Research in context
Evidence before the study
We searched PubMed for articles published between Jan 1, 2004, and Dec 31, 2014, using the search string “uncommon EGFR mutations OR rare EGFR mutations AND NSCLC”. Of 150 articles, 19 examined the sensitivity of uncommon EGFR mutations to EGFR tyrosine kinase inhibitors, either in vitro or in vivo. These studies reported that Gly719Xaa and Leu861Gln mutations confer sensitivity to first-generation, reversible EGFR tyrosine kinase inhibitors in some but not all cases, while Thr790Met and exon 20 insertion mutations generally conferred resistance to EGFR tyrosine kinase inhibitors. However, most of these studies did not prospectively analyse treatment effects in a clinical trial setting, and were restricted to analysis of a few patients.
Added value of this study
To the best of our knowledge, this is the largest analysis of prospective clinical trial data of patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations after treatment with an irreversible ERBB family blocker or chemotherapy. Afatinib showed activity in patients with point mutations or duplications in exons 18–21, suggesting that this group of uncommon mutations can be categorised as sensitising EGFR mutations. However, similar to first-generation, reversible EGFR tyrosine kinase inhibitors, afatinib did not provide clinical benefit to patients harbouring de-novo Thr790Met or exon 20 insertion mutations, and results of an exploratory analysis showed that chemotherapy might be a preferable first-line option for patients with these mutations.
Implications of all the available evidence
Data from our study suggest that afatinib is a treatment option for patients with some uncommon EGFR mutations. Performing larger randomised trials in patients with uncommon EGFR mutations is unlikely in view of the small population size and genetic diversity of these tumours; although limitations exist (eg, inclusion of patients treated beyond progression), a global registry might be more feasible to obtain additional data for these particular patients.