Epidermal Growth Factor Receptor Inhibition in Mutation-Positive Non–Small-Cell Lung Cancer: Is Afatinib Better or Simply Newer?

In the last decade we have witnessed a major evolution in both molecular diagnostics and individualized therapy in the management of advanced non–small-cell lung cancer (NSCLC). The identification of epidermal growth factor receptor (EGFR) mutation and the centrality of EGFR tyrosine kinase inhibitors (TKIs) in patients whose tumors harbor these mutations have irrevocably altered how we view NSCLC. The more recent recognition of echinoderm microtubuleassociated protein-like 4/anaplastic lymphoma kinase and ROS1 translocations as molecular drivers, for which specific treatment exists, has altered our perspective still more. NSCLC is no longer considered a monolithic illness, but it is now readily recognized as a constellation of genotypic entities for which targeted therapy has an increasing role. In this regard, despite clinical, radiographic, and even histologic similarities from tumor to tumor, the genotypic footprint, one believes, should ultimately trump phenotype when it comes to therapeutic decision making. As part of this evolution, we are now observing the second wave of EGFR TKIs. In their seminal article, Sequist et al highlight the results of the LUX-Lung 3 trial, which compared afatinib, a secondgeneration irreversible TKI, to cisplatin and pemetrexed in the firstline treatment of treatment-naive patients with advanced adenocarcinoma of the lung and EGFR mutation. Afatinib is clearly superior with respect to response rate (RR) and progression-free survival (PFS), and these benefits are even more pronounced in the vast majority of patients whose tumors harbor the common activating mutations in exons 19 and 21 (Table 1). In this regard, the LUX-Lung 3 trial joins a number of other trials examining erlotinib and gefitinib in the identical therapeutic setting, each of which has consistently shown a statistically significant and clinically meaningful RR and PFS benefit compared with standard chemotherapy (Table 2). Although many would argue that the results of the LUX-Lung 3 trial were entirely expected and scarcely surprising, this landmark phase III effort comparing afatinib with standard chemotherapy in patients with NSCLC and EGFR mutation is distinguished by a number of factors. It is the largest trial to date in the first-line EGFR mutant setting to be published; it is the first randomized phase III trial to compare a second-generation irreversible EGFR TKI with activity against both human epidermal growth factor receptor 1 (HER1) and HER2 versus platinum-based cytotoxics; it employs a state-of-the-art comparator (pemetrexed and cisplatin); it fully integrates quality-oflife (QoL) evaluation into outcome analysis; it is the first global trial of this sort; and it is explicitly a registration trial. Among those trials that have been confined to patients with actionable EGFR mutations, this trial enrolled nearly double the number of participants, well over 300, making it far more robust and thereby tightening the CIs around the benefits already noted in similar studies. The global nature of this trial and its size make the findings a Table 1. Top-Line Results of the LUX-Lung 3 Trial