To evaluate the efficacy and toxicity of erlotinib as first line treatment in patients with locally advanced/metastatic (stages IIIB/IV) NSCLC, with clinical predictors of response to tyrosine kinase inhibitors (erlotinib, gefitinib), such as female gender, never-smoking status and adenocarcinoma histology. Furthermore, erlotinib-sensitivity will be correlated with the presence of EGFR mutations in exons 18, 19 and 21, in this population

A randomized, placebo-controlled phase III trial of erlotinib versus placebo, with more than 700 patients demonstrated that therapy with this tyrosine kinase inhibitor (TKI) prolongs survival after first or second line therapy in patients with advanced NSCLC. Statistically significant and clinically relevant differences were observed for overall and progression free survival in favour of erlotinib. Moreover, several clinical factors had been correlated with response to gefitinib or erlotinib, including never smoking status, female gender, Asian ethnicity and adenocarcinoma histology (especially bronchioalveolar carcinoma).

Inclusion Criteria:

• Histologically or cytologically confirmed, unresectable locally advanced (stage IIIB with pleural effusion) and/or metastatic (stage IV) NSCLC
• No previous therapy for advanced/metastatic NSCLC is allowed
• age >18 years
• bidimensionally measurable disease
• non-smokers (or ex-smokers with less than 5 pack-years smoking history)
• adenocarcinoma histology
• performance status (WHO) 0-3
• adequate liver (serum bilirubin <1.5 times the upper normal limit (UNL); AST and ALT <2.5 times the UNL in the absence of demonstrable liver metastases, or <5 times the UNL in the presence of liver metastases); adequate renal function (serum creatinine <1.5 times the UNL); and bone marrow (neutrophils ≥ 1.5x 109 /L, and platelets ≥ 100x 109 /L) function
• previous radiotherapy, either in the adjuvant setting or for the treatment of metastatic disease is allowed provided that the measurable lesions are outside the radiation fields
• patient able to take oral medication
• tissue sample for tumour mutational analysis is required

Exclusion Criteria:

• serious chronic skin conditions (e.g. psoriasis, eczema) that would preclude study participation
• active infection
• history of significant cardiac disease (unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, ventricular arrhythmias)
• malnutrition (loss of ≥ 20% of the original body weight)
• performance status: 4
• psychiatric illness or social situation that would preclude study compliance
• pregnant or lactating women