Clinical features and outcomes of unresectable locally advanced non-small cell lung cancer with uncommon EGFR Mutations: A retrospective multi-center Chinese study

Abstract ntroduction: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations forms a distinct subgroup. The optimal management for uncommon EGFR mutant locally advanced NSCLC remains uncertain. This study aims to investigate the clinical features and outcomes. Methods: A multi-center retrospective study was conducted to review 511 patients with EGFR mutant unresectable stage III NSCLC between 2012 and 2018 from 12 Chinese institutions. The study analyzed the characteristics, prognostic factors, and treatment outcomes for these patients with common and uncommon mutation (excluding 19del or 21L858R). The patients were divided into three groups based on their primary treatment: chemoradiation (CRT), EGFR-tyrosine kinase inhibitors (EGFR-TKIs), and radiation therapy (RT) with EGFR-TKIs. The results Of 49 (9.6%) patients had uncommon mutation, including single exon 18 G719X, exon 20 insertion, exon 20 S768I, T790M, and exon 21 L861Q, present in 22.4%, 18.4%, 8.2%, 8.2%, and 4.1% of patients, respectively. Compound mutations were found in 34.7% of patients. There was a significant difference in PFS based on EGFR mutation status (median 11.9 vs. 17.5 months, P = 0.005). However, no difference was found in OS (P = 0.143). The median PFS for the uncommon mutation group was 11.9, 5.0, and 14.8 months for CRT, EGFR-TKI, and RT+TKIs, respectively (P=0.027). The median OS for the same groups was 43.6, 30.9, and NR months (P=0.179). Compared to EGFR-TKIs, CRT and RT+TKIs significantly improved PFS (P= 0.022, 0.042), and showed a trend towards superior OS compared to upfront TKIs (P= 0.487, 0.065). Among common mutations, RT+EGFR-TKIs achieved the longest PFS and OS compared to the CRT or EGFR-TKIs group. Conclusions: This study provides a systematic and first summary of the clinical features and outcomes of patients with unresectable local advanced NSCLC and EGFR uncommon mutations. The results suggest that RT combined with next-generation EGFR-TKIs may be a promising treatment option. It is recommended that EGFR-TKIs not be used as the primary treatment for patients with uncommon EGFR mutations.