Ask AI
Back Back
Avutometinib Defactinib for KRASm LGSOC
Overcoming Clinical Challenges in Integrating Avutometinib/Defactinib Into Routine Practice for KRAS-Mutated Low-Grade Serous Ovarian Carcinoma

Released: February 24, 2026

Rachel Grisham
Rachel Grisham, MD
Kathleen N. Moore
Kathleen N. Moore, MD, MS, FASCO
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • LGSOC tumor tissue–based molecular testing is critical for patient selection for avutometinib/defactinib; current circulating tumor DNA detection in liquid biopsy is insufficient.
  • Avutometinib/defactinib is associated with a median duration of response of 31 months in patients with LGSOC.
  • Key avutometinib/defactinib associated adverse events include increased creatine phosphokinase and acneiform rash.

Low-grade serous ovarian carcinoma (LGSOC) is a biologically distinct malignancy with unique molecular drivers and clinical behavior. The treatment landscape is rapidly evolving, with targeted therapies reshaping expectations for durable disease control. As the recently approved therapy avutometinib/defactinib, a dual RAF/MEK clamp and FAK inhibitor, is integrated into care for patients with KRAS-mutated LGSOC, several important clinical and practical challenges must be addressed to ensure its optimal use in routine practice.

Biomarker-Driven Patient Selection and Testing Gaps 

Kathleen N. Moore, MD, MS, FASCO:
Optimal use of this combined therapy requires accurate and consistent identification of patients whose tumors harbor KRAS mutations. In my practice, comprehensive tumor-based molecular profiling occurs early in the disease course and is essential for understanding tumor biology and informing treatment sequencing. Because avutometinib/defactinib is indicated specifically for patients with KRAS-mutant LGSOC, incomplete or delayed testing directly limits patient access. 

Rachel Grisham, MD:
The method of testing is just as important as what is being tested for. Since LGSOC is a poor shedder tumor, somatic testing performed only on circulating tumor DNA from a liquid biopsy may miss actionable genomic alterations. For any targeted approach, I strongly advocate for tumor tissue–based testing to ensure that patients who could benefit are not excluded.

Sequencing in an Expanding Targeted Therapy Landscape 

Kathleen N. Moore, MD, MS, FASCO:
Fortunately for our patients with LGSOC, many treatment options are currently available or under investigation, including endocrine-based strategies, MEK inhibitors, CDK4/6 inhibitors, antibody–drug conjugates, and combination approaches. However, the optimal sequencing strategy is not yet clear. Should avutometinib/defactinib be used early in the course of treatment? Should it be combined with endocrine therapy? Should it be reserved for the setting of resistance to previous therapy? Until comparative data can address these questions, healthcare professionals will have to make decisions without clear evidence-based guidance. 

Rachel Grisham, MD:
From my perspective, sequencing is especially important because many new therapies in LGSOC can produce lasting durable responses, as demonstrated in the phase II ENGOT-ov60/GOG-3052/RAMP 201 trial of avutometinib with or without defactinib, where the median duration of response among patients receiving the combination was more than 31 months. This, of course, is wonderful for our patients, but it also means resistance biology and cross-resistance patterns need to be understood. For avutometinib/defactinib to be fully integrated into routine practice, it will be essential to increase our understanding of how it performs after prior specific targeted therapies and how to transition patients between agents with different mechanisms of action.

Long-term Tolerability and Operational Complexity 

Kathleen N. Moore, MD, MS, FASCO:
LGSOC is often managed as a chronic disease, so long-term tolerability matters. Structured toxicity monitoring and the use of well-developed management algorithms implemented in clinical studies like the phase II/III GOG281 trials will be critical. However, once avutometinib/defactinib is more broadly integrated into practice, this type of “cookbook” approach must be effectively translated. Class-specific toxicities, like increased creatine phosphokinase and acneiform rash, require proactive monitoring and multidisciplinary support, and if not managed carefully, these adverse effects can create a barrier to long-term adherence. 

Rachel Grisham, MD:
I completely agree. We have learned that proactive toxicity mitigation makes a big difference for patients taking MEK inhibitors. Patient education, close toxicity monitoring, and early intervention are essential, particularly when patients remain on therapy for years. If avutometinib/defactinib is to deliver durable benefit in the real world, we need systems in place to support adherence, manage toxicities, and preserve quality of life.

Your Thoughts
Do you have any experience with prescribing avutometinib/defactinib for patients with KRAS-mutated LGSOC? Tell us about your experiences and what you have learned, or ask us your questions about this therapy and the management of these patients. We would love to hear from you!

Continue

Poll

1.

How often do you order or confirm braid molecular testing for actionable biomarkers in your patients with LGSOC?

Submit