Avutometinib/Defactinib Combo Drives Responses in Recurrent Low-Grade Serous Ovarian Cancer

Treatment with the combination of avutometinib (VS-6766) and defactinib (VS-6063) led to a clinically meaningful overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer, according to data from the RAMP 201 trial (NCT04625270) presented at the 2025 Society of Gynecological Oncology Annual Meeting on Women’s Cancer.1

Findings showed that evaluable patients treated with avutometinib at 3.2 mg and defactinib at 200 mg (n = 109) experienced a confirmed ORR of 31% comprising a complete response (CR) rate of 2% and a partial response (PR) rate of 29%. The stable disease (SD) and progressive disease (PD) rates were 57% and 8%, respectively, and 4% of patients were not evaluable for response.

In patients with KRAS-mutated disease (n = 57), the ORR was 44% with CR and PR rates of 4% and 40%, respectively. In those with KRAS wild-type disease (n = 52), the ORR and PR rate were both 17%.

“These data, in combination with a tolerable safety profile, support the potential for avutometinib and defactinib as a new standard of care for women with recurrent low-grade serous ovarian cancer,” lead study author Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said during a presentation of the data.

In December 2024, the FDA granted priority review to a new drug application (NDA) seeking the approval of avutometinib in combination with defactinib for the treatment of adult patients with recurrent low-grade serous ovarian cancer who received at least 1 prior systemic therapy and harbor a KRAS mutation.2 The acceptance of the NDA was based on data from RAMP 201.

RAMP 201 Overview

The registration-directed phase 2 trial enrolled patients with recurrent low-grade serous ovarian cancer who received prior platinum-based chemotherapy and had measurable disease per RECIST 1.1 crtieria.1 Notably, prior treatment with a MEK inhibitor was permitted.

During the study, patients received avutometinib at 3.2 mg twice per week plus defactinib at 200 mg twice per day; avutometinib at 1.6 mg twice per week plus defactinib at 200 mg twice per day; or avutometinib at 4.0 mg twice per week as monotherapy. In all arms, avutometinib was given on a 3-weeks-on, 1-week-off schedule. The 3.2-mg dose of avutometinib evaluated in the selection phase was established as the go-forward dose.

ORR per RECIST 1.1 criteria in the overall population and the KRAS-mutated population served as the trial’s primary end point.

Among patients treated with the combination using the 3.2-mg dose of avutometinib (n = 115), the median age was 54 years (range, 21-87). Most patients were White (77%). Sixty-eight percent of patients had an ECOG performance status of 0, and 32% had an ECOG performance status of 1. Patients received a median of 3 prior lines of systemic therapy (range, 1-9). Prior treatments included platinum-based chemotherapy (99%), hormonal therapy (86%), bevacizumab (Avastin; 51%), and a MEK inhibitor (22%).

At a median follow-up of 13.6 months (range, 1.4-39.5), 28% of patients were ongoing study treatment. Among the 72% to discontinue treatment, reasons comprised disease progression (40%), adverse effects (AEs; 10%), patient withdrawal (9%), other (9%), and clinical deterioration (4%).

Additional Efficacy and Safety Data

In the overall population treated with the go-forward dose of the combination, the median DOR was 31.1 months (95% CI, 14.8-31.1). The median DOR was 31.1 months (95% CI, 14.8-31.1) in the KRAS-mutated population and 9.2 months (95% CI, 5.5-not evaluable) in the KRAS wild-type population.

Patients in the overall population achieved a median PFS of 12.9 months (95% CI, 10.9-20.2), and the 6- and 12-month PFS rates were 79% (95% CI, 70%-86%) and 58% (95% CI, 47%-68%), respectively. The KRAS-mutated population experienced a median PFS of 22.0 months (95% CI, 11.1-36.6) with a 6-month PFS rate of 88% (95% CI, 76%-95%) and a 12-month PFS rate of 62% (95% CI, 48%-77%). The median PFS was 12.8 months (95% CI, 7.4-18.4) in the KRAS wild-type population with 6- and 12-month PFS rates of 69% (95% CI, 53%-80%) and 53% (95% CI, 37%-69%), respectively.

Data from a subgroup analysis for the KRAS-mutated population showed that the ORR was 47% among patients who did not receive a prior MEK inhibitor (n = 45) vs 33% for those who previously received a MEK inhibitor (n = 12). The ORR was 53% for those not treated with prior bevacizumab (n = 34) vs 30% for those previously given bevacizumab (n = 23). Patients who received 1 to 3 prior lines of therapy (n = 35) experienced an ORR of 49% vs 36% for those who received more than 3 prior lines of therapy (n = 22).

In the KRAS wild-type population, findings from the subgroup analysis demonstrated that the ORR was 18% for those with no history of MEK inhibition (n = 39) vs 15% for those previously given a MEK inhibitor (n = 13). The ORR was 25% for those not previously treated with bevacizumab (n = 20) vs 13% for those who received prior bevacizumab (n = 32). The ORR was 21% for patients who received 1 to 3 prior lines of therapy (n = 28) and 13% for those who received more than 3 prior lines of therapy (n = 24).

Regarding safety, patients treated with the go-forward dose received avutometinib at a mean relative dose intensity of 0.84 and defactinib at a mean relative dose intensity of 0.77. AEs led to dose interruptions, dose reductions, and treatment discontinuation in 80%, 37%, and 10% of patients, respectively. Serious AEs considered related to study treatment occurred in 7% of patients; however, the only serious treatment-related AE (TRAE) observed in more than 1 patient was abdominal pain. At 3 months following data cutoff, no additional AEs leading to treatment discontinuation, AEs leading to death, or serious AEs considered related to study treatment were reported.

The most common TRAEs included nausea (any-grade, 67%; grade ≥3, 3%), increased blood creatine phosphokinase levels (60%; 24%), diarrhea (58%; 8%), peripheral edema (53%; 1%), rash (50%; 3%), fatigue (44%; 3%), vomiting (43%; 3%), blurred vision (41%; 0%), acneiform dermatitis (34%; 4%), increased blood bilirubin/hyperbilirubinemia (33%; 4%), increased aspartate aminotransferase levels (31%; 2%), dry skin (26%; 0%), anemia (23%; 5%), and increased alanine aminotransferase levels (22%; 2%).

Data for Low-Dose Avutometinib

Patients who received avutometinib at 1.6 mg twice per week plus defactinib at 200 mg twice per day (n = 23) experienced an ORR of 4% and a SD rate of 74%. Notably, 22% of patients in this arm experienced progressive disease within 4 months of treatment compared with 12% of patients treated at the go-forward dose.

AEs led to treatment discontinuation in 15% of patients treated at the lower dose of avutometinib.

The go-forward dose is being further evaluated vs investigator’s choice of therapy in patients with recurrent low-grade serous ovarian cancer in the ongoing phase 3 RAMP 301 trial (NCT06072781).

Disclosures: Grisham reported the following financial relationships over the past 24 months, all of which have ended: AstraZeneca, GSK, Verastem Oncology, Cardinal Health, Genmab, Incyte, and Incyclix.

References

1. Grisham RN, Van Nieuwenhuysen E, Aghajanian C, et al. Avutometinib + defactinib in recurrent low-grade serous ovarian cancer (ENGOT-ov60/GOG-3052/RAMP 201): dose intensity and subgroup analysis. Presented at: 2025 SGO Annual Meeting on Women’s Cancer; March 14-17, 2025. Seattle, WA. Abstract 814605.
2. Verastem Oncology announces FDA acceptance and priority review of new drug application for avutometinib in combination with defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. December 30, 2024. Accessed March 17, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-announces-fda-acceptance-and-priority-review