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Purpose  To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors.    Methods  Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre- and post-afatinib tumor biopsies and normal tissue.    Results  A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3–3.3) and 2.7 months (95% CI 0.9–4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2–13.4) and 3.6 months (95% CI 2.3–5.0), p = 0.14) were observed in T790M+ patients compared to T790M- mutations.  Somatic mutations in  TP53 ,  ADAMTS2 ,  CNN2  and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new  EGFR  mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes ( HLA-DRB1 ,  AQP7 ,  FAM198A ,  SEC31A ,  CNTLN , and  ESX1 ) in three afatinib responding patients. No known EGFR-TKI resistant-associated copy number gains were acquired in the post-afatinib samples.    Conclusion  No differences in survival were observed in patients with  EGFR -T790M treated with afatinib compared to those without T790M. Tumors from patients who had progressive disease during afatinib treatment were enriched for mutations in genes involved in Wnt and PI3K-AKT pathways.

plos one

Overall survival in EGFR mutated non-small-cell lung cancer patients treated with afatinib after EGFR TKI and resistant mechanisms upon disease progression