RAF1 alterations are rare in metastatic colorectal cancer, occurring in approximately 0.5% of cases, and there are no established treatment guidelines for these patients. The biology of RAF1-driven tumors and optimal therapeutic strategies remain areas of active investigation. When rare drivers like RAF1 mutations are identified, individualized approaches are often considered, particularly when standard options are limited or contraindicated.
The report describes a patient with metastatic colorectal cancer harboring a RAF1 S257L mutation and RAS wild-type status. The patient also had concurrent type 1 Gaucher disease. Baseline cytopenias related to the Gaucher disease and overall condition precluded standard cytotoxic chemotherapy and enrollment in clinical trials, constraining conventional treatment avenues.
Prior to the individualized approach, the patient received sequential standard agents used in mCRC: fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. The irinotecan-containing regimen had also been administered with the anti-EGFR antibody panitumumab. Treatment courses were complicated by recurrent neutropenic sepsis, which further limited tolerability and therapeutic options.
In the context of a RAF1 S257L driver and limited systemic options, the treating team pursued an off-label targeted strategy aimed at the RAF–MEK–ERK axis. They combined avutometinib, described as a RAF/MEK clamp inhibitor, with defactinib (a FAK inhibitor) and the anti-EGFR antibody cetuximab. The rationale, as presented in the case, was to target the RAF-driven MAPK pathway while maintaining EGFR blockade in an RAS wild-type tumor, translating molecular tumor board recommendations into an individualized regimen.
After initiation of the off-label combination (avutometinib + defactinib with cetuximab), the patient experienced a radiographic response and a decline in tumor biomarker levels. Hematologic recovery was observed, allowing improvement in clinical status: the patient's Eastern Cooperative Oncology Group (ECOG) performance status improved from 3 to 0. The clinical benefit from this regimen lasted approximately six months according to the report.
At the time of progression on the individualized regimen, circulating tumor DNA (ctDNA) analysis was performed. ctDNA revealed persistence of the RAF1 S257L mutation at high allele fraction and showed RAF1 amplification. In addition, newly acquired alterations were detected: EGFR ectodomain mutations, KRAS alterations, and a MAP2K1 alteration. This constellation of findings constituted a polyclonal pattern of convergent reactivation of the MAPK/EGFR signaling axis and explained the acquired resistance to the RAF/MEK clamp approach plus EGFR blockade.
This case illustrates several clinical points: when canonical systemic therapies are contraindicated or not tolerated, a molecular tumor board can translate a rare driver alteration into a rational, individualized treatment strategy. Off-label targeted combinations may yield meaningful clinical and radiographic responses and permit recovery of performance status in selected patients. Serial liquid biopsy (ctDNA) provided actionable insight at progression by identifying multiple, convergent resistance mechanisms that reactivated MAPK/EGFR signaling, informing considerations for subsequent management or trial selection.
RAF1-altered mCRC is uncommon and lacks standardized treatment guidance. In this reported patient with RAF1 S257L mutation and concurrent Gaucher disease, an off-label regimen including avutometinib plus cetuximab (with defactinib) produced a radiographic and clinical response with hematologic recovery and ECOG improvement lasting about six months. ctDNA at progression demonstrated persistence and amplification of RAF1 alongside newly acquired EGFR, KRAS, and MAP2K1 alterations, reflecting polyclonal MAPK/EGFR reactivation as the mechanism of resistance. The case underscores the value of molecular tumor boards in devising individualized regimens for rare drivers and the utility of serial liquid biopsy to define resistance biology and guide next steps.