Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum-doublet chemotherapy. After disease progression, the patient was administered first generation EGFR-TKI gefitinib based on next generation sequencing results. After five months, a second biopsy was performed and both the tumor and plasma samples indicated an acquired EGFR exon 20 T790M mutation. The patient was subsequently administered AZD9291, which resulted in disease control for a time. Our results indicate that a TP53 exon 8 mutation might act as a negative predictive biomarker for third generation EGFR-TKIs.