Clinical Activity of Afatinib in Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Spanish Retrospective Multicenter Study

We report the results of the molecular and clinical characterization and the efficacy of afatinib in a cohort of patients with advanced nonesmall-cell lung cancer (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) mutations in Spanish clinical practice. In patients with uncommon EGFR-mutant NSCLC, the most common mutations occurred on exon 18 in amino acid G719, either alone or in combination with another mutation; other uncommon mutations were detected in exons 18, 19, 20, 21, and 22. In clinical practice, afatinib was active in patients with uncommon EGFR-mutant NSCLC, particularly in patients with complex and single mutations; however, in patients with EGFR ins20 (EGFR exon 20 insertions), treatment with afatinib provided a lower clinical benefit, indicating that further treatment strategies are needed for patients with this type of uncommon EGFR mutation. Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations (u-EGFRm) are a heterogeneous group of molecular alterations and have also been reported as comutations with other EGFR mutations (complex mutations) in nonesmall-cell lung cancer (NSCLC). Afatinib has shown activity against some u-EGFRm, and we examined its efficacy in Spanish clinical practice. Patients and Methods: Data of 67 patients with advanced NSCLC with u-EGFRm treated with afatinib between 2012 and 2017 at 23 Spanish institutions were reviewed. u-EGFRm were analyzed as complex mutations (group A), EGFR exon 20 insertions (ins20; group B), or single mutations (group C). Efficacy was evaluated in terms of overall survival (OS) and tumor response. Results: Group A complex u-EGFRm consisted of double mutations of G719X+E709F, G719X+S768I, G719X+L861Q, L858R+T790M, L858R+S768I, L858R+S765I, del19+S768I, del19+L747S, or R776C+L861Q. No differences in clinical characteristics were found between groups A (n= 20), B (n= 23), and C (n= 24). Afatinib was administered as first-line therapy in 80% of patients. Median time of receipt of therapy was 4.2 months (range, 2.0-12.9 months). Median OS for the entire cohort was 19.9 months (95% confidence interval, 9.7, 30.1). Hazard ratios for OS were 0.26 (95% confidence interval, 0.10, 0.71; P=.008) and 0.40 (95% confidence interval, 0.17, 0.95; P=.037) for groups A and C compared to B, respectively. Response was significantly higher in groups A (70%) and C (54%) compared to B (13%; pairwise comparison P