Afatinib in lung cancer harboring EGFR mutation in the LUX-Lung trials: six plus three is greater than seven?

Non-small cell lung cancer (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) gene, about 90% of which is either small deletion in exon 19 (Del19) or a leucine to an arginine substitution at codon 858 (L858R), is very sensitive to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib (1). Phase III trials comparing these agents with platinum doublet chemotherapy showed significant prolongation of progression free survival (PFS) in favor of EGFR-TKIs (Figure 1A) (2-5). Nonetheless, those tumors inevitably acquire resistance about half of which are due to secondary EGFR mutations resulting in threonine to methionine substitution at codon 790 (T790M) (13). In these clinical trials, patients with acquired resistance to the first-line EGFR-TKI are likely to be treated by platinum doublet as a second-line treatment, while those patients treated initially by platinum doublet therapy are to be treated by EGFR-TKI that works well in this second-line setting. Owing to this “crossover” of treatment, there has been no statistically significant difference in overall survival (OS) of the patients in these trials (2-5) (Figure 1A)