OBJECTIVES: ALK-targeted therapy with crizotinib offers significant improvement in clinical outcomes for the treatment of EML4–ALK fusion positive NSCLC. We estimated the cost-effectiveness of EML4-ALK testing in combination with first-line crizotinib for ALK positive NSCLC in Ontario. METHODS: A cost-effectiveness analysis was conducted, using a Markov model from the Canadian public health (Ontario) perspective and a lifetime horizon in Stage IV NSCLC patients with non-squamous histology. Transition probabilities and mortality rates were calculated from the Ontario Cancer Registry and Cancer Care Ontario New Drug Funding Program (CCO NDFP). Costs were obtained from the Ontario Case Costing Initiative, CCO NDFP, University Health Network and the literature. Population-based ALK testing included initial IHC testing followed by FISH confirmation for positive cases. RESULTS: The strategy of genomic testing linked to targeted crizotinib treatment gained 0.11 QALYs compared to no testing or crizotinib treatment in the advanced non-squamous NSCLC population. The incremental cost was CAD $4,179 per patient compared to the previous standard of care without ALK testing; the incremental cost-effectiveness ratio for the base case was $392,538 per QALY. The incremental cost and ICER for crizotinib therapy in known ALK positive advanced NSCLC patients was $96,554 and $254,617/QALY. The cost of testing was less relevant to the ICER at a biomarker frequency of 7% and higher. The major drivers of cost-effectiveness are drug cost and low biomarker frequency in the population. CONCLUSIONS: EML4–ALK genomic testing in combination with crizotinib treatment for all Stage IV non-squamous NSCLC patients is not cost-effective in the setting of high drug costs and a low biomarker frequency in the general population. Modifying these key drivers will be important in improving the cost-effectiveness and accessibility to novel therapies with major clinical benefit in advanced NSCLC.