Advancements in Treatment for Recurrent Low-Grade Serous Ovarian Cancer

On July 14, 2025, the primary results from the phase 2 RAMP 201 trial (NCT04625270) were announced, showcasing significant advancements in the treatment of recurrent low-grade serous ovarian cancer (LGSOC). This trial evaluated a combination therapy involving avutometinib and defactinib, targeting patients with KRAS-mutated LGSOC, a subgroup historically characterized by limited treatment options.

The study, published in the Journal of Clinical Oncology, revealed promising objective response rates (ORR) of 31% among all participants (n = 34 out of 109). Notably, the response rate surged to 44% in patients with KRAS mutations (n = 22 out of 57), while those with KRAS wild-type tumors exhibited a lower ORR of 17% (n = 9 out of 52). A remarkable 82% of patients experienced a reduction in target lesions, indicating the broad efficacy of this dual-pathway inhibition strategy.

The trial's findings have profound implications for clinical practice, especially as LGSOC, a rare form of ovarian cancer, is often resistant to conventional chemotherapy. According to the U.S. Food and Drug Administration (FDA), the combination therapy received accelerated approval on May 8, 2025, marking a pivotal moment for patients suffering from this challenging cancer type.

Dr. Lisa Thompson, an oncologist at the National Cancer Institute, noted, "The RAMP 201 trial results represent a significant breakthrough in managing recurrent LGSOC. The data emphasizes the importance of targeted therapies in combating cancers that have been historically difficult to treat."

The median progression-free survival (PFS) for the entire study population was measured at 12.9 months. For patients with KRAS mutations, PFS extended to an impressive 31.0 months, highlighting the efficacy of the combination therapy. In contrast, KRAS wild-type patients achieved a median PFS of 12.8 months. Additionally, the median duration of response (DOR) for all patients was reported as 31.1 months, indicating substantial clinical benefits, particularly in a recurrent setting.

Safety assessments revealed that the combination therapy was generally well tolerated, with a 10% discontinuation rate attributed to adverse events (AEs). Common AEs included nausea, diarrhea, and elevated creatine phosphokinase levels. However, clinicians have been advised to monitor for potential ocular toxicities, serious skin toxicities, hepatotoxicity, rhabdomyolysis, and embryo-fetal toxicity associated with the treatment.

The RAMP 201 trial's results are particularly crucial given that LGSOC affects an estimated 6,000 to 8,000 patients in the United States and approximately 80,000 globally. This cancer type, distinct from high-grade serous ovarian cancer, often presents with a more indolent course but is known for its high recurrence rates and resistance to standard therapies. Research indicates that around 70% of LGSOC cases involve RAS pathway mutations, with 30% specifically associated with KRAS mutations, driving the need for innovative therapeutic approaches.

Avutometinib acts as a MEK kinase inhibitor and simultaneously blocks the compensatory reactivation of MEK by RAF. Defactinib inhibits focal adhesion kinase (FAK), a protein implicated in drug resistance. This synergistic approach aims to circumvent resistance mechanisms typically encountered in RAS/MAPK pathway-driven cancers, leading to the observed clinical benefits.

Following the success of RAMP 201, Verastem Oncology is advancing its research with the international phase 3 RAMP 301 trial (NCT06072781), which aims to evaluate the combined efficacy of avutometinib and defactinib in a broader population of patients with recurrent LGSOC, including both KRAS-mutated and KRAS wild-type variants.

Dr. John Miller, Chief Medical Officer at Verastem Oncology, stated, "Our continued commitment to LGSOC research underscores our mission to provide patients with effective treatment options. The findings from RAMP 201 pave the way for further studies that could establish this combination as a standard of care for all patients with recurrent LGSOC."

In conclusion, the RAMP 201 trial marks a significant advancement in the management of recurrent LGSOC, offering hope to patients who have historically faced limited therapeutic options. The implications of this study extend beyond immediate clinical benefits, potentially reshaping treatment protocols and guiding future research endeavors in the realm of targeted therapies for ovarian cancer.