Maintenance therapy comes of age for non-small-cell lung cancer, but at what cost?
There is perhaps no other topic that has engendered such controversy and confusion than that of epidermal growth factor receptor (EGFR) therapy biomarkers. Candidate markers, all of which have supporters and detractors, include EGFR protein expression, EGFR gene copy number, and EGFR and KRAS mutation status. The first question that must be asked is: Why has this confusion arisen? There likely is no simple answer to this question, but there are several possibilities.
Some degree of misinterpretation of biomarker analyses from the initial trials of EGFR tyrosine kinase inhibitors (TKIs) may have arisen because these trials were small and without control arms; as such, they could only identify predictive markers of response and could not determine the prognostic effect of the markers, nor could they identify a differential survival benefit from treatment. Subsequently, the early randomized trials of EGFR TKIs did not mandate tissue collection for all patients; their biomarker studies were, therefore, underpowered, and most analyses were unplanned and retrospective. Despite these limitations, correlative studies from the two placebo-controlled third-line trials of EGFR TKIs, NCIC Clinical Trials Group Study BR.21 and Iressa Survival Evaluation in Lung Cancer (ISEL), clearly identified patients who derived greater or lesser benefit from therapy on the basis of EGFR protein assessed by immunohistochemistry (IHC), EGFR gene copy number, and both EGFR and KRAS mutation status.
The trends were the same for both studies, although not all markers had the power to demonstrate statistical significance. These trials also provided a pure evaluation of the effect of markers on overall survival (OS) because when they were conducted, both cross-over and subsequent systemic therapies were minimal...