Research in context
Evidence before this study
We searched the literature published from Jan 1, 2009, to Jan 5, 2016, using PubMed and of trials presented as abstracts at major oncology meetings (annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the World Conference of Lung Cancer). Using the search terms “NSCLC” and “randomised”, and “erlotinib” or “gefitinib”, or “afatinib”, we reviewed manuscripts and abstracts reporting phase 2 and 3 trials investigating EGFR-targeted drugs in patients with EGFR mutation-positive NSCLC in a first-line setting. Based on this review, we confirmed that to the best of our knowledge, apart from LUX-Lung 7, only one other first-line head-to-head trial has been completed to date (gefitinib vs erlotinib in Chinese patients; completed in 2014, NCT01024413). Therefore, at the onset of LUX-Lung 7, there were no prospective data to guide the selection of the most appropriate tyrosine kinase inhibitor in patients with EGFR mutation-positive NSCLC. A search of ClinicalTrials.gov showed that several randomised trials comparing EGFR tyrosine kinase inhibitors are ongoing, including: a phase 2 trial comparing erlotinib and gefitinib (NCT01955421); a phase 3 trial comparing dacomitinib (a second-generation tyrosine kinase inhibitor) versus gefitinib (NCT01774721); and two phase 3 trials comparing the third-generation tyrosine kinase inhibitors, osimertinib and ASP8273, versus gefitinib or erlotinib (NCT02296125 and NCT02588261, respectively).
Added value of this study
To our knowledge, this study is the first randomised multicentre trial comparing two EGFR-targeting drugs in a setting in which both are approved, providing efficacy and safety evidence in a head-to-head comparison. This study showed that afatinib has improved efficacy compared with gefitinib over a range of clinically relevant endpoints including progression-free survival, time-to-treatment failure, and the proportion of patients achieving an objective response. The improvement in efficacy was noted both in patients with exon 19 deletion and Leu858Arg mutations. The adverse event profile was predictable and manageable; the discontinuation rate due to treatment-related adverse events was the same as with gefitinib.
Implications of all the available evidence
LUX-Lung 7 indicates that irreversible ErbB blockade with afatinib could be more effective than reversible EGFR inhibition in the treatment of EGFR mutation-positive NSCLC. The results suggest that first-generation and second-generation tyrosine kinase inhibitors are not interchangeable and imply that the broader and irreversible mechanism of action of afatinib compared with gefitinib could have led to better tumour control.