Tyrosine kinase inhibitors (TKI's) were used in the second and third line setting while the science of the epidermal growth factor receptor (EGFR) biomarker was evolving. It was debated for many years on what biomarker if any could identify patients with tumors who had deregulation of the EGFR receptor Was it over expression of the protein, gene copy number or mutation of the epidermal growth factor receptor that would best identify the patients who benefit most from "targeted" therapy.

In the IPASS trial, the first line setting was the platform to be tested. Asian non smoking patients with adenocarcinoma histology treated with gifitinib experienced an improvement in their progression free survival (PFS) compared to chemotherapy (2). When analyzing the data for EGFR mutation, there was a doubling in PFS in favour for gefitinib. Testing patients for the epidermal growth factor receptor mutation in the first line setting identified a group that most benefitted from an EGFR TKI. Gefitinib became a front runner in this group of patients with EGFR M+ tumors. Targeted therapy had arrived.

Question: What about non-Asian patients? Are they different genetically? Would the same EGFR mutation have the same implications in treatment and response and survival with an EGFR inhibitor in non-Asian patients?

The answers to these first questions are easy. While the hazard ratio of the first line Asian erlotinib OPTIMAL study was 0.16 P<0.0001, it was not a registration trial (3). In the registration EURTAC trial, the hazard ratio was 0.37 P<0.0001 not too different than the Asian gefitinib IPASS trial with a hazard ratio of 0.48 P<0.0001. In cross trial comparisons, EGFR mutations are less common in a non Asian population. Over 1,200 patients had to be screened in EURTAC to find 174 patients (15%) compared to 549 to find 186 (34%) for OPTIMAL trial done in Asia. The observed differences in incidence of EGFR mutations do not appear to translate into differences in the predictive value of the mutation. A patient with an EGFR mutation is similar regardless of race.

A second relevant question is whether erlotinib and gefitinib are equivalent. This question is more difficult to answer.

Gefitinib and erlotinib are orally bioavailable synthetic anilinoquinazolines and share a common chemical backbone structure, however have different overall structures. The structural difference may affect plasma, tumour distribution, metabolism, and clinical efficacy. Administration of erlotinib at the maximum tolerated dose (MTD) of 150 mg once daily achieves an approximate 3.5-fold higher steady-state plasma trough concentration than gefitinib administered at the recommended dose of 250 mg once daily (4).

With the greater concentrations comes greater toxicity. Grade 3 rash was observed in approximately 5% with gefitinib in IPASS, versus 13% with erlotinib in EURTAC. This may be both good and bad news. Increased toxicity especially in the palliative stage is to be avoided. But clinicians have become more familiar with the management of dermatologic toxicity associated with EGFR inhibitors and in multiple trials in this class of drugs have shown a correlation between grade of rash, and survival. Similar results have been observed with monoclonal antibodies targeting the EGFR receptor in metastatic colorectal cancer with dose escalation resulted in greater dermatologic toxicity and with that, improved response rates of the tumor (5).

If only hazard ratios are regarded and dermatologic toxicities cannot be well managed, gefitinib wins. If one believes that dose levels is an important finding and that adverse advents may lead to improved efficacy, than erlotinib wins.

The EURTAC study was performed in a non-Asian population adding to the literature supporting the benefit of erlotinib. Now there is established evidence for the efficacy of erlotinib in non-selected patients in the second line setting and in selected patients in the first line setting.

The authors conclude correctly in this landmark trial of erlotinib in the first line setting in a non Asian population with lung cancer. Routine assessment of EGFR mutations should be done and if positive treated with an EGFR TKI approved in the institution.