Background: The efficacy of the oral ALK inhibitor crizotinib as 1st-line treatment for advanced ALK-positive NSCLC compared with standard chemotherapy is unknown. A multicenter, randomized open-label phase III study was conducted to compare the efficacy and safety of crizotinib vs. pemetrexed–platinum chemotherapy (PPC) in this setting. Methods: Between Jan 2011 and Jul 2013, 343 pts with previously untreated advanced non-squamous ALK-positive NSCLC were randomized 1:1 to receive crizotinib 250 mg PO BID (n=172) or PPC (pemetrexed 500 mg/m² + either cisplatin 75 mg/m² or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n=171). Continuation of/crossover to crizotinib after PD (per independent radiologic review) was allowed for pts randomized to crizotinib or PPC, respectively. The primary endpoint was PFS. Secondary endpoints included ORR, OS, safety, and pt-reported outcomes. Results: Proportions of pts in the crizotinib and PPC treatment groups with each stratification factor were 45% and 47% Asians, 94% and 95% with ECOG PS 0/1, and 26% and 28% with previously treated brain metastases, respectively. The study met its primary objective, demonstrating superiority of crizotinib over PPC in prolonging PFS (median 10.9 vs. 7.0 mo; HR: 0.454; 95% CI: 0.346−0.596; P<0.0001). The ORR was significantly higher with crizotinib (74% vs. 45%; P<0.0001). With 68% of pts still in follow-up, a statistically significant improvement in OS was not demonstrated (HR: 0.821; 95% CI: 0.536−1.255; P=0.1804). At time of data cut-off 109 pts on PPC had crossed over to crizotinib. AEs with crizotinib and PPC were consistent with those previously reported in patients with advanced ALK-positive or unselected NSCLC, respectively. The most common all-causality AEs with crizotinib were vision disorder and GI symptoms. Conclusions: First-line crizotinib treatment showed significant improvements in PFS and ORR compared with standard chemotherapy and had an acceptable safety profile. These findings establish crizotinib as the standard of care for pts with previously untreated advanced ALK-positive non-squamous NSCLC. Clinical trial information: 2010-021336-33.