Avutometinib/Defactinib Yields Responses in Low-Grade Serous Ovarian Cancer

The combination of avutometinib and defactinib (Avmapki Fakzynja Co-pack) continued to demonstrate durable efficacy and an acceptable safety profile in patients with low-grade serous ovarian cancer (LGSOC). Updated data from the phase 2 RAMP 201 trial (NCT04625270) were presented at the 2026 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.¹

With 1 additional year of follow-up since the primary analysis of RAMP-201, patients who received the combination (n = 109) achieved a confirmed overall response rate (ORR) of 31%, including a 2% complete response (CR) rate. Patients also experienced stable disease (57%), progressive disease (8%), or were not evaluable (NE; 4%). The median duration of response (DOR) was 31.1 months (95% CI, 14.8-NE); the 12- and 24-month DOR rates were 71% (95% CI, 55%-87%) and 56% (95% CI, 34%-77%), respectively. The median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-19.6); the 12- and 24-month PFS rates were 58% (95% CI, 47%-69%) and 25% (95% CI, 13%-38%), respectively.

“We saw in this long-term analysis that these responses were durable, with a median DOR of 31.1 months for the overall study population,” Rachel N. Grisham, MD, Section Head, Ovarian Cancer at Memorial Sloan Kettering (MSK) Cancer Center in New York, New York, and the director of gynecologic medical oncology at MSK Westchester, said during the presentation.

In May 2025, the FDA granted accelerated approval to avutometinib plus defactinib for the treatment of adult patients with KRAS-mutated recurrent LGSOC who received prior systemic therapy.² The regulatory decision was supported by data from the primary analysis of RAMP-201.

How was RAMP 201 designed?

RAMP 201 enrolled patients with recurrent LGSOC who received prior platinum chemotherapy.¹ Patients were also required to have measurable disease per RECIST 1.1 criteria. Prior MEK inhibitor treatment was permitted.

In parts A and B, patients received avutometinib at 3.2 mg biweekly plus defactinib at 200 mg twice daily or avutometinib monotherapy at 4.0 mg biweekly; those in part C also received avutometinib at 3.2 mg biweekly plus defactinib at 200 mg twice daily. Patients in part D received avutometinib at 1.6 mg biweekly plus defactinib at 200 mg twice daily. Both the monotherapy and combination cohorts followed an oral-dosing schedule for 3-weeks-on, 1-week-off.

The primary end point was ORR per blinded independent central review per RECIST 1.1 criteria, both in the overall population and in patients with KRAS-mutated disease. Secondary end points included investigator-assessed ORR, DOR, disease control rate, PFS, and overall survival.³

At baseline, the median age in the overall population was 54 years (range, 21-87). ¹ Most patients were White (77%), had an ECOG performance status of 0 (68%), and were from the United States (53%). The median number of prior systemic regimens was 3 (range, 1-9). Prior treatment modalities included platinum-based chemotherapy (99%), hormonal therapy (86%), bevacizumab (Avastin; 51%), and MEK inhibitor therapy (22%).

The median follow-up for patients who were still receiving treatment was 24.9 months (range, 22.4-52.5). The median duration of treatment was 9.0 months (range, < 1.0-52.2) and the mean relative dose intensity was 0.8 for avutometinib and defactinib.

What were the additional safety and efficacy data that were presented during SGO?

Patients with KRAS-mutated disease (n = 57) achieved a confirmed ORR of 44%, including a 4% CR rate. The respective rates of patients who experienced stable disease, progressive disease, or were NE were 49%, 4%, and 4%. The median DOR was 31.1 months (95% CI, 21.2-NE); the 12- and 24-month DOR rates were 79% (95% CI, 62%-95%) and 64% (95% CI, 41%-88%), respectively. The median PFS was 19.6 months (95% CI, 11.1-36.6); the 12- and 24-month PFS rates were 63% (95% CI, 48%-77%) and 39% (95% CI, 22%-56%), respectively.

The median duration of treatment among patients with KRAS-mutated disease was 12.6 months (range, 9.2-21.9). The median time to response was 3.7 months (range, 1.7-9.2). Fifty-two percent of patients remained on therapy for over 1 year.

Patients with KRAS wild-type disease (n = 52) achieved a confirmed ORR of 17%, all of which were partial responses. The respective rates of patients who experienced stable disease, progressive disease, or were NE were 65%, 14%, and 4%. The median DOR was 12.0 months (95% CI, 5.5-NE); the 12- and 24-month DOR rates were 50% (95% CI, 15%-85%) and NE, respectively. The median PFS was 12.7 months (95% CI, 7.4-12.9); the 12- and 24-month PFS rates were 53% (95% CI, 37%-69%) and 0%, respectively.

The median duration of treatment among patients with KRAS wild-type disease was 7.2 months (range, < 1-29.2). The median time to response was 3.6 months (range, 1.8-7.2). Thirty percent of patients remained on therapy for over 1 year.

In terms of safety, the frequency and nature of the adverse effect (AE) profile of the combination was generally consistent with findings from the primary analysis. No new safety signals were reported and there were few new-onset AEs.

The most common any-grade AEs included nausea (68%), increased blood creatine phosphokinase levels (60%), diarrhea (59%), peripheral edema (53%), and rash (51%). Grade 3 or higher AEs included increased blood creatine phosphokinase levels (26%), diarrhea (8%), and anemia (7%).

AEs were managed via dose modifications and prophylaxis for skin reactions. Most patients had AEs leading to a dose interruption (84%) and 37% had AEs leading to dose reductions. Patients discontinued treatment due to AEs at a rate of 12%.

In the overall population, 85% of patients discontinued treatment. Reasons for discontinuation included disease progression per RECIST 1.1 criteria (51%), AEs/unacceptable toxicity (12%), withdrawal of consent (9%), other reasons (9%), and clinical deterioration (4%). Notably, no patients were forced to discontinue treatment due to death.

“No new safety signals were identified and the treatment was tolerable. These results confirm that the combination of avutometinib and defactinib provides durable efficacy, both for patients with KRAS-mutant and KRAS wild-type LGSOC with a toxicity profile amenable to long term treatment administration.”

Disclosures: Grisham holds consulting roles with AstraZeneca, GSK, Merck, Verastem, Corcept, Incyte, Incyclix, and GenMab.

References

1. Grisham RN, Nieuwenhuysen EV, Santin AD, et al. Long-term efficacy and safety of avutometinib + defactinib in patients with recurrent low-grade serous ovarian cancer: results from ENGOT-ov60/GTG-UK/GOG-3052. Presented at: 2026 SGO Annual Meeting on Women’s Cancer; April 10-13, 2026; San Juan, PR.
2. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. FDA. May 8, 2025. Accessed April 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low
3. A study of avutometinib (VS-6766) v. avutometinib (VS-6766) + defactinib in recurrent low-grade serous ovarian cancer with and without a KRAS mutation (RAMP 201). ClinicalTrials.gov. Updated January 29, 2025. Accessed April 10, 2026. https://clinicaltrials.gov/study/NCT04625270