The results from the Spanish Lung Cancer Group demonstrated the feasibility of prospectively testing for EGFR mutation prior to EGFR TKI initiation (2). This was further supported by several phase III trials evaluating first-line therapy with EGFR TKIs versus platinum doublet chemotherapy in advanced NSCLC (3-8). The IPASS and First-SIGNAL trials evaluated first line gefitinib versus standard chemotherapy in patients selected based on clinical factors known to be associated with a higher prevalence of EGFR mutations (4,7). Planned subgroup analysis based on EGFR mutational status was conducted in the IPASS trial and demonstrated that those with EGFR mutations had a better progression free survival (PFS) with first line gefitinib than chemotherapy and those without EGFR mutations responded significantly better to standard chemotherapy (7). Two additional trials that only included patients with EGFR mutation- positive tumors (WJOTG3405 and NEJ002) had results that confirmed those from IPASS and First- SIGNAL. While gefitinib is not currently approved for use in the United States, it is routinely prescribed as first line therapy for those who are EGFR mutation-positive outside the U.S. The OPTIMAL phase III trial, the first to prospectively compare erlotinib (approved for use in the U.S.) with chemotherapy in patients with EGFR mutationpositive tumors, had similar results to the gefitinib trials with a longer PFS in those treated with the EGFR TKI (8). Results from the European phase III EURTAC study also demonstrated longer PFS with first-line erlotinib versus chemotherapy in patients with EGFR mutation-positive (9) NSCLC, further supporting the use of molecular testing prior to the initiation of therapy.

One of the questions left unanswered is whether or not molecular testing of EGFR receptor status is useful in the selection of maintenance therapy. In this issue of Translational Lung Cancer Research, a reprint of a study published in the Journal of Clinical Oncology by Brugger et al. (10) reports on the molecular analyses from the Sequential Tarceva in Unresectable Non-Small-Cell Lung Cancer (SATURN) trial (11). An important aspect of this trial was the successful collection of tissue samples for biomarker analysis in the majority of patients enrolled in the study. The study was also powered for and met both primary endpoints: improvement in PFS of all in the intention to treat group and in PFS of patients with EGFR positive tumors determined by IHC. In the SATURN study, PFS was prolonged for 1 month in both EGFR IHC positive and negative patients arguing against the use of this biomarker in selecting maintenance therapy in those with clinically stable disease. Additionally, though this was not the primary endpoint of the study, Brugger et al. assessed EGFR by mutational status using PCR and found this method a better predictor of PFS with erlotinib maintenance therapy. Those with an EGFR mutation had a dramatically greater PFS benefit with erlotinib versus placebo than those with EGFR wild type. Future study will be needed to confirm this finding using RT-PCR testing for EGFR.

While this study was not designed to identify the utility of biomarkers as prognostic tests, some useful information emerged. Not surprisingly, those who were EGFR mutation + had an improved overall survival, while those that were found to be KRAS mutation + had a worse progression free survival.

The SATURN trial draws the conclusions that erlotinib should be a consideration as maintenance therapy in patients with NSCLC who do not progress following 4 cycles of platinum based chemotherapy, but does not suggest that erlotinib selection should be based on molecular analysis. So what is the clinical application for EGFR mutational testing in drug selection? Certainly there is ample evidence to support testing prior to the initiation of first line therapy and if the information is available, then an EGFR-TKI should be given first line to those with sensitizing EGFR mutations. Should an EGFR TKI be given as maintenance in those without EGFR mutations? The data from this trial is a qualified maybe as there is a statistically significant improvement in PFS of just one month without any improvement in overall survival when used as maintenance therapy irrespective of EGFR IHC status. Maintenance therapy in patients with NSCLC that has not progressed after first line therapy is increasingly accepted in practice and both erlotinib and pemetrexed are approved for this indication. Given the exploratory results of EGFR mutational testing using RT-PCR one strategy to consider when selecting maintenance therapy would be to use erlotinib in those that are EGFR positive by RTPCR if they have not already received erlotinib first line therapy and pemetrexed or erlotinib in those that are EGFR wild type by RT-PCR. A trial comparing the two approved maintenance therapies is warranted in patients with nonsquamous NSCLC who are EGFR mutation-negative.