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Abstract Epidermal growth factor receptor (EGFR)‐mutated squamous cell carcinoma (SCC) is less common than adenocarcinoma. The third‐generation EGFR‐tyrosine kinase inhibitor, osimertinib, is effective in EGFR‐mutated lung adenocarcinoma, but its efficacy in EGFR‐mutated lung SCC is unclear. The patient was an 83‐year‐old male. He was diagnosed with SCC of the lung, and molecular analysis revealed that the tumor was positive for EGFR exon19 deletion. He was treated with osimertinib 80 mg/day. No adverse events were observed, but after 18 days of therapy, he complained of dyspnea, and a computed tomography scan showed enlarged lung cancer. The case was categorized as a progressive disease. The patient died 3 weeks later. The autopsy findings confirmed the diagnosis of lung SCC, with morphology and immunohistochemical staining identical to the tumor obtained by bronchoscopy. Next‐generation sequencing showed the presence of TP53 R158L, CDK6, and KRAS amplifications. The current case report shows that next‐generation sequencing can explain why osimertinib is ineffective in EGFR‐mutated SCC.