Background: Some prospective studies have shown that second-generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second-line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. Methods: Patients with EGFR-mutated advanced-stage NSCLC who received first-line EGFR-TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second-line chemotherapy were enrolled. We compared progression-free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan–Meier and log-rank tests. Results: In total, 209 (54.8%) patients had a negative T790M mutation test and received second-line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. Conclusion: This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.
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