A distinct molecular subset of non-small-cell lung cancer (NSCLC), driven by mutated EGFR has become the subject of intense investigation. Specific activating mutations in the tyrosine kinase domain of EGFR have been correlated with striking responses to EGFR tyrosine-kinase inhibitors (TKIs) such as erlotinib and gefitinib. EGFR TKIs alone or in combination with chemotherapy do not improve outcomes significantly compared with chemotherapy in clinically or molecularly unselected patients with previously untreated advanced NSCLC. However, in carefully selected populations, first-line therapy with either of these agents improves response rates and progression-free survival (PFS) compared with chemotherapy.

Gefitinib monotherapy improved median PFS by up to 5 months vs. chemotherapy in patients with EGFR-mutated oncogene-addicted NSCLC in three studies conducted in Asia. Erlotinib monotherapy produced equivalent results in Chinese patients with EGFR-driven NSCLC with nearly a three-times improved median PFS for erlotinib compared with chemotherapy. Although small studies suggested equivalent benefit with erlotinib in the first-line setting in non-Asian cohorts, data were not available from a well-designed RCT until now, with the publication of the EURTAC trial in The Lancet Oncology.

EURTAC was an-label, randomised trial conducted at 42 hospitals in France, Italy, and Spain. It involved 174 patients with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed); one patient received treatment before randomisation and was withdrawn from the study; The remaining patients were randomised to receive oral erlotinib 150mg per day (n= 86) or 3 week cycles of standard IV chemotherapy (n= 87) of cisplatin 75mg/m2 on day 1 plus docetaxel (75mg/m2 on day 1) or gemcitabine (1250 mg/m2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m2 or AUC 5 with gemcitabine 1000 mg/m2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs. 1 vs. 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Safety was assessed in all patients who received study drug (≥1 dose).

The pre-planned interim analysis showed that the study met its primary endpoint and the study was thus closed. At data cut-off (Jan 26, 2011):

• Median PFS was 9.7 months in the erlotinib group vs. 5.2 months in the standard chemotherapy group (hazard ratio 0.37, 95% CI, 0.25 to 0.54; p<0.0001); this improvement in PFS did not result in improved overall survival.

• Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients on erlotinib vs. none of 82 in chemotherapy group), neutropenia (none vs. 18 [22%]), anaemia (1 [1%] vs. 3 [4%]), and increased amino-transferase concentrations (2 [2%] vs. 0).

• 5 (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy.

• One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes.

The researchers conclude that these findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors.

An accompanying Comment article calls on the lung cancer research community to prioritise studies targeting other pathways implicated in primary and acquired EGFR resistance. The authors note that a “comprehensive assessment of the genomic landscape of EGFR-mutated oncogene-addicted NSCLC with whole genome or exome sequencing before any therapy and serially on progression will help us to understand better the molecular mechanisms determining clonal evolution to guide rational drug development, not only in the salvage setting, but also in the first-line setting. When (and not if) such assessment happens, personalised therapy truly will have come of age, signifying the beginning of an end to empirical approaches.”