Frontline Afatinib in EGFR-Mutant NSCLC

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LUX-Lung-3 and LUX-Lung-6 are the two randomized studies of patients with EGFR mutation-positive non-small cell lung cancer that examined the irreversible EGFR inhibitor afatinib in comparison with chemotherapy. According to Lecia Sequist, MD, MPH, unlike previous trials conducted with the TKIs gefitinib or erlotinib, which showed only progression-free survival (PFS) and superior overall response rates (ORR), trials exploring afatinib also demonstrated an overall survival (OS) advantage. The platinum doublet chemotherapy regimen administered in the comparator arm was slightly different between the two trials: LUX-Lung-3 used cisplatin/pemetrexed and LUX-Lung-6 used cisplatin/gemcitabine. In both trials, patients with the exon 19 deletion had a substantial survival advantage with afatinib, with approximately a year median survival difference.

This substantial OS benefit was not seen in patients with the other common EGFR mutation subtype, L858R (exon 21). While these patients had PFS and ORR benefits, they did not have a survival advantage. Corey J. Langer, MD, stresses that exon 19 deletions and L858R alterations (exon 21) are clearly two distinct populations. Moving forward, trials need to be designed to examine responses in these and additional less common mutations. Langer also describes how the LUX-Lung trials were unique in that they actually included analyses of the less common mutations. Unfortunately, none appeared to reap the benefits of afatinib.

Finally, Langer describes his approach to patients with varying types of mutations. In general, despite a demonstrated of a survival benefit, patients with L858R mutations should still receive upfront treatment with a TKI rather than chemotherapy.