RAF/MEK clamp inhibition with avutometinib and cetuximab in RAF1 S257L-mutated, anti-EGFR-refractory metastatic colorectal cancer in Gaucher's disease
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Updated: Aug 21, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Ashley Rose1,2, Alix Rosenberg3, Udhayvir Singh Grewal4
1Lenox Hill Hospital, New York, NY 10075, United States.
Abstract:
RAF1 alterations are rare in metastatic colorectal cancer (mCRC), occurring in roughly 0.5% of cases, and lack established treatment guidance. We present a patient with RAF1 S257L-mutated, RAS wild-type mCRC and concurrent type 1 Gaucher disease, whose baseline cytopenias precluded standard chemotherapy and clinical-trial enrollment. After progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens (the latter with the anti-EGFR antibody panitumumab) complicated by recurrent neutropenic sepsis, he received off-label avutometinib and defactinib (an oral RAF/MEK clamp inhibitor plus a FAK inhibitor) combined with cetuximab. He achieved a radiographic response, biomarker decline, hematologic recovery, and improvement in ECOG performance status from 3 to 0, with benefit lasting approximately 6 months. At progression, circulating tumor DNA revealed persistence of RAF1 S257L at high allele fraction with RAF1 amplification, together with newly acquired EGFR ectodomain mutations, KRAS alterations, and a MAP2K1 alteration-a polyclonal pattern of convergent MAPK/EGFR reactivation. This case illustrates how a molecular tumor board can translate a rare driver into a rational, individualized regimen and how serial liquid biopsy informs resistance and next steps.
Insights
Targeting rare RAF1 mutations in metastatic colorectal cancer (mCRC) is challenging. This case study shows a patient with RAF1-mutated mCRC achieved significant response with a combination therapy, highlighting personalized treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- RAF1 alterations are uncommon in metastatic colorectal cancer (mCRC), representing about 0.5% of cases.
- Limited treatment options and established guidance exist for patients with RAF1-mutated mCRC.
- Concurrent conditions, such as Gaucher disease, can further complicate treatment by causing cytopenias, precluding standard chemotherapy.
Purpose of the Study:
- To present a case of a patient with RAF1 S257L-mutated, RAS wild-type mCRC and Gaucher disease.
- To describe the use of an individualized treatment regimen involving targeted therapy and immunotherapy in a patient with refractory mCRC.
- To illustrate the utility of molecular tumor boards and serial liquid biopsies in guiding treatment and understanding resistance mechanisms.
Main Methods:
- A patient with RAF1 S257L-mutated, RAS wild-type mCRC and type 1 Gaucher disease was treated.
- The patient received off-label avutometinib (RAF/MEK clamp inhibitor) and defactinib (FAK inhibitor) in combination with cetuximab after progression on standard regimens.
- Serial liquid biopsies were performed to monitor tumor evolution and identify resistance mechanisms.
Main Results:
- The patient achieved a radiographic response, biomarker decline, hematologic recovery, and improved ECOG performance status from 3 to 0.
- The treatment provided clinical benefit for approximately 6 months.
- At progression, liquid biopsy revealed RAF1 amplification and newly acquired mutations in EGFR, KRAS, and MAP2K1, indicating polyclonal MAPK/EGFR reactivation.
Conclusions:
- Targeted therapy combined with immunotherapy can be an effective strategy for patients with rare RAF1-mutated mCRC, especially when standard treatments are not feasible.
- Molecular tumor board consultation is crucial for developing rational, individualized treatment plans for rare genetic drivers.
- Serial liquid biopsies are valuable tools for monitoring treatment response, detecting resistance mechanisms, and guiding subsequent therapeutic decisions.
