Abstract
Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients’ subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novo EGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40–80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20–70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.
Highlights
Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) identifies a molecularly selected subgroup of patients who benefit from targeted therapies
Three generations of EGFR tyrosine kinase inhibitors (TKIs)—namely gefitinib, erlotinib, afatinib, dacomitinib, osimertinib—demonstrated survival benefit over platinumbased chemotherapy and are world-wide approved in the first-line setting of advanced or metastatic EGFR mutant NSCLC, and a fair number of novel compounds are under investigation to prevent or overcome EGFR TKI resistance
Full-text articles were read, and further selection was made based on their relevance: studies limited to single uncommon mutations, or those not reporting the proportion of compound mutations within the uncommon EGFR definition, were excluded
Summary
Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) identifies a molecularly selected subgroup of patients who benefit from targeted therapies. Evidence on the efficacy of EGFR TKIs in NSCLC patients harboring uncommon EGFR mutations is limited to a few prospective studies with afatinib (LUX-lung 2, 3 and 6) [1], one prospective study with osimertinib (KCSG-LU15–09) [2], and mostly retrospective series and case reports [3,4,5]. Another consistent subclass is represented by compound ( defined as complex or double or multiple) mutations. These data are highly heterogeneous, as the identification of compound mutations is dependent on the molecular testing methods adopted, often not able to properly detect the intratumor clonal heterogeneity
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