RAF/MEK clamp inhibition with avutometinib and cetuximab in RAF1 S257L-mutated, anti-EGFR-refractory metastatic colorectal cancer in Gaucher's disease.

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.