Treatment of recurrent low grade serous ovarian cancer: MEK inhibition and the RAMP 201 trial

Low-grade serous ovarian cancer (LGSOC) has long been the “orphan cousin” of high-grade serous ovarian cancer (HGSOC)—rarer, genomically distinct, and frustratingly chemo-resistant, yet often affecting younger patients who live for many years with recurrent disease (1). Despite the advanced stage at diagnosis, accounting for approximately 2–9% of ovarian cancers, LGSOC typically exhibits an indolent disease course with slower progression and a longer median overall survival (approximately 92 months) compared to patients with HGSOC (approximately 72 months) (2).

Although initial management of high-grade and low-grade serous ovarian carcinoma is broadly similar, these entities differ markedly in their molecular, clinical, and pathologic characteristics. Unlike HGSOC, which is characterized by ubiquitous TP53 mutations, LGSOC more commonly exhibits activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) (5%) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (19–55%) (1). Activating KRAS/BRAF mutations lead to constitutive activation of MAPK, which, in turn, increases the activity of protein kinases and transcription factors, ultimately contributing to tumour progression. Additionally, LGSOC demonstrates a higher prevalence of oestrogen receptor and progesterone receptor expression, suggesting greater hormonal responsiveness than HGSOC (3). Despite these biologic differences, primary treatment remains maximal cytoreductive surgery followed by systemic treatment, most commonly with platinum and taxane-based therapy. Unfortunately, however, LGSOC is relatively chemo-resistant to first-line treatment (4,5). Residual disease following surgical cytoreduction is a decisive prognostic factor, and patients with suboptimal debulking have significantly lower response rates to systemic chemotherapy compared with those with HGSOC (6).

Therapeutic options for recurrent disease are limited. Given the typically indolent behaviour, secondary and even tertiary cytoreductive surgery may be feasible and beneficial in selected patients (7). Increased hormone receptivity with 80% and 54% of LGSOC showing oestrogen and progesterone receptor positivity respectively also provides a rationale for endocrine therapy agents such as letrozole or tamoxifen commonly used in tumours with high oestrogen receptor expression (3,8,9). In patients with BRAF glutamic acid for valine mutation in codon 600 (V600E), combined BRAF and Mitogen-activated protein kinase kinase (MEK) inhibition has emerged as a potential targeted strategy (10).

Over the past decade, MEK (MAPK/ERK kinase) inhibitors have been evaluated as a therapeutic approach in recurrent LGSOC, given the high prevalence of MAPK pathway activation. The Gynecology Oncology Group (GOG) 239 phase II trial was the first to examine MEK inhibition with selumetinib in patients with recurrent LGSOC and reported an objective response rate of 15%, with 65% of patients achieving stable disease, and a median progression-free survival of 11 months (11). Notably, no clear correlation between KRAS/BRAF mutational status and treatment response was observed.

Subsequently, three phase II/III trials further assessed MEK inhibition. GOG 281 examined trametinib versus the physician’s choice of standard-of-care chemotherapy for recurrent LGSOC. It demonstrated a median progression-free survival of 13 months in the trametinib arm versus 7.2 months with standard therapy, with improvements in both progression-free survival and objective response rate, irrespective of MAPK mutational status (12). By contrast, MILO/ENGOT-ov11, evaluating binimetinib versus physician’s-choice chemotherapy (PCC), was stopped early for futility, although post-hoc analysis suggested enhanced benefit in KRAS-mutated tumours (13). Differences in trial design may partially explain the disparate results between GOG 281 and MILO. Specifically, the PCC arm of MILO demonstrated better-than-anticipated outcomes, possibly attributable to differences in inclusion criteria, including the restriction to fewer than three prior lines of therapy in MILO (versus no such restriction in GOG 281) and the inclusion of endocrine therapy in the control arm of GOG 281. Together, these trials confirmed MEK inhibition as an active strategy but left unresolved questions about durability, tolerability, and optimal molecular selection.

Most recently, the phase II ENGOT-OV60/GOG-3052/RAMP 201 trial evaluated avutometinib with or without defactinib in patients with recurrent LGSOC (13). Unlike earlier trials testing MEK inhibition alone, avutometinib functions as a dual RAF/MEK inhibitor (“RAF/MEK clamp”). MEK inhibition alone can trigger compensatory reactivation of MEK via upstream RAF signalling; avutometinib is designed to suppress both nodes of this pathway. Defactinib, a focal adhesion kinase (FAK) inhibitor, is added to counteract further resistance mechanisms mediated through FAK signalling, another pathway implicated in escape from MAPK pathway blockade.

In the initial phase of this trial, patients were randomly assigned either single-agent avutometinib 4.0 mg orally twice a week or avutometinib 3.2 mg twice a week in combination with defactinib 200 mg twice daily, with both regimens administered on a 4-week cycle (3 weeks on treatment, 1 week off). The combination regimen of avutometinib plus defactinib was selected as the go-forward regimen based on an interim objective response rate of 28% compared with 7% for avutometinib monotherapy. In total, 115 patients received the combination therapy and 70 received avutometinib alone.

In the final analysis, the objective response rate in the combination arm was 31% (44% in KRAS-mutated vs. 17% in KRAS-wild-type tumours), compared with 17% in the monotherapy arm (23% in KRAS-mutated vs. 13% in KRAS-wild-type tumours). The median progression-free survival for the combination arm was 12.9 months [95% confidence interval (CI): 10.9–20.2], including 22.0 months (95% CI: 11.1–36.6) in KRAS-mutated tumours and 12.8 months (95% CI: 7.4–18.4) in KRAS-wild-type tumours. The 6- and 12-month progression-free survival rates were 79% (95% CI: 70–86%) and 58% (95% CI: 47–68%), respectively.

Like GOG 281, most patients enrolled in GOG 3052 had received three or more prior lines of systemic treatment. However, prior treatment exposure differed meaningfully from earlier MEK inhibitor trials: more than 20% of patients had received a prior MEK inhibitor, and over 50% had received bevacizumab. Although the study was not powered to evaluate outcomes by prior therapy definitively, these exposures may influence response to subsequent RAF/MEK and FAK inhibition and warrant further investigation.

Overall, the results of GOG 3052 align with those of GOG 281 in supporting the clinical relevance of targeting the MAPK pathway in recurrent LGSOC, while suggesting that FAK coinhibition may further enhance benefit. Significantly, the reduced avutometinib dose used in combination with defactinib was associated with a relatively low treatment discontinuation rate due to adverse events (10%) with the most reported adverse effects being nausea, diarrhea, peripheral edema, and rash. This compares favourably with discontinuation rates reported for trametinib (~40%) and binimetinib (~20%) in prior studies (12,13). This improved tolerability profile is particularly relevant in a disease characterized by chronicity and prolonged treatment courses.

Cross-trial comparisons must be interpreted with caution, particularly in the absence of a standard-of-care control arm within GOG 3052. It also remains uncertain whether the association between KRAS mutations and improved response is unique to the avutometinib-defactinib combination or reflects a broader predictive role of MAPK pathway alterations across MEK-directed strategies. Unlike earlier trials, GOG 3052 prospectively stratified patients by KRAS mutational status. While reductions in target lesions were observed regardless of KRAS status, higher overall response rate and longer progression-free survival were seen in KRAS-mutated tumours. These findings are consistent with prior data suggesting improved chemotherapy response and overall survival among patients with MAPK pathway-mutated LGSOC (14). Based on these results, on May 8, 2025, the Food and Drug Administration (FDA) granted accelerated approval of avutometinib plus defactinib for patients with KRAS-mutated recurrent LGSOC.

Several questions remain about the applicability of this data. First, a randomized comparison of avutometinib plus defactinib against contemporary standards such as trametinib, endocrine therapy, or chemotherapy does not yet exist. That ongoing phase III RAMP 301 (GOG-3097/ENGOT-ov81), randomizes patients with recurrent LGSOC to avutometinib/defactinib versus investigator’s choice (pegylated liposomal doxorubicin, weekly paclitaxel, topotecan, letrozole, or anastrozole), with hierarchical progression-free survival analysis in KRAS-mutant and all-comer cohorts, and hopefully will answer this question (14). Second, how best to sequence therapies is unresolved: should patients with KRAS-mutant disease now receive avutometinib plus defactinib first, reserving trametinib or hormonal combinations for later lines, or vice versa? Moreover, what is the residual benefit of dual RAF/MEK-FAK inhibition after prior MEK inhibitor progression? Third, biomarker refinement beyond KRAS is urgently needed. A broad set of MAPK pathway alterations has been shown to correlate with better outcomes, suggesting that other RAS/RAF/MEK pathway lesions—or even FAK pathway changes—might identify patients likely to benefit from this regimen despite KRAS wildtype status (15). Integration of next-generation sequencing, longitudinal circulating tumour DNA, and functional studies into future trials could help move from “KRAS-mutant vs. wild-type” to a more nuanced, pathway-level driven biomarker framework.

In summary, therapeutic options for recurrent LGSOC remain limited, and the disease’s relative chemoresistance underscores the need for targeted approaches. The GOG 3052/RAMP 201 findings are consistent with pre-clinical data demonstrating enhanced tumour growth inhibition with concurrent RAF/MEK and FAK inhibition, suggesting that this combination represents a promising treatment strategy (16). The ongoing phase III trial will be critical to validating these findings, clarifying the predictive role of MAPK pathway mutations, and defining the comparative efficacy and durability of avutometinib plus defactinib versus standard‑of‑care therapies in this rare but challenging malignancy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-71/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-71/coif). The authors have no conflicts of interest to declare.

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