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Primary results from the phase 2 RAMP 201 trial (NCT04625270) evaluating the combination therapy of avutometinib and defactinib (Avmapki Fakzynja co-pack) for patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) show that this dual-pathway inhibition strategy offers a promising new avenue for a patient population with historically limited effective treatment options.1
The results, published in the Journal of Clinical Oncology, demonstrated robust objective response rates (ORR) with the avutometinib and defactinib combination, even in patients who had undergone multiple prior lines of therapy. The ORR was 31% (n = 34/109), with a notably higher response rate of 44% (n = 22/57) observed in patients harboring KRAS mutations. In the KRAS wild-type cohort, the ORR stood at 17% (n = 9/52). A compelling aspect of the data was the significant proportion of patients (82%) experiencing some reduction in target lesions, irrespective of their KRAS mutation status, underscoring the broad potential of this therapeutic approach.
These findings supported the FDA’s accelerated approval of the combination earlier this year, on May 8, 2025.2
Furthermore, the trial’s efficacy data highlighted durable responses and meaningful progression-free survival (PFS).1 The median PFS for the overall study population was 12.9 months. For KRAS-mutant patients, this extended to an impressive 31.0 months, while KRAS wild-type patients achieved a median PFS of 12.8 months. The median duration of response (DOR) for all patients was 31.1 months. This extended DOR, particularly in a recurrent setting, signals a substantial clinical benefit.
The safety profile of the avutometinib and defactinib combination was generally well tolerated in the RAMP 201 trial, with a 10% discontinuation rate due to adverse events (AEs). Common AEs observed included nausea, diarrhea, and increased creatine phosphokinase levels, consistent with the known mechanisms of action of these inhibitors. Important safety information for the combination includes warnings and precautions regarding potential ocular toxicities, serious skin toxicities, hepatotoxicity, rhabdomyolysis, and embryo-fetal toxicity. Clinicians should be aware of these potential risks and monitor patients accordingly.
These positive outcomes are crucial given the challenges associated with LGSOC, a rare and highly recurrent form of ovarian cancer that affects an estimated 6000 to 8000 patients in the US and 80,000 globally. Distinct from high-grade serous ovarian cancer, LGSOC often presents with a more indolent course but is typically resistant to conventional chemotherapy, leading to high recurrence rates and a persistent need for novel therapies. Approximately 70% of LGSOC cases exhibit mutations within the RAS pathway, with about 30% specifically presenting with a KRAS mutation.
The therapeutic rationale behind the avutometinib and defactinib combination targets key oncogenic pathways. Avutometinib functions as a MEK kinase inhibitor while simultaneously blocking the compensatory reactivation of MEK by RAF. Defactinib, on the other hand, inhibits FAK, a protein recognized for its role in mediating drug resistance. This synergistic inhibition aims to overcome resistance mechanisms often observed in RAS/MAPK pathway-driven cancers, leading to the observed clinical responses.
Beyond the FDA accelerated approval for KRAS-mutated recurrent LGSOC, the clinical implications of the RAMP 201 results are further reflected in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, where the combination is currently a Category 2A recommendation for this specific patient subset. Verastem Oncology has indicated plans to submit the RAMP 201 publication to the NCCN to support the potential inclusion of the KRAS wild-type population in these guidelines, which could expand access to this treatment.
Building on the success of RAMP 201, Verastem Oncology is continuing to advance its research in LGSOC with the ongoing international phase 3 RAMP 301 trial (NCT06072781).3 This pivotal trial is designed to further evaluate the avutometinib and defactinib combination in a broader population of patients with recurrent LGSOC, encompassing both KRAS-mutated and KRAS wild-type disease, aiming to solidify its role as a standard of care.