Background: OPTIMAL demonstrated the superiority of erlotinib (E) vs gemcitabine/carboplatin (G/C) in terms of progression-free survival (PFS), objective response rate (ORR) and tolerability in first-line advanced NSCLC patients with EGFR Act Mut+ disease. We provide updated PFS data and the first report of the pre-planned QoL analyses. Methods: Chemonaïve patients with EGFR Act Mut+ advanced NSCLC, ECOG PS 0–2 and measurable disease (n=165) were randomized to E (150mg/d, until unacceptable toxicity or progressive disease [PD]), or G/C (G [1000mg/m², d1, 8] + C [AUC5, d1], q3w for up to 4 cycles), and stratified by histology, smoking status and mutation type. The primary endpoint was PFS; secondary endpoints included ORR, overall survival, QoL (FACT-L, TOI, LCSS) and safety. The QoL questionnaire was administered at randomization and every 6 weeks until PD. Clinical improvement in QoL was predefined as an improvement of ≥6 total points on the FACT-L and TOI, or an improvement of ≥2 total points on the LCSS. P-values for QoL were calculated with logistic regression, with PS, smoking history and gender as covariates. Results: Of 165 patients randomized, 154 were included in the study population (82 E; 72 G/C). In the primary analysis, PFS was significantly prolonged with E vs G/C: median PFS of 13.1 vs 4.6 mos; HR 0.16; p<0.0001 (Zhou et al, ESMO 2010). By the cut-off date of Jan 7, 2011, an updated analysis showed median PFS of 13.7 vs 4.6 mos; HR 0.164; p<0.0001). Patients with a baseline and ≥1 post-baseline QoL assessment (n=128; 83.2% of study patients) were included in the QoL analysis (74 E; 54 G/C). Compared with the G/C group, the E group had a clinically relevant improvement in QoL, as assessed by scores on the FACT-L (73% vs 29.6%; odds ratio [OR] 6.9; 95% CI 3.07–15.48; p<0.0001), the LCSS (75.7% vs 31.5%; OR 6.77; 95% CI 3.04–15.05; p<0.0001) and the TOI ( 71.6% vs 24.1%; OR 7.79; 95% CI 3.44–17.66; p<0.0001). Conclusions: E improved PFS compared with G/C as first-line treatment for EGFR Act Mut+ NSCLC. Patients’ QoL was also significantly improved with E vs G/C.