Avutometinib/Defactinib Shows SOC Potential in LG Serous Ovarian Cancer

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The addition of avutometinib to defactinib showed promising safety and efficacy for patients with low-grade serous ovarian cancer.

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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

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