From a practical point of view, in our daily clinical practice, we can dichotomise metastatic NSCLC patients in two groups according to EGFR status: on one hand those without EGFR mutations - also named "EGFR wild type"- and on the other hand those harboring EGFR mutations. For the first group, standard platinum based chemotherapy, with pemetrexed and bevacizumab for adenocarcinoma and a combination of cisplatin and gemcitabine or taxanes or vinorelbine for squamous cell carcinoma, continues to be the gold standard of treatment. Furthermore, two recent phase III trials, comparing erlotinib with chemotherapy as first line treatment in unselected and treatment-naive patients, clearly demonstrated that offering an EGFR TKI as front line therapy without any assessment of EGFR status translated into a detrimental effect on patient survival (3,4).

Vice versa, if we consider EGFR mutant patients, the best treatment option as front line therapy is EGFR TKIs, while platinum based chemotherapy could be a valid option as salvage therapy at the time of progression of disease. Five large randomized phase III clinical trials, conducted in more than 1,100 Asian patients with EGFR mutant NSCLC, have demonstrated that the best front-line therapy for these subjects is a tyrosine kinase inhibitor (TKI), such as Gefitinib or Erlotinib (2,5-10). The FIRST SIGNAL was a trial enrolling 313 Korean NSCLC patients with the primary end point of superiority of first-line gefitinib versus standard platinum-doublet chemotherapy in never smokers and adenocarcinomas (5). The study failed to demonstrated a survival advantage for gefitinib in unselected population (22.3 versus 22.9 months; HR 0.932, 95% CI 0.716-1.213; P=0.0640), although patients with EGFR mutations in the chemotherapy arm had lower PFS that those receiving gefitinib. The Iressa Pan-Asia Study (IPASS) randomized 1,217 patients with adenocarcinoma and unknown EGFR status to receive front line gefitinib or four cycles of carboplatin-paclitaxel (2). In the subgroup analysis of the 261 patients with proven EGFR mutations, a statistically significant improvement in PFS emerged for patients receiving gefitinib (PFS 9.5 versus 6.3 months; HR 0.48, 95% CI 0.36-0.64; P<0.001). Conversely, gefinitib treatment was detrimental in EGFR wild type patients (HR for progression or death 2.85; 95% CI 2.05-3.98; P<0.001). The WJTOG 3405 trial randomly assigned only EGFR mutant patients to gefitinib monotherapy or to four cycles of cisplatin-docetaxel (6). Subjects receiving gefitinib had longer PFS than did those in chemotherapy arm (9.2 versus 6.3 months; HR 0.49, 95% CI 0.34-0.71; P<0.001). In the NEJ002 trial, in which patients with EGFR mutations were randomly allocated to first line gefitinib or to four cycles of standard carboplatin-paclitaxel, treatment with gefitinib doubled PFS (10.8 versus 5.4 months; HR 0.30, 95% CI 0.22-0.41; P<0.001) (7). More recently, Zhou and colleagues published the results of the OPTIMAL trial, a phase III study comparing erlotinib monotherapy with carboplatin-gemcitabine in Chinese EGFR mutant patients (8). An impressive HR of 0.16 (95% CI 0.10-0.26) for PFS was reported for subjects allocated to experimental arm (median 13.1 months for erlotinib versus 4.6 months for standard chemotherapy). Nevertheless, the huge difference in outcome between EGFR-TKI therapy and chemotherapy was related to unexpected low performance of the chemotherapy arm. Moreover, the chemotherapy regimen chosen as standard arm, the absence of an independent tumor response revision and, last but not least, the fact that investigators were informed that patients were all EGFR mutated could impacted on study results.

A topic question is if it is possible to translate these findings to European population. In fact we know that some differences exist between Asian and European patients: incidence of EGFR mutations is lower at our longitude and sensitivity to both chemotherapy and anti-EGFR TKIs seems not to be the same. This might simply reflect a different tumor biology or a different genetic make-up of the host.

In 2009, Rosell and colleagues published the results of a prospective trial designed with the aim to evaluate the feasibility of a large-scale screening for EGFR mutations in Spanish patients with metastatic NSCLC (9). According to trial design patients with proven activating EGFR mutations were considered for erlotinib, as first or subsequent line of treatment. Overall, 2,105 patients with advanced NSCLC from 129 centers were prospectively tested. Mutations were detected in 350 subjects (16%), mostly women, never smokers and with adenocarcinomas; of them, 217 received erlotinib treatment as first- (113 patients) or second-third line therapy (104 patients). Median PFS was 14 months, quite similar to than previously reported in Asian population. Two other important issues derived from this work: first, EGFR screening was feasible with laboratory results available in a reasonable time of seven days; second, testing EGFR mutations before starting therapy guided treatment choice.

In a recent issue of Lancet Oncology, the same authors (10) reported the final results of EURTAC trial, the first phase III study comparing erlotinib versus standard platinum-based chemotherapy as first line treatment in European patients with NSCLC harboring EGFR mutations. The study, enrolling 173 patients, met its primary end point of PFS. Patients treated with erlotinib had a 63% relative reduction in risk of progression compared with those receiving standard chemotherapy (9.7 versus 5.2 months, HR 0.37). Treatment with erlotinib was also associated with higher response rate (58% versus 15%, ITT population) and better toxicity profile. Notably, the subset analyses confirmed a significant PFS benefit in favor of erlotinib arm independently of age (>65 versus <65 years), gender, performance status (EGOG PS 0 versus 1 versus 2) and histology (adenocarcinoma versus other histologies). Subgroup analyses according to smoking status showed that the impact of the treatment was minimal in former smokers compared to current or never smokers in terms of PFS. This finding was unexpected and not in agreement with previous studies. In the OPTIMAL trial, as well as in WJTOG3405 and NEJ002 studies, both current and former smokers - even if evaluated as a single subgroup - had longer PFS when treated with TKIs. Similarly in the IPASS trial, in which eligible patients had to be never or light former smokers, no difference in PFS was seen between the two groups. It is not possible to exclude that the higher PFS benefit observed in the EURTAC trial in smokers versus former smokers was obtained by chance because of the very small number of patients included in these two subgroups.

Finally, it is important to highlight that in none of the above mentioned trials, the improvement in PFS translated in a significant advantage in overall survival in favor of gefitinib or erlotinib therapy for patients harboring EGFR mutations. In such trials in fact, the vast majority of patients assigned to the chemotherapy arm received an EGFR-TKI as second or thirdline therapy, with an inevitable confounding effect on survival results. Despite this, in all trials a “clinically significant” trend in the hazard ratio for overall survival was slightly in favor of EGFR TKIs, reinforcing the conviction that if we consider EGFR mutant patients, they gain the greater benefit when an EGFR TKIs is administered early during the course of their disease.