Cost Effectiveness of Crizotinib for Anaplastic Lymphoma Kinase–Positive, Non–Small-Cell Lung Cancer: Who Is Going to Blink at the Cost?
Authors: Ronan J. Kelly, Bruce E. Hillner, Thomas J. Smith
Journal: Journal of Clinical Oncology (2014)

In 2014, lung cancer is the poster child for personalized medicine, and identifying targetable oncogenic drivers is now considered standard of care in stage IV disease. The anaplastic lymphoma kinase (ALK) gene has emerged as an important oncogenic driver in a small population of patients with adenocarcinoma. Crizotinib has received accelerated US Food and Drug Administration approval when used in conjunction with its companion diagnostic test to identify patients with the EML4-ALK gene rearrangement. No one who treats patients with lung cancer questions the exciting results obtained with crizotinib, or the need for a highly specific test. A recent phase III study compared crizotinib with standard chemotherapy in patients with locally advanced or metastatic ALK-positive lung cancer who had received one previous platinum-based regimen. Everything favored crizotinib: median progression-free survival (PFS), 7.7 versus 3.0 months; response rate, 65% versus 20%; and symptoms and quality of life were also substantially better. Overall survival was not improved, but 64% of the group receiving chemotherapy crossed over to crizotinib. Two main questions remain unanswered: Can we afford to screen everyone with lung cancer, given that only 3% to 5% of the population will be ALK positive, and can we afford to pay for crizotinib? In the article prompting this editorial, Djalalov et al present their results of a cost-effectiveness analysis of both EML4-ALK fusion testing and first-line crizotinib using a Markov model in newly diagnosed, previously untreated patients with stage IV non–small-cell lung cancer (NSCLC) and nonsquamous histology. The authors compared strategies for treatment: crizotinib for patients who test ALK positive versus standard chemotherapy for those who test negative. The incremental cost-effectiveness ratio (ICER) or change in costs divided by the change in benefits is commonly used in health economics to provide a practical approach to decision making regarding health interventions. The costs are described in monetary units, whereas the benefits or effects on health status are measured in quality-adjusted life years (QALYs) gained or lost. Using a relative efficacy estimate in the first-line setting that was derived from the second-line phase III trial, the author’s projected that first-line crizotinib gives 0.64 years (7.7 months) extra survival, or 0.38 QALYs, at an additional cost of $95,000 compared with standard of care, leading to ICERs of $148,000 per additional life year, or $250,000/ QALY gained. The authors concluded that EML4-ALK fusion testing and crizotinib treatment for patients positive for ALK is not costeffective (from a Canadian perspective) because of the low biomarker frequency in the population—and the high drug costs. Are their conclusions valid, what do they mean, and is crizotinib affordable? The model seems valid. The authors simulated the clinical trial of what happens if patients positive for ALK start with crizotinib while we await the results of the ongoing first-line phase III PROFILE 1014 trial (A Clinical Trial Testing the Efficacy of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin or Carboplatin in Patients With ALK Positive Nonsquamous Cancer of the Lung). In this analysis, all patients receive crizotinib (or do not, if ALK negative), then cisplatin plus gemcitabine, then second-line pemetrexed, then thirdline erlotinib, regardless of epidermal growth factor receptor status. The authors transform the added 0.64 years of life to 0.38 qualityadjusted years by assuming that the quality of life is only 3% better for patients receiving crizotinib compared with regular chemotherapy. This seems ungenerous, given the rapid and often dramatic symptom improvement seen in practice, which should translate into greater quality time while receiving the drug. Their test strategy for ALK assessment is efficient—a critically important aspect, given the need to screen 100 patients to find approximately three who test positive. The only US Food and Drug Administration–approved test is the Vysis LSI ALK Break Apart FISH Probe Kit (Abbott Molecular, Des Plaines, IL), with near 100% accuracy but at a cost of more than $250/test. The correlation of results of ALK immunohistochemistry (IHC) and ALK fluorescent in situ hybridization (FISH) are excellent, but IHC has not been validated as a predictive marker for response to an ALK inhibitor in a large patient cohort. The US guidelines state that ALK IHC, if carefully validated, may be considered for screening patients with lung adenocarcinoma. The authors used ALK IHC (approximately $40) with 95% sensitivity as their baseline, with subsequent verification with ALK FISH if needed. Djalalov et al indicate that EML4-ALK fusion testing with crizotinib treatment for patients positive for ALK “is not cost-effective in the setting of high drug costs and a low biomarker JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 10 APRIL 1 2014