EML-4ALK AS A PREDICTIVE MARKER FOR RESPONSE TO EGFR THERAPY

Investigators at Massachusetts General Hospital in Boston conducted an analysis of the fusion oncogene EML4-ALK and the more well-studied epidermal growth factor receptor (EGFR) mutation among a group of patients with non-small-cell lung cancer who possessed at least 2 of the following features: (a) female sex; (b) no smoking or only a light smoking history; (c) Asian ethnicity; and (d) adenocarcinoma. Of the 141 tumors satisfying these criteria, 22% were found to have a mutation in EGFR, 13% had the EML4-ALK mutation, and 65% did not have a mutation in either EGFR or EML4-ALK ("wild-type").

The subgroup of individuals with EML4-ALK mutations was younger and more likely to be male compared with the wild-type and EGFR-mutation populations. Similar to the EGFR-mutation patients, those with EML4-ALK mutations were more likely to be light smokers or never-smokers. All but 1 of the 19 EML4-ALK mutant tumors were adenocarcinomas.

Of the 10 EML4-ALK patients who received treatment with an EGFR tyrosine kinase inhibitor, none achieved an objective response. By contrast, the response rate in this population to standard cytotoxic chemotherapy as well as the overall survival rate were similar to those seen in the wild-type patient population.

Viewpoint

Although this interesting study requires confirmation by other investigators, its data suggest that the documented presence of an EML4-ALK mutation, which is observed in as many as 10% to 15% of patients with non-small-cell lung cancer, indicates that the malignancy will be unresponsive to tyrosine kinase inhibition of EGFR.

Of particular interest in this report is that among the patients who were light smokers or never-smokers and did not possess an EGFR mutation, one third were found to have an EML4-ALK mutation. These data add to growing evidence for the relevance of specific molecular testing in non-small-cell lung cancer such that, in the relatively near future, it might be possible to develop therapeutic paradigms optimized for the individual patient based on unique characteristics of each cancer. Such decisions will include not only the particular drugs that should be used, but also (as appears to be the situation with EML4-ALK) the agents that should be avoided due to a predicted lack of efficacy.

Furthermore, these data demonstrate the serious limitations associated with making management decisions based solely on morphology and clinical history; some earlier reports suggested that the combination of no or limited smoking history and adenocarcinoma morphology would indicate a high probability of response to EGFR inhibition.