CI, 62%-91%) maintained a response at 6 months and 72% (95% CI, 54%-89%) maintained a response at 12 months.

A planned subgroup analysis showed that the confirmed ORR among those treated with a prior MEK inhibitor was 24% (95% CI, 9%-45%) vs 33% (95% CI, 23%-44%) who were not treated with one. Additionally, the confirmed ORR was 20% (95% CI, 10%-33%) among those treated with prior bevacizumab (Avastin) vs 43% (95% CI, 29%-57%) who did not receive prior bevacizumab. Furthermore, the confirmed ORR was 24% (95% CI, 13%-39%) among those who received more than 3 prior lines of therapy vs 37% (95% CI, 25%-50%) among those who received 1 to 3 prior lines of therapy.

Among patients treated with the combination therapy, the median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2). Among patients with KRAS-mutant disease, the median PFS was 22.0 months (95% CI, 11.1-36.6), and among those with KRAS wild-type disease, it was 12.8 months (95% CI, 7.4-18.4). For all patients, the 6- and 12-month PFS rates were 79% (95% CI, 70%-86%) vs 58% (95% CI, 47%-68%).

“The publication of the primary analysis of the [phase 2] RAMP 201 study in recurrent low-grade serous ovarian cancer in the Journal of Clinical Oncology reflects the meaningful clinical advancement demonstrated by the combination of avutometinib plus defactinib for patients with recurrent low-grade serous ovarian cancer,” John Hayslip, MD, chief medical officer at Verastem Oncology, said in a news release on the publication². “The findings supported the recent FDA approval of the combination in KRAS-mutated recurrent low-grade serous ovarian cancer and our ongoing global phase 3 RAMP 301 (NCT06072781) trial of the combination in recurrent low-grade serous ovarian cancer with and without a KRAS mutation.”

Patients 18 years and older with histologically confirmed low-grade serous ovarian cancer (LGSOC) were initially randomly assigned 1:1 to receive avutometinib/defactinib or avutometinib monotherapy in parts A and B of the trial. In part C, the combination was identified as the go-forward regimen and expanded, and in part D, a lower dose of avutometinib was assessed in combination with defactinib.

Patients in the combination arm received oral avutometinib at 1.6 mg or 3.2 mg twice weekly and 200 mg of oral defactinib twice daily for 3 weeks, followed by a 1-week rest period for a 4-week cycle. Patients in the monotherapy arm received 4.0 mg oral avutometinib twice weekly for 3 weeks, followed by a 1-week rest period.

Those in the combination (n = 115) and monotherapy (n = 70) arms had a median age of 54 years (range, 21-87) and 54 years (range, 21-77), 77% vs 84% were White, and 68% vs 71% had an ECOG performance status of 0. The median number of systemic therapies received in each arm was 3 (range, 1-9) and 3 (range, 1-10), 99% vs 99% received prior platinum-based chemotherapy, and 86% vs 83% received prior hormonal therapy. In each respective arm, the receipt of prior bevacizumab was observed in 51% vs 49% of patients, and the receipt of prior MEK inhibition was observed in 22% vs 26%.

The primary end point of the study was ORR per RECIST v1.1 as assessed by blinded independent committee review. Secondary end points included DOR, investigator-assessed ORR, PFS, overall survival, safety, and pharmacokinetics.

Safety data revealed that the most frequently reported treatment-related adverse effects (TRAEs) included nausea (67%), diarrhea (58%), peripheral edema (53%), rash (50%), fatigue (44%), and vomiting (43%). The most frequent TRAEs at grades 3 or 4 in severity included diarrhea (8%), anemia (5%), and dermatitis acneiform (4%). Additionally, treatment-related increased creatine phosphokinase (CPK) occurred in 60% of patients, with 19% experiencing grade 3 events and 5% experiencing grade 5 events.

AEs leading to treatment discontinuation occurred in 10% of patients; the most common of which came from elevated CPK in 4% of patients. Additionally, treatment-related skin reactions occurring in at least 20% of patients included rash (50%), dermatitis acneiform (34%), and dry skin (26%), with most being grade 1 or 2 in severity. Treatment-related serious AEs occurred in 7% of patients, and 5 deaths were observed in the combination arm, all of which were not considered related to study treatment.

References

1. Banerjee SN, Nieuwenhuysen EV, Aghajanian C, et al. Efficacy and safety of avutometinib ± defactinib in recurrent low-grade serous ovarian cancer: primary analysis of ENGOT-OV60/GOG-3052/RAMP 201. J Clin Oncol. doi:10.1200/JCO-25-00112
2. Verastem Oncology announces publication of the primary results from the phase 2 RAMP 201 trial of avutometinib in combination with defactinib in patients with recurrent low-grade serous ovarian cancer in the Journal of Clinical Oncology. News release. Verastem Oncology. July 11, 2025. Accessed July 14, 2025. https://tinyurl.com/2r4v3pbe