Abstract
In contrast to the established role of epidermal growth factor receptor (EGFR) inhibitors for the first-line treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR blockade and of EGFR molecular testing in the second-line treatment remains less clear. The irreversible pan-ErbB family inhibitor afatinib (Gi(l)otrif®) was recently FDA- and EMA-approved for the second-line treatment of NSCLC with squamous cell histology irrespective of the EGFR mutational status (LUX-Lung 8). Contrariwise, results from the TAILOR and DELTA trials among retrospective biomarker analyses show the predictive value of the EGFR mutational status for efficacy of reversible EGFR inhibitors also as a second-line therapy. This mini review critically summarizes the current role of EGFR-targeting strategies in the second-line treatment of NSCLC with special respect to afatinib in light of emerging T790M-specific EGFR and immune check point inhibitors. The review also emphasizes the urgent need for reliable biomarkers to guide therapeutic decision-making and outlines prospective changes to the second-line landscape with some of the current second-line treatment concepts likely to be moved to the first-line.
Highlights
Over the past decade, various genomic alterations relevant for non-small cell lung cancer (NSCLC) biology (“oncogene addiction”) were discovered and have subsequently changed the treatment paradigm from a histology-oriented to a biomarker-driven approach [reviewed by Thomas et al [1]]
With the advent of innovative treatment concepts as e.g., immune checkpoint blockade or T790M-specific epidermal growth factor receptor (EGFR) inhibition, it is likely that EGFR tyrosine kinase inhibitor (TKI) will be further pushed into the first-line where they already today face ongoing head-to-head comparisons with the EGFR T790M-specific inhibitor osimertinib to identify the most effective upfront treatment option for patients with EGFR-mutant NSCLC (e.g., FLAURA trial: osimertinib versus gefitinib or erlotinib)
This is supported by several first-line phase-III clinical trials, which showed higher response rates (>70%) [5, 43] as if the EGFR TKI was given in the second-line (27–67.4%) even though some of the reported data on response rates have been conflicting [5, 18, 19, 43, 44]
Summary
Various genomic alterations relevant for non-small cell lung cancer (NSCLC) biology (“oncogene addiction”) were discovered and have subsequently changed the treatment paradigm from a histology-oriented to a biomarker-driven approach [reviewed by Thomas et al [1]]. Docetaxel was the gold standard second-line treatment [2] until erlotinib (Tarceva®), a first-generation tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) was FDA-approved in 2004 as maintenance therapy and for second and subsequent line treatment, after failure of chemotherapy in unselected patients [3]. Not less than three EGFR TKIs—erlotinib, gefitinib (Iressa®) and the pan-ErbB family inhibitor afatinib (Giotrif®)—are licensed for the first-line treatment. The relevance of EGFR mutations for the second-line decision-making process remained less clear, and erlotinib (for all NSCLC) as well as afatinib (for squamous cell histology only) have initially been FDA-approved irrespective of EGFR mutational status or other predictive markers [3, 8]. Several recent prospective clinical trials (TAILOR, DELTA) and retrospective biomarker analyses challenge this broad approval and emphasize the need for EGFR mutational re-testing ahead of the second-line therapy if not performed at diagnosis [9, 10]
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