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Epidermal growth factor receptor ( EGFR )  19del  and  L858R  mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to  EGFR  tyrosine kinase inhibitors (TKIs), whereas  20ins  and  T790M  mutations confer drug-resistance to  EGFR -TKIs. The role of the remaining uncommon  EGFR  mutations remains elusive.    Methods  We retrospectively screened a group of NSCLC patients with uncommon  EGFR  mutations other than  20ins  and  T790M . The mutation patterns, use of different generations of  EGFR -TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single  19del  or  L858R  were included for comparison.    Results  A total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations ( EGFR cm, n = 97), uncommon mutation plus common mutations ( EGFR um+ EGFR cm, n = 52), complex uncommon mutations (complex  EGFR um, n = 22), and single uncommon mutations (single  EGFR um, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in  EGFR cm (ORR: 81.0%  vs . 75.0%, p = 0.773; mPFS: 19.1  vs . 12.0m, p = 0.036),  EGFR um+ EGFR cm (ORR: 100%  vs . 54.5%, p = 0.017; mPFS: NE  vs . 13.6m, p = 0.032), and single  EGFR um (ORR: 78.6%  vs . 21.4%, p = 0.007; mPFS: 10.1  vs . 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046).  TP53  mutation was the most common co-alteration and showed significantly shorter mPFS than  TP53  wild-type patients (7.0  vs . 31.1m, p < 0.001). Multivariate analysis revealed that concurrent  19del/L858R  and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively.    Conclusions  Uncommon  EGFR  mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to  EGFR -TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon  EGFR  mutations. Concurrent  19del/L858R  and tumor-suppressor gene alterations, especially  TP53 , can be established as prognostic biomarkers.

frontiers in oncology

The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations—The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations