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A new combination therapy targeting cancer cell signaling has demonstrated promising results in treating low-grade serous ovarian cancer (LGSOC), a subtype of ovarian cancer known for its resistance to standard chemotherapy. The findings, published in Nature Medicine, stem from a first-in-human phase 1 clinical trial testing the oral combination of avutometinib, a RAF–MEK clamp, and defactinib, a focal adhesion kinase (FAK) inhibitor.
The study, known as the FRAME trial, enrolled patients with a range of solid tumors, but it was the LGSOC cohort that delivered the most notable outcome. Among 26 patients with this form of cancer, the trial reported an objective response rate (ORR) of 42.3% and a median progression-free survival (mPFS) of 20.1 months. In comparison, prior trials involving MEK inhibitors alone in LGSOC yielded response rates between 15% and 26%, with shorter progression-free intervals of 9 to 13 months.
The FDA granted accelerated approval for the avutometinib-defactinib combination on May 8, 2025, specifically for patients with recurrent LGSOC harboring KRAS mutations. Approximately 30% of LGSOC patients carry such mutations, which have historically correlated with poor response to traditional treatments.
The trial’s success is particularly significant given previous failures to combine MEK and FAK inhibitors. Earlier attempts were marred by high toxicity and limited efficacy, attributed largely to continuous dosing regimens and adverse drug interactions. The FRAME study navigated this challenge by adopting a novel, pharmacokinetically-informed intermittent dosing strategy.
The recommended phase 2 dose was established at avutometinib 3.2 mg, administered twice weekly, alongside defactinib 200 mg twice daily, both given for three weeks on and one week off in 28-day cycles. This regimen showed improved tolerability compared with prior MEK-only treatments. Among LGSOC patients, only one participant (4%) discontinued treatment due to side effects.
The research team observed that the combination effectively suppressed key cancer signaling pathways, including reductions in phosphorylated MEK, ERK, and FAK proteins. The unexpected synergistic effect, where defactinib counteracted FAK activation triggered by avutometinib alone, provides a potential mechanistic explanation for the combination’s efficacy.
Genetic sequencing also played a role in interpreting the trial’s impact. Among 12 patients with KRAS-mutated LGSOC, the ORR reached 58.3%, and median progression-free survival extended to 30.8 months, figures substantially higher than those seen with MEK monotherapies in comparable populations.
Despite the promising outcomes, the authors caution that this was a phase 1 study with a limited sample size and not powered to definitively assess survival metrics. Moreover, not all patients in the trial underwent tumor genotyping, complicating interpretation of the results across all cohorts.
Still, the results have prompted further investigation. Two ongoing randomized trials, RAMP201 and RAMP301, are now evaluating the combination therapy against single-agent avutometinib and standard-of-care treatments in LGSOC, respectively.
Read the full study in Nature Medicine by following this link.