• Eur. J. Cancer · Dec 2020

    Clinical impact of uncommon epidermal growth factor receptor exon 19 insertion-deletion variants on epidermal growth factor receptor-tyrosine kinase inhibitor efficacy in non-small-cell lung cancer.

    • Xingzhou Peng, Xiaoyan Long, Li Liu, Liang Zeng, Haiyan Yang, Wenjuan Jiang, Dehua Liao, Kunyan Li, Jing Wang, Analyn Lizaso, Xinru Mao, Qinqin Xu, Aaron S Mansfield, Nong Yang, and Yongchang Zhang.
    • Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Graduate School, University of South China, Hengyang, Hunan, 421001, China.
    • Eur. J. Cancer. 2020 Dec 1; 141: 199-208.

    AimOur study aimed to evaluate the efficacy and resistance mechanisms of first-line epidermal growth factor receptor (EGFR) inhibitor therapy in patients with advanced non-small-cell lung cancer (NSCLC) harbouring uncommon EGFR exon 19 deletion-insertion (19delins) variants.MethodsTargeted sequencing data of 2467 treatment-naive patients with NSCLC from January 2015 to August 2018 were retrospectively screened for EGFR exon 19 deletion (19del) variants. Clinical outcomes of 93 patients with uncommon EGFR 19delins and 93 patients with common EGFR 19del were selected through propensity score matching at a ratio of 1:1.ResultsWe identified 10 previously unreported EGFR 19delins variants. L747_P753delinsS, L747_A750delinsP and E746_S752delinsV were the most frequent variants, accounting for 33.1% (42/127), 23.6% (30/127) and 12.6% (16/127) of the cases, respectively. Despite similar baseline characteristics, treatment history and response rates, patients with uncommon 19delins had significantly longer median progression-free survival (mPFS) than those with common 19del (19.0 months vs. 13.0 months; p = 0.0016). At progression from first-line EGFR inhibitor therapy, patients with uncommon 19delins and common 19del had similar rates of developing resistance mechanisms including the acquisition of EGFR T790M (45.8% vs 57.8%), small-cell transformation (3.4% vs 3.6%) and MET amplification (5.1% vs 4.8%). For patients whose tumours acquired T790M and who received second-line osimertinib, the mPFS was significantly shorter for patients with uncommon 19delins (n = 27) than those with common 19del (n = 47, 5.0 months vs. 12.0 months; p < 0.0001).ConclusionOur results suggest that patients with uncommon EGFR 19delins have improved clinical outcomes with first-generation EGFR inhibitor treatment, but inferior outcomes upon the development of T790M resistance mutations.Copyright © 2020 Elsevier Ltd. All rights reserved.

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