Case Report: Treatment of an unresectable mucoepidermoid carcinoma with osimertinib.

BACKGROUND: Mucoepidermoid carcinoma (MEC) is a common salivary gland malignancy, yet no established systemic standard exists for unresectable disease, and response rates to conventional chemotherapy are low. Most MECs are driven by the CRTC1-MAML2 fusion, which induces amphiregulin (AREG) overexpression and an autocrine AREG-EGFR loop that hyperactivates EGFR independently of activating kinase-domain mutations, providing a rationale for tumor-agnostic EGFR blockade. CASE PRESENTATION: A 72-year-old man presented with a slowly enlarging right submandibular mass, diagnosed as low-grade MEC of the floor of the mouth. The tumor was considered unresectable owing to anticipated functional and cosmetic morbidity, and radiotherapy was deferred because of extensive mandibular involvement. Comprehensive genomic profiling identified no high-tier actionable alteration and did not interrogate gene fusions. On the basis of the AREG-EGFR autocrine axis described in MEC, osimertinib 80 mg once daily was initiated. The patient achieved a 33% reduction in the longest tumor diameter, meeting RECIST 1.1 criteria for a partial response, with symptomatic improvement and only grade 1 toxicity. Osimertinib was maintained at 80 mg once daily throughout, with approximately seven and a half months of disease control before non-target progression prompted palliative radiotherapy, for a total of 13 months of continuous treatment on this tumor-agnostic strategy. The patient remained clinically stable at last follow-up. CONCLUSION: To our knowledge, this is the first reported partial response to a third-generation EGFR-TKI in oral MEC. The case supports prospective evaluation of fusion-informed, EGFR-directed therapy in this rare malignancy.