Avutometinib/Defactinib Shows SOC Potential in LG Serous Ovarian Cancer

Nausea, diarrhea, peripheral edema, and rash were common among patients taking avutometinib and defactinib.

The combination of avutometinib with defactinib (Avmapki Fakzynja Co-Pack) demonstrated clinically meaningful response rate, duration of response, and survival for patients with low-grade serous ovarian cancer (LGSOC) in data from a primary analysis of the phase 2 RAMP 201 trial (NCT04625270) support the duo as a potential standard of care for this patient population.¹

Data from this trial led to the drug combination’s FDA approval in patients with KRAS-mutated LGSOC in May 2025.² Patients enrolled in RAMP 201, an open-label study, had each received at least 1 line of prior platinum chemotherapy and were stratified by KRAS mutational status.¹

Response Rates and Survival

Results published in the Journal of Clinical Oncology demonstrated a confirmed objective response rate (ORR) of 31% (95% CI, 23%-41%) for all 115 patients with LGSOC who received combination therapy, which included 58 patients with KRAS mutations and 57 with KRAS wild-type disease. Of 34 patients who achieved objective response, 25 had KRAS mutations and 9 did not. Among those harboring KRAS mutations, the ORR was 44% (95% CI, 31%-58%)², vs 17% in those with KRAS wild-type disease.^1,2

Two patients (2%) achieved complete response, both of whom had KRAS mutations (4%); an additional 32 patients (29%) achieved partial response, including 23 (40%) with KRAS mutations and 9 (17%) with KRAS wild-type disease.¹ Of the general patient population, 62 (57%) reached stable disease, comprising 65% of patients without KRAS mutations and 49% of those with KRAS mutations.

The median duration of response (DOR) for all patients was 31.1 months (95% CI, 14.8-31.1), with median DORs of 31.1 months (95% CI, 14.8-31.1) for those with KRAS mutations and 9.2 months (95% CI, 5.5-NE) for patients without.

Of those with confirmed objective response, 81% (95% CI, 62%-91%) in the general patient population, 87% (95% CI, 66%-96%) of patients with KRAS-mutated disease, and 63% (95% CI, 23%-86%) for those with wild-type disease maintained their response at 6 months. Likewise, at 12 months, 72% (95% CI, 54%-89%) of all patients and 82% (95% CI, 65%-98%) of those with KRAS mutations maintained response at 12 months, with the same statistic not estimable for patients with KRAS wild-type disease. Median time to confirmed response was 3.7 months.

Median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2), 22.0 months (95% CI, 11.1-36.6), and 12.8 months (95% CI, 7.3-18.4) in all evaluated patients with LGSOC (n = 109), patients with KRAS mutations (n = 57), and patients with KRAS wild-type disease, respectively.

What Adverse Events Were Associated With Avutometinib/Defactinib?

The most common treatment-related nonlaboratory adverse events (AEs) of any grade were nausea (67%), diarrhea (58%), peripheral edema (53%), rash (50%), fatigue (44%), and vomiting (43%). Likewise, the most common grade 3 or 4 treatment-related nonlaboratory AEs were diarrhea (8%), anemia (5%), and dermatitis acneiform (4%).

Regarding laboratory abnormalities, 60% of patients experienced elevated creatine phosphokinase (CPK), including 19% having grade 3 events and 5% having grade 4 events. Ten percent of patients discontinued treatment due to AEs, most commonly because of increased CPK (4%).

Over 20% of patients had treatment-related dermatologic AEs, with rash occurring in 50%, dermatitis acneiform in 34%, and dry skin in 26%. The median time to dermatologic AE was 15 days, and the median duration of symptoms was 35 days. Additionally, 41% of patients had blurred vision because of treatment, with most cases beginning in the first week of treatment, the median onset to blurred vision being 2 days. No instances of blurred vision exceeded grade 2 in severity or required treatment discontinuation.

An additional 22% of patients required reduction or hold of study drug due to elevated blood bilirubin and hyperbilirubinemia.

Serious AEs (SAEs) related to treatment occurred in 7% of patients, and 5 deaths occurred either on treatment or within 30 days of continuation. No deaths were related to treatment.

Efficacy Data by Prior Therapy

A preplanned subgroup analysis investigated ORR by prior therapy types. For patients treated with previous MEK inhibitors, ORR was 24% (95% CI, 9%-45%), vs 33% (95% CI, 23%-44%) in those who had no previous MEK inhibitor; patients treated with prior bevacizumab had an ORR of 20% (95% CI, 10%-33%) vs 43% (95% CI, 29%-57%) in those without prior treatment with bevacizumab (Avastin).

Patients with more than 3 prior treatment regimens had an ORR of 24% (95% CI, 13%-39%) vs 37% (95% CI, 25%-50%) in those who had received 1 to 3 prior lines of therapy.

Selection of Avutometinib Combination Therapy Vs Monotherapy

RAMP 201 aimed to assess the efficacy and safety of both avutometinib monotherapy and combination therapy with defactinib. Parts A and B assigned patients stratified by KRAS mutational status and randomly assigned 1:1 to receive either 4.0 mg of oral avutometinib twice weekly for 3 weeks or 3.2 mg of oral avutometinib twice weekly plus 200 mg of oral defactinib twice daily for 3 weeks, with each regimen followed by 1 week of rest, comprising 4-week cycles.

In Part A, 33 patients received monotherapy, and 31 patients received combination therapy. At the prespecified time of analysis, ORR was 28% vs 7% for the combination therapy and monotherapy groups, respectively. An updated analysis revealed ORR of 39% compared with 9% in those groups, respectively. Both arms had similar safety profiles.

References

1. Banerjee SN, Van Nieuwenhuysen E, 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. Published online July 11, 2025. doi:10.1200/JCO-25-00112
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 August 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low