Case report: First report of metastatic esophageal squamous cell carcinoma with EGFR p.S768I mutation: remarkable response to third-generation EGFR-TKI.

We present a 59-year-old male with metastatic esophageal squamous cell carcinoma (ESCC) harboring an uncommon epidermal growth factor receptor (EGFR) exon 20 p.S768I mutation identified through liquid biopsy. Following progression on conventional therapies, the patient received the third-generation EGFR tyrosine kinase inhibitor (TKI), Firmonertinib. This treatment resulted in near-complete radiographic remission of primary esophageal lesions, mediastinal lymphadenopathy, pulmonary nodules, cerebral and hepatic metastases within six weeks, accompanied by rapid clinical improvement. This exceptional response underscores the clinical relevance of comprehensive molecular profiling in treatment-refractory ESCC and provides preliminary evidence supporting the therapeutic potential of EGFR-TKIs against rare EGFR mutations in advanced ESCC. This represents the first globally reported case of an ESCC patient with the rare EGFR p.S768I mutation who was successfully treated and achieved 4 months of near-complete response. Further validation in larger cohorts is needed to establish the efficacy of EGFR-TKIs in ESCC patients with rare EGFR mutations.