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The use of EGFR TKIs in patients harboring classical EGFR mutations results in response rates (ORR), median progression-free survival (PFS), and overall survival in the order of 70 %, 12 months, and 2 years, respectively. First-line treatment is preferred as ORR, PFS, and quality of life are improved compared to chemotherapy. Gefitinib and erlotinib are referred to as first-generation EGFR TKIs. The second-generation TKIs afatinib and dacomitinib exhibit irreversible binding to ATP and inhibit multiple receptors of the ErbB/HER receptor family. Studies evaluating their potential superiority over first-generation TKIs are underway. All patients eventually develop resistance. A minority are primary resistant, i.e., not responding and progressing within 3 months. Possible mechanisms include resistance mutations (e.g., exon 20 insertions or T790M mutations), coexisting genetic alterations (e.g., KRAS mutations, MET amplification), or germline alteration of proapoptotic proteins. Secondary resistance is mediated by T790M mutation in 50–60 % of cases. Further mechanisms are alternative pathway activation and kinase switching or histologic transformation. New treatment options in acquired resistance are rapidly evolving. However, premature termination of EGFR TKI should be avoided as it may lead to “disease flare.” Early clinical phase I/II studies with third-generation EGFR TKIs, which selectively bind sensitizing as well as T790M resistance mutations, showed encouraging response rates of 28–64 %. Adjuvant EGFR TKI therapy may lead to increased disease-free survival, but results of further studies need to be awaited.