Published Ahead of Print on February 24, 2014 as 10.1200/JCO.2013.53.1186 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.53.1186
JOURNAL OF CLINICAL ONCOLOGY
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Cost Effectiveness of EML4-ALK Fusion Testing and First-Line Crizotinib Treatment for Patients With Advanced ALK-Positive Non–Small-Cell Lung Cancer Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, Ming-Sound Tsao, Jean-Claude Cutz, and Natasha B. Leighl See accompanying editorial doi: 10.1200/JCO.2013.54.6002 Sandjar Djalalov, Jaclyn Beca, and Jeffrey S. Hoch, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital and Cancer Care Ontario; Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, and Natasha B. Leighl, Canadian Centre for Applied Research in Cancer Control; Murray Krahn, Toronto Health Economics and Technology Assessment Collaborative; Ming-Sound Tsao and Natasha B. Leighl, Ontario Cancer Institute and Princess Margaret Cancer Centre, Toronto; and Jean-Claude Cutz, McMaster University, Hamilton, Ontario, Canada. Published online ahead of print at www.jco.org on February 24, 2014. The Cancer Care Ontario Pharmacoeconomics Research Unit is supported by Cancer Care Ontario, and the Canadian Centre for Applied Research in Cancer Control is supported by the Canadian Cancer Society. The findings do not necessarily represent the views of the funders. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Natasha B. Leighl, MD, MMedSc, Princess Margaret Hospital, 5th Floor, Room 105, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3299-1/$20.00 DOI: 10.1200/JCO.2013.53.1186
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Purpose ALK-targeted therapy with crizotinib offers significant improvement in clinical outcomes for the treatment of EML4-ALK fusion–positive non–small-cell lung cancer (NSCLC). We estimated the cost effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment in Ontario. Patients and Methods A cost-effectiveness analysis was conducted using a Markov model from the Canadian Public health (Ontario) perspective and a lifetime horizon in patients with stage IV NSCLC with nonsquamous 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 literature. Results Molecular testing with first-line targeted crizotinib treatment in the population with advanced nonsquamous NSCLC resulted in a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care. The incremental cost was Canadian $2,725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with known EML4-ALK–positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained. The major driver of cost effectiveness was drug price. Conclusion EML4-ALK fusion testing in stage IV nonsquamous NSCLC with crizotinib treatment for ALKpositive patients is not cost effective in the setting of high drug costs and a low biomarker frequency in the population. J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Lung cancer remains the leading cause of death resulting from cancer in North America1 and worldwide. Non–small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers, predominantly of nonsquamous subtype, including adenocarcinoma.2 Most patients have advanced disease at the time of diagnosis. Although cytotoxic chemotherapy is the mainstay of treatment in advanced NSCLC, its effectiveness has reached a plateau, and therapeutic outcomes remain disappointing.3,4 Recent advances in the understanding of the molecular biology of lung cancer
have led to practice-changing developments in molecularly targeted therapy. Over the past decade, activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been identified as the major predictor of benefit with EGFR tyrosine kinase inhibitors (TKIs), and EGFR TKI therapy is the initial treatment of choice in patients with advanced EGFR mutation–positive NSCLC. More recently, the fusion of echinoderm microtubule–associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes has been identified as an oncogenic driver in NSCLC. Although initially described in a case of squamous carcinoma of the © 2014 by American Society of Clinical Oncology
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lung, this fusion gene is more commonly found in never-smokers with EGFR wild-type lung adenocarcinoma. Crizotinib is a TKI with known activity against EML4-ALK, MET, and ROS-1. Crizotinib therapy dramatically increased response rates (RRs) and progressionfree survival (PFS) in patients with advanced NSCLC with ALK rearrangements compared with second-line chemotherapy (RR, 65.3% v 19.5%; P ⬍ .001; median PFS, 7.7 v 3.0 months, respectively; hazard ratio [HR], 0.49; P ⬍ .001)5 and in heavily pretreated patients with NSCLC with ALK translocations (RR, 50% to 60%; median PFS, 8 to 10 months).6,7 The frequency of ALK translocations in advanced nonsquamous NSCLC has been estimated at between 2% and 7%.8 The current US Food and Drug Administration and Health Canada label for crizotinib use in NSCLC is for crizotinib monotherapy in advanced ALK-positive NSCLC, without restriction in prior therapies. It is expected that the ongoing trials in first-line advanced ALK-positive NSCLC will demonstrate superiority with crizotinib. There are several methods for detecting ALK-fusion gene rearrangements in tumor tissue. Fluorescent in situ hybridization (FISH), using the Abbott Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Des Plaines, IL), has emerged as the gold standard and was used in initial clinical studies to select patients most likely to benefit from ALK inhibitor therapies. Other methods include reverse transcriptase polymerase chain reaction– based assays, immunohistochemistry (IHC) for aberrant expression of ALK protein, and Sanger sequencing. FISH has been shown to be both sensitive and specific but requires specialized technical resources and expertise and is time consuming; as a result, the assay is not readily available in all laboratories. Although reverse transcriptase polymerase chain reaction can detect both EML4 and ALK fusion, it is prone to false-positive results secondary to contamination and should only be conducted in specialized settings, with verification of positive results.8 IHC can be performed quickly and with relative ease in pathology laboratories and can be used on smaller tissue samples. New antibodies have been developed, increasing the sensitivity and specificity of IHC testing for ALK.9 Until recently, the evidence supporting ALK IHC in routine clinical practice was limited.10 However, the accuracy of IHC molecular testing was recently examined in several studies and was shown to correlate highly with FISH results, supporting the use of IHC for detecting EML4-ALK fusion.11,11a,12 In 2011, the US Food and Drug Administration approved crizotinib for patients with NSCLC whose tumors harbor the EML4-ALK fusion gene, as detected by the Vysis ALK Break Apart FISH Probe companion diagnostic (Abbott Molecular). However, there are challenges to implementing molecular testing with FISH for ALK fusion in NSCLC, including the high incidence of the disease, low frequency of ALK fusion, and complexity, cost, and tissue requirements for testing. Using a more widely available molecular testing method such as IHC to detect positive or equivocal cases, with FISH confirmation as needed, would reduce cost and facilitate population-based molecular testing. Many jurisdictions use this approach for the detection of HER2-amplified breast cancer to direct use of trastuzumab therapy.13 In our study, we evaluated the cost effectiveness of both EML4-ALK fusion testing and first-line therapy with crizotinib for patients with advanced ALK fusion–positive NSCLC, from the perspective of the Canadian public health care system. 2
© 2014 by American Society of Clinical Oncology
PATIENTS AND METHODS Overview and Treatment Strategies A decision analytic model was developed to compare lifetime benefits and direct medical costs between two strategies in patients with advanced NSCLC (Fig 1). The target population was treatment-naive Ontario patients with advanced nonsquamous NSCLC. Our main analysis for molecular testing and targeted treatment involved patients with advanced NSCLC and compared EML4-ALK fusion molecular testing for all patients and targeted crizotinib treatment for patients with EML4-ALK fusion–positive NSCLC with standard care. Our supplementary analysis for treatment involved known patients with EML4-ALK fusion– positive NSCLC and compared crizotinib treatment with standard care, without testing patients with advanced NSCLC. In the standard care strategy, patients receive conventional treatment for NSCLC, which includes platinum doublet (cisplatin and gemcitabine) as firstline therapy, pemetrexed as second-line therapy, and erlotinib as third-line therapy.14 The EML4-ALK fusion molecular testing strategy involved EML4ALK fusion molecular testing in all patients diagnosed with nonsquamous NSCLC with good performance status (Eastern Cooperative Oncology Group/Zubrod performance status ⱕ 2). For those who accepted testing, tumor samples were screened for ALK fusion protein with IHC in a certified laboratory in Ontario (Clinical Laboratory Improvement Amendments). Positive IHC staining was confirmed using FISH testing. If there was inadequate tissue for testing, patients could undergo repeat biopsy. Those with EML4ALK–positive tumors received crizotinib 250 mg orally twice per day as firstline therapy, followed by conventional treatments for NSCLC on progression. Those with EML4-ALK–negative or unknown tumors received conventional treatments for NSCLC. In both strategies, patients also received best supportive care (BSC) when not receiving systemic therapy. Model Structure A Markov model was developed to reflect the natural history of advanced NSCLC. During each 3-week cycle, patients faced the following possibilities: one, continuing on therapy; two, stopping therapy with stable disease; three, progression of disease and starting subsequent therapy; four, progression of disease and receiving BSC alone; and five, death. Platinum doublet chemotherapy with gemcitabine/cisplatin was administered for up to four cycles, and pemetrexed therapy was administered for four cycles based on median treatment duration in previous randomized trials.15 Crizotinib and erlotinib were administered until disease progression or treatment discontinuation for adverse events (Fig 2). Economic Assumptions We performed a cost-utility analysis from the perspective of the provincial government single-payer system, the Ontario Ministry of Health and Long-Term Care. Both benefits and direct medical costs were discounted at 5% per annum based on Canadian guidelines.16 Health benefits were expressed as life-years and quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental cost difference between strategies by the incremental difference in health outcomes (life-years and QALYs). A lifetime horizon was used for the model (4.2 years). Probabilities The frequency of the EML4-ALK fusion gene in Canadian patients with advanced nonsquamous NSCLC has been estimated at 3.4%, the test failure rate resulting from inadequate tissue at 10%, and rebiopsy frequency at 15%, obtained from expert opinion and an ongoing pan-Canadian study17 (Table 1). The probability of patients with cancer accepting pharmacogenomic testing is 95% based on a recent study.22 Progression during first-line crizotinib therapy was estimated from a phase I study of 82 patients with EML4-ALK– positive advanced NSCLC receiving the recommended crizotinib dose of 250 mg twice per day.6 A Weibull model was fitted to the Kaplan-Meier PFS curve to estimate transition probabilities for each 3-week cycle. The mortality rate during first-line crizotinib therapy was estimated from a retrospective analysis of crizotinib therapy versus observation in patients with JOURNAL OF CLINICAL ONCOLOGY
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
FISH test confirmed
[+] EML4-ALK fusion positive
M
FISH test not confirmed
M
Tissue adequate EML4-ALK fusion negative and unknown (failure)
Accept IHC test
M Rebiopsy
[+]
Fig 1. Decision tree. M indicates movement into the Markov model, depicted in Figure 2. FISH, fluorescent in situ hybridization; IHC, immunohistochemistry.
Yes Tissue inadequate
No rebiopsy
M M
IHC test not accepted
EML4-ALK fusion testing
No
M
EML4-ALK fusion–positive advanced NSCLC.23 It was estimated that 70% of patients experiencing progression with crizotinib would be eligible for subsequent chemotherapy, whereas 30% would receive BSC alone, based on clinical expert opinion (Canadian investigators participating in crizotinib trials). Transition probabilities and mortality rates for platinum doublet therapy with gemcitabine/cisplatin, pemetrexed therapy, and BSC were calculated based on median time to next treatment or death from a review of 8,113 patients obtained from the Cancer Care Ontario New Drug Funding Program– and Activity Level Reporting–linked databases from 2005 to 2009.24 Probabilities for erlotinib progression were obtained from two clinical trials with 513 patients. To assess the validity of the model, we verified outcomes generated by the model at 20 and 40 weeks with reported trial outcomes for PFS.18 Utility Estimates Utility scores were derived from a mixed-model regression analysis for different stages of NSCLC and grade 3 to 4 toxicities commonly associated with chemotherapy treatments,20 using as inputs estimates of clinical response and main toxicities for conventional treatments19 and crizotinib18 (Table 1). Cost The costs for EML4-ALK fusion testing using IHC and FISH were obtained from the University Health Network laboratory medicine program. The cost of repeat biopsy was obtained from the Ontario Case Costing Initiative.21 The direct medical cost of each treatment included drug costs, administration costs, management of adverse events, and usual medical care. The costs of intravenous drugs were obtained from the Cancer Care Ontario New Drug Funding Program and oral medications from the outpatient pharmacy at the www.jco.org
Princess Margaret Cancer Centre (Toronto, Ontario, Canada), including 10% markup per current pharmacy practice. All estimated costs were adjusted to 2012 Canadian dollars using the consumer price index for Ontario (Table 1). ALK Testing Specificity and Sensitivity The specificity and sensitivity of FISH testing for EML4-ALK fusion are presumed to be 100%, because they are the current gold standard. Using the most commonly used IHC antibodies, we found from systematic review a weighted average of 93% sensitivity and 99% specificity for IHC (Appendix Table A1, online only). Because clinical opinion and unpublished results from the IHC testing studies suggest that IHC can be optimized beyond the results of the systematic review, the final inputs for the model were 95% sensitivity and 100% specificity. Assumptions We assumed that the benefit from crizotinib in pretreated EML4-ALK fusion–positive patients18 would be similar to that from crizotinib use in the first-line setting. Although this is a conservative estimate of benefit, data from ongoing first-line trials are not yet available. In addition, transition probabilities for progression and mortality rates for each treatment were deemed similar in the molecular testing versus standard care strategies. Sensitivity Analysis We varied all parameters separately in one-way and selected two-way sensitivity analyses. For crizotinib, we used the 95% CIs of parameters from regression as the upper and lower limits. For other parameters, we varied probabilities and utilities by 20% and costs by 30% (ranges listed in Table 1). © 2014 by American Society of Clinical Oncology
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EML4-ALK positive only
Crizotinib
EML4-ALK negative and unknown
Best supportive care
Platinum doublet
Best supportive care
Pemetrexed
Death
Post-treatment “stable”
Fig 2. Markov model.
Post-treatment “stable”
Best supportive care
Erlotinib
Best supportive care
We also conducted scenarios to assess the impact of our assumptions about testing and treatment.
RESULTS
The use of EML4-ALK fusion testing and targeted crizotinib treatment for EML4-ALK–positive advanced NSCLC results in added benefits (0.011 QALYs) as well as extra costs ($2,725; costs given in Canadian dollars throughout) for the average patient with NSCLC (Table 2). Of these extra costs, $60 was attributed to the cost of molecular testing. EML4-ALK fusion molecular testing and targeted crizotinib treatment in advanced NSCLC cost an additional $255,970 per QALY gained compared with standard care with no testing and no crizotinib treatment. From the supplementary analysis for treatment, the extra cost for a patient receiving treatment with crizotinib was $95,043, and the resulting ICER was $250,632 per QALY gained for patients with EML4-ALK–positive NSCLC treated with crizotinib instead of standard care. The results of the one-way sensitivity analysis indicated that the primary drivers of the ICER were the relative treatment-related utility with crizotinib and the cost of crizotinib treatment (Fig 3). The large impact of treatment-related utility resulted from its benefit or harm 4
© 2014 by American Society of Clinical Oncology
relative to the comparator. The base value for crizotinib utility was 0.03 higher than that for platinum doublet, and the ICER increased if the utility with crizotinib decreased (tested to 0.08 ⬍ platinum doublet in sensitivity analysis). The model was also sensitive to progression with crizotinib; if crizotinib performed less effectively in the real world compared with the trial, the ICER would increase. The model was not sensitive to the costs of molecular testing. The relationship between the ICER and EML4-ALK frequency in NSCLC is shown in Appendix Figure A1 (online only). The impact of biomarker frequency on cost effectiveness was minimal, whereas the ICER was moderately sensitive to lower biomarker frequencies. The ICER remained high with higher EML4-ALK frequencies, because the high drug costs offset the health gains (ie, finding more people who benefit means more people using an expensive treatment). The ICER had a linear relationship with the cost of crizotinib treatment (Appendix Fig A2, online only). In a scenario in which the crizotinib cost was zero, EML4-ALK fusion molecular testing and targeted crizotinib treatment was cost saving, indicating high sensitivity to crizotinib pricing. With potential payer concerns about the adoption of testing, we explored scenarios examining different testing strategies. If, instead of JOURNAL OF CLINICAL ONCOLOGY
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
Table 1. Transition Probabilities, Utilities, and Costs Variable
Value
Lower Limit
Upper Limit
0.017
0.014
0.020
Kwak et al18
0.199 0.155 0.22
0.159 0.124 0.176
0.239 0.186 0.264
CCO NDFP CCO NDFP CCO NDFP
0.0051
0.004
0.006
Kwak et al18
0.146 0.170
0.117 0.136
0.175 0.204
CCO NDFP CCO NDFP
0.015
0.012
0.018
Shaw et al5
0.05 0.069 0.074 0.107
0.040 0.055 0.059 0.086
0.060 0.083 0.089 0.128
Chen19 Chen19 Chen19 Chen19
0.5668
0.453
0.680
Author calculations, Nafees et al20
0.5353
0.428
0.642
Chen,19 Nafees et al20
0.6166
0.493
0.740
Chen,19 Nafees et al20
0.4537 0.5704 0.4798 0.4734
0.363 0.456 0.384 0.379
0.544 0.684 0.576 0.568
Chen,19 Chen,19 Chen,19 Chen,19
Source
Transition probabilities Progression Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Mortality rates Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC Utilities Crizotinib Platinum doublet (cisplatin and gemcitabine) during treatment Platinum doublet (cisplatin and gemcitabine) after treatment Pemetrexed during treatment Pemetrexed after treatment Erlotinib BSC Costs IHC test FISH test Rebiopsy Crizotinib
$40 $388 $712 $7,000
$28 $272 $498 $4,900
$52 $504 $926 $9,100
UHN Molecular Diagnostics Laboratory UHN Molecular Diagnostics Laboratory Ontario Case Costing Initiative21 PMH Pharmacy (Sandjar Djalalov, personal communication, August 2012)
Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC
$1,527 $5,900 $2,229 $582
$1,069 $4,130 $1,560 $407
$1,985 $7,670 $2,898 $757
Chen19 Chen19 Chen19 Chen19
Nafees Nafees Nafees Nafees
et et et et
al20 al20 al20 al20
NOTE. All treatment costs are for 3-week cycle and given in Canadian dollars. Abbreviations: BSC, best supportive care; CCO NDFP, Cancer Care Ontario New Drug Funding Program; IHC, immunohistochemistry; PMH, Princess Margaret Hospital; UHN, University Health Network.
IHC molecular testing, all patients were tested with the more expensive FISH test, the ICER increased by 11% to $284,511 per QALY gained. If only IHC testing was used without FISH confirmation for EML4-ALK–positive patients, the ICER decreased only slightly to $254,939 per QALY gained. Finally, if the health care system bore none of the costs related to testing, the ICER would decrease to $250,632 per QALY gained. DISCUSSION
This study examined the cost effectiveness of EML4-ALK fusion testing with targeted crizotinib treatment for patients with NSCLC www.jco.org
using a Markov model and Ontario administrative data. We estimated that for patients with stage IV nonsquamous NSCLC at initiation of therapy, the incremental cost-effectiveness ratio of a targeted pharmacogenomic strategy using EML4-ALK fusion testing and targeted crizotinib therapy versus standard care was $255,970 per QALY gained. Although the acceptability of an ICER value is subjective as well as dependent on jurisdiction, societal values, and total budget, among other things, this estimate is likely not considered cost effective in the current setting. This can be explained in part by the low prevalence of EML4-ALK fusion in patients with NSCLC and more importantly by the high cost of crizotinib. A similar effect was seen in an exploratory analysis of © 2014 by American Society of Clinical Oncology
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Table 2. Cost-Utility and Cost-Effectiveness Analysis Cost Strategy Screening and treatment model for advanced NSCLC Standard care EML4-ALK fusion testing Treatment model among EML4-ALK–positive patients Standard care Crizotinib first line
QALY
LY
ICER
Total
Incremental
Total
Incremental
Total
Incremental
Cost per QALY
Cost per LY
$14,912 $17,638
$2,725
0.302 0.313
0.011
0.62 0.64
0.018
$255,970
$160,583
$14,912 $109,955
$95,043
0.302 0.681
0.379
0.62 1.26
0.642
$250,632
$148,011
NOTE. Standard care was as follows: no testing; treatment with platinum doublet as first line, pemetrexed as second line, and erlotinib as third line. New strategy was: EML4-ALK fusion testing with crizotinib treatment as first line for EML4-ALK–positive patients, followed by conventional treatments for NSCLC. Abbreviations: ICER, incremental cost-effectiveness ratio; LY, life-year; NSCLC, non–small-cell lung cancer; QALY, quality-adjusted life-year.
ALK molecular testing, which used hypothetic life-year gains based on PFS with crizotinib to evaluate ALK molecular testing modalities and the effects of testing parameters such as cost and frequency of the biomarker on cost-effectiveness estimates.25 The use of genomic testing facilitates personalized treatment for smaller targeted populations, which may provide less incentive for pharmaceutical companies to develop drugs in small populations and in turn may drive up costs. Of approximately 8,000 new patient cases of lung cancer diagnosed in Ontario annually,26 an estimated 6,880 patients (86%) have nonsquamous NSCLC,24 and most would have advanced disease (approximately 5,160) and be
eligible for EML4-ALK fusion molecular testing. On the basis of EML4-ALK fusion frequency in this population, approximately 175 patients would be eligible for crizotinib treatment. The annual cost of ALK IHC testing with FISH confirmation in Ontario is estimated at $308,052, whereas the total cost of crizotinib treatment for patients with EML4-ALK–positive NSCLC in Ontario would be approximately $20 million at the current list price. Sensitivity analyses demonstrated the large impact of crizotinib cost on the cost effectiveness of the targeted pharmacogenomic strategy. At the current EML4-ALK fusion frequency (3% to 7%), substantial cost reductions might be needed to lower the ICER to a more
Parameters
Cycle cost for crizotinib Treatment-related utility on crizotinib Outcome discount rate Mortality on crizotinib Cost discount rate Treatment-related utility on platinum doublet Mortality from best supportive care Utility of best supportive care Cycle cost of pemetrexed Mortality on platinum doublet During-treatment utility on pemetrexed Probability of progression on platinum doublet Probability of progression on crizotinib Mortality on pemetrexed During-treatment utility on erlotinib Cycle cost for platinum doublet IHC test cost EML4-ALK fusion frequency Specificity of IHC test Mortality on erlotinib Probability of progressing to BSC on crizotinib Probability of progressing to BSC on platinum doublet Post-treatment utility on platinum doublet Cycle cost for erlotinib Cycle cost for best supportive care Post-treatment utility on pemetrexed FISH test cost $150,000
Fig 3. One-way sensitivity analysis. BSC, best supportive care; FISH, fluorescent in situ hybridization; ICER, incremental cost-effectiveness ratio; IHC, immunohistochemistry.
$200,000
$250,000
$300,000
$350,000
Magnitude of Change in ICER
6
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EML4-ALK Prevalence
Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
0.01 0.05
Base Case
0.10 0.15 0.20 ICER: ≤ $50,000/QALY gained ≤ $100,000/QALY gained ≤ $150,000/QALY gained
0.25 0.30 0.35 0.40 1,000
2,000
3,000
4,000
5,000
6,000
7,000
Cycle Cost ($CAD) Fig 4. Two-way sensitivity analysis of crizotinib cost versus ALK prevalence. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
acceptable value (Fig 4). In addition to lower drug costs, more targeted molecular testing or improved effectiveness would make this strategy more economically feasible. Introducing genomic testing to the larger NSCLC population as efficiently as possible remains a challenge. Selecting patients for genomic testing on the basis of ⱖ two clinical characteristics (younger age, female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology) would increase the prevalence of EML4-ALK fusion to 13% among 141 tumors evaluated,27 which would improve the cost effectiveness of the molecular testing and targeted treatment strategy. Recent studies have also found EML4-ALK, EGFR, and KRAS mutations to be mutually exclusive.28,29 Considering only never/light smokers without EGFR mutation, the frequency of EML4-ALK fusion could increase to as high as 33%, although this estimate is based on small numbers.27 Alternatively, multiplex testing, or testing for several genomic abnormalities in parallel, could be used to efficiently identify patient subgroups who would benefit from existing targeted therapies4,30 and spare the majority of patients from receiving noneffective treatments with associated toxicity and costs. In the future, economic evaluations of multiplex testing to guide treatment for patients with NSCLC could help inform decision makers. This study has several limitations. This evaluation was not conducted from head-to-head clinical data but was instead based on clinical and population-based studies. The probability of progression during crizotinib treatment was obtained from a single-arm phase I clinical trial including relatively young patients with good performance status. Probabilities for other lines of therapies were obtained from a review of an older population with nonsquamous NSCLC with poorer performance status. Because these data are noncomparative, the magnitude of benefit with crizotinib compared with conventional treatments is uncertain. Second, the utility score for each model state was estimated from a previous study,20 based on a formula derived from multivariable regression analysis for patients with NSCLC to REFERENCES 1. American Cancer Society: Cancer Facts and Figures 2013. http://www.cancer.org/acs/groups/content/ @epidemiologysurveilance/documents/document/acspc036845.pdf 2. Herbst RS, Heymach JV, Lippman SM: Lung cancer. N Engl J Med 359:1367-1380, 2008 www.jco.org
differentiate by clinical response and toxicities associated with drugs. This approach has not yet been validated. Finally, the external generalizability of these figures may be limited by the perspective taken for the analysis. A central public health care payer such as the province of Ontario commonly has lower administrative and drug costs relative to other jurisdictions, such as the United States.31,32 In conclusion, this is the first study to our knowledge investigating the cost effectiveness of targeted crizotinib therapy for treatment of advanced NSCLC with a Markov model. The results of our study suggest that EML4-ALK fusion molecular testing and targeted crizotinib treatment for patients with advanced nonsquamous NSCLC are currently not likely to be considered cost effective. Lower drug costs, more targeted molecular testing, or improved effectiveness would be required to make this strategy more economically feasible. The results of our study are preliminary, because they are based on noncomparative data; thus, future head-to-head clinical trials will provide valuable insight into the optimal treatment of advanced NSCLC. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jean-Claude Cutz, Pfizer (C) Stock Ownership: None Honoraria: Ming-Sound Tsao, Pfizer; Jean-Claude Cutz, Pfizer Research Funding: Ming-Sound Tsao, Pfizer; Jean-Claude Cutz, Pfizer Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Conception and design: Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, Natasha B. Leighl Financial support: Jeffrey S. Hoch Administrative support: Jeffrey S. Hoch, Ming-Sound Tsao Provision of study materials or patients: Ming-Sound Tsao, Jean-Claude Cutz, Natasha B. Leighl Collection and assembly of data: Sandjar Djalalov, Ming-Sound Tsao, Jean-Claude Cutz, Natasha B. Leighl Data analysis and interpretation: Sandjar Djalalov, Jaclyn Beca, Natasha B. Leighl Manuscript writing: All authors Final approval of manuscript: All authors
3. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 4. Dienstmann R, Martinez P, Felip E: Personalizing therapy with targeted agents in non-small cell lung cancer. Oncotarget 2:165-177, 2011 5. Shaw AT, Kim DW, Nakagawa K, et al: Phase III study of crizotinib ves pemetrexed or docetaxel
chemotherapy in patients with advanced ALKpositive NSCLC (profile 1007). Presented at the 37th European Society for Medical Oncology Congress, Vienna, Austria, September 28-October 2, 2012 (abstr 2862) 6. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol 13:1011-1019, 2012
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7. Kim DW, Ahn MJ, Shi Y, et al: Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 30:499s, 2012 (suppl; abstr 7533) 8. Crystal AS, Shaw AT: New targets in advanced NSCLC: EML4-ALK. Clin Adv Hematol Oncol 9:207-214, 2011 9. Takeuchi K, Choi YL, Togashi Y, et al: KIF5BALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:31433149, 2009 10. Mino-Kenudson M, Chirieac LR, Law K, et al: A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561-1571, 2010 11. Paik JH, Choe G, Kim H, et al: Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: Correlation with fluorescence in situ hybridization. J Thorac Oncol 6:466-472, 2011 11a. McLeer-Florin A, Moro-Sibilot D, Melis A, et al: Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: A French study. J Thorac Oncol 7:348-354, 2012 12. Yi ES, Boland JM, Maleszewski JJ, et al: Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 6:459-465, 2011 13. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131:1843, 2007
14. Leighl NB: Treatment paradigms for patients with metastatic non-small-cell lung cancer: First-, second-, and third-line. Curr Oncol 19:S52-S58, 2012 (suppl 1) 15. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 16. Guidelines for the Economic Evaluation of Health Technologies: Canada (ed 3). Ottawa, Ontario, Canada, Canadian Agency for Drugs and Technologies in Health, 2006 17. Tsao MS, Craddock K, Brandao G, et al: Canadian ALK (CALK): A pan-Canadian multicenter study to optimize and standardize ALK immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) for ALK gene rearrangements. J Clin Oncol 31, 2013 (suppl 15; abstr 8096) 18. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010 19. Chen W: Cost-Effectiveness of Epidermal Growth Factor Receptor Gene Mutation Testing For Patients With Advanced Non-Small Cell Lung Cancer Living in Ontario. http://old_theta.phm.utoronto. ca/papers/theta_EGFR-testing-for-lung-cancer.pdf 20. Nafees B, Stafford M, Gavriel S, et al: Health state utilities for non small cell lung cancer. Health Qual Life Outcomes 6:84, 2008 21. Ontario Case Costing Initiative (OCCI). http:// www.occp.com/mainPage.htm 22. Hon H, Qiu X, Tobros K, et al: Cancer patient acceptance, understanding, and willingness to pay for pharmacogenetic testing (PGT). J Clin Oncol 30:383s, 2012 (suppl; abstr 6005) 23. Shaw AT, Yeap BY, Solomon BJ, et al: Effect of crizotinib on overall survival in patients with
advanced non-small-cell lung cancer harbouring ALK gene rearrangement: A retrospective analysis. Lancet Oncol 12:1004-1012, 2011 24. Sacher AG, Le LW, Lau A, et al: Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer agents. J Clin Oncol 30:505s, 2012 (suppl; abstr 7606) 25. Atherly AJ, Camidge DR: The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer 106:1100-1106, 2012 26. Canadian Cancer Society Steering Committee on Cancer Statistics: Canadian Cancer Statistics 2011. Toronto, Ontario, Canada, Canadian Cancer Society, 2011 27. Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with non– small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009 28. Wong DW, Leung EL, So KK, et al: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723-1733, 2009 29. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-smallcell lung cancer. Nature 448:561-566, 2007 30. Janku F, Garrido-Laguna I, Petruzelka LB, et al: Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 6:1601-1612, 2011 31. Woolhandler S, Campbell T, Himmelstein DU: Costs of health care administration in the United States and Canada. N Engl J Med 349:768-775, 2003 32. Sguires D: Explaining High Health Care Spending in the United States: An International Comparison of Supply, Utilization, Prices, and Quality. http://www.commonwealthfund.org/Publications/IssueBriefs/2012/May/High-Health-Care-Spending.aspx
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
Acknowledgment We thank the peer reviewers for their comments. Appendix
Table A1. Weighted Average of Sensitivity and Specificity for IHC EML4-ALK Fusion Testing Antibody
Sensitivity (%)
Specificity (%)
Source
ALK1; Dako (Carpinteria, CA) 5A4; Abcam (Cambridge, United Kingdom) Polyclonal anti-ALK; Invitrogen (Carlsbad, CA) D5F3; Cell Signaling Technology (Danvers, MA) Overall
91 100 100 100 93
99 100 NA 99 99
Yi et al,12 Mino-Kenudson et al,10 Boland et al,ⴱ Rodig et al† Takeuchi et al9 Wong et al28 Mino-Kenudson et al10
Abbreviations: IHC, immunohistochemistry; NA, not applicable. ⴱ Boland JM, et al: Hum Pathol 40:1152-1158, 2009 †Rodig SJ, et al: Clin Cancer Res 15:5216-5223, 2009
ICER ($/QALY gained)
268,000
264,000
262,000
256,000
252,000 Baseline value
248,000 0
3.4
10
20
30
40
ALK Frequency in NSCLC (%) Fig A1. One-way sensitivity analysis of ALK frequency in non–small-cell lung cancer (NSCLC). ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
400,000
ICER ($/QALY gained)
350,000 300,000 250,000 200,000 150,000 Baseline value
100,000 50,000
0
2,000
4,000
6,000
8,000
10,000
Crizotinib per Cycle ($CAN) Fig A2. One-way sensitivity analysis of cost of crizotinib per cycle. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
www.jco.org
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9
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Cost Effectiveness of EML4-ALK Fusion Testing and First-Line Crizotinib Treatment for Patients With Advanced ALK-Positive Non–Small-Cell Lung Cancer Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, Ming-Sound Tsao, Jean-Claude Cutz, and Natasha B. Leighl See accompanying editorial doi: 10.1200/JCO.2013.54.6002 Sandjar Djalalov, Jaclyn Beca, and Jeffrey S. Hoch, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital and Cancer Care Ontario; Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, and Natasha B. Leighl, Canadian Centre for Applied Research in Cancer Control; Murray Krahn, Toronto Health Economics and Technology Assessment Collaborative; Ming-Sound Tsao and Natasha B. Leighl, Ontario Cancer Institute and Princess Margaret Cancer Centre, Toronto; and Jean-Claude Cutz, McMaster University, Hamilton, Ontario, Canada. Published online ahead of print at www.jco.org on February 24, 2014. The Cancer Care Ontario Pharmacoeconomics Research Unit is supported by Cancer Care Ontario, and the Canadian Centre for Applied Research in Cancer Control is supported by the Canadian Cancer Society. The findings do not necessarily represent the views of the funders. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Natasha B. Leighl, MD, MMedSc, Princess Margaret Hospital, 5th Floor, Room 105, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3299-1/$20.00 DOI: 10.1200/JCO.2013.53.1186
A
B
S
T
R
A
C
T
Purpose ALK-targeted therapy with crizotinib offers significant improvement in clinical outcomes for the treatment of EML4-ALK fusion–positive non–small-cell lung cancer (NSCLC). We estimated the cost effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment in Ontario. Patients and Methods A cost-effectiveness analysis was conducted using a Markov model from the Canadian Public health (Ontario) perspective and a lifetime horizon in patients with stage IV NSCLC with nonsquamous 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 literature. Results Molecular testing with first-line targeted crizotinib treatment in the population with advanced nonsquamous NSCLC resulted in a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care. The incremental cost was Canadian $2,725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with known EML4-ALK–positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained. The major driver of cost effectiveness was drug price. Conclusion EML4-ALK fusion testing in stage IV nonsquamous NSCLC with crizotinib treatment for ALKpositive patients is not cost effective in the setting of high drug costs and a low biomarker frequency in the population. J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Lung cancer remains the leading cause of death resulting from cancer in North America1 and worldwide. Non–small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers, predominantly of nonsquamous subtype, including adenocarcinoma.2 Most patients have advanced disease at the time of diagnosis. Although cytotoxic chemotherapy is the mainstay of treatment in advanced NSCLC, its effectiveness has reached a plateau, and therapeutic outcomes remain disappointing.3,4 Recent advances in the understanding of the molecular biology of lung cancer
have led to practice-changing developments in molecularly targeted therapy. Over the past decade, activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been identified as the major predictor of benefit with EGFR tyrosine kinase inhibitors (TKIs), and EGFR TKI therapy is the initial treatment of choice in patients with advanced EGFR mutation–positive NSCLC. More recently, the fusion of echinoderm microtubule–associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes has been identified as an oncogenic driver in NSCLC. Although initially described in a case of squamous carcinoma of the © 2014 by American Society of Clinical Oncology
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lung, this fusion gene is more commonly found in never-smokers with EGFR wild-type lung adenocarcinoma. Crizotinib is a TKI with known activity against EML4-ALK, MET, and ROS-1. Crizotinib therapy dramatically increased response rates (RRs) and progressionfree survival (PFS) in patients with advanced NSCLC with ALK rearrangements compared with second-line chemotherapy (RR, 65.3% v 19.5%; P ⬍ .001; median PFS, 7.7 v 3.0 months, respectively; hazard ratio [HR], 0.49; P ⬍ .001)5 and in heavily pretreated patients with NSCLC with ALK translocations (RR, 50% to 60%; median PFS, 8 to 10 months).6,7 The frequency of ALK translocations in advanced nonsquamous NSCLC has been estimated at between 2% and 7%.8 The current US Food and Drug Administration and Health Canada label for crizotinib use in NSCLC is for crizotinib monotherapy in advanced ALK-positive NSCLC, without restriction in prior therapies. It is expected that the ongoing trials in first-line advanced ALK-positive NSCLC will demonstrate superiority with crizotinib. There are several methods for detecting ALK-fusion gene rearrangements in tumor tissue. Fluorescent in situ hybridization (FISH), using the Abbott Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Des Plaines, IL), has emerged as the gold standard and was used in initial clinical studies to select patients most likely to benefit from ALK inhibitor therapies. Other methods include reverse transcriptase polymerase chain reaction– based assays, immunohistochemistry (IHC) for aberrant expression of ALK protein, and Sanger sequencing. FISH has been shown to be both sensitive and specific but requires specialized technical resources and expertise and is time consuming; as a result, the assay is not readily available in all laboratories. Although reverse transcriptase polymerase chain reaction can detect both EML4 and ALK fusion, it is prone to false-positive results secondary to contamination and should only be conducted in specialized settings, with verification of positive results.8 IHC can be performed quickly and with relative ease in pathology laboratories and can be used on smaller tissue samples. New antibodies have been developed, increasing the sensitivity and specificity of IHC testing for ALK.9 Until recently, the evidence supporting ALK IHC in routine clinical practice was limited.10 However, the accuracy of IHC molecular testing was recently examined in several studies and was shown to correlate highly with FISH results, supporting the use of IHC for detecting EML4-ALK fusion.11,11a,12 In 2011, the US Food and Drug Administration approved crizotinib for patients with NSCLC whose tumors harbor the EML4-ALK fusion gene, as detected by the Vysis ALK Break Apart FISH Probe companion diagnostic (Abbott Molecular). However, there are challenges to implementing molecular testing with FISH for ALK fusion in NSCLC, including the high incidence of the disease, low frequency of ALK fusion, and complexity, cost, and tissue requirements for testing. Using a more widely available molecular testing method such as IHC to detect positive or equivocal cases, with FISH confirmation as needed, would reduce cost and facilitate population-based molecular testing. Many jurisdictions use this approach for the detection of HER2-amplified breast cancer to direct use of trastuzumab therapy.13 In our study, we evaluated the cost effectiveness of both EML4-ALK fusion testing and first-line therapy with crizotinib for patients with advanced ALK fusion–positive NSCLC, from the perspective of the Canadian public health care system. 2
© 2014 by American Society of Clinical Oncology
PATIENTS AND METHODS Overview and Treatment Strategies A decision analytic model was developed to compare lifetime benefits and direct medical costs between two strategies in patients with advanced NSCLC (Fig 1). The target population was treatment-naive Ontario patients with advanced nonsquamous NSCLC. Our main analysis for molecular testing and targeted treatment involved patients with advanced NSCLC and compared EML4-ALK fusion molecular testing for all patients and targeted crizotinib treatment for patients with EML4-ALK fusion–positive NSCLC with standard care. Our supplementary analysis for treatment involved known patients with EML4-ALK fusion– positive NSCLC and compared crizotinib treatment with standard care, without testing patients with advanced NSCLC. In the standard care strategy, patients receive conventional treatment for NSCLC, which includes platinum doublet (cisplatin and gemcitabine) as firstline therapy, pemetrexed as second-line therapy, and erlotinib as third-line therapy.14 The EML4-ALK fusion molecular testing strategy involved EML4ALK fusion molecular testing in all patients diagnosed with nonsquamous NSCLC with good performance status (Eastern Cooperative Oncology Group/Zubrod performance status ⱕ 2). For those who accepted testing, tumor samples were screened for ALK fusion protein with IHC in a certified laboratory in Ontario (Clinical Laboratory Improvement Amendments). Positive IHC staining was confirmed using FISH testing. If there was inadequate tissue for testing, patients could undergo repeat biopsy. Those with EML4ALK–positive tumors received crizotinib 250 mg orally twice per day as firstline therapy, followed by conventional treatments for NSCLC on progression. Those with EML4-ALK–negative or unknown tumors received conventional treatments for NSCLC. In both strategies, patients also received best supportive care (BSC) when not receiving systemic therapy. Model Structure A Markov model was developed to reflect the natural history of advanced NSCLC. During each 3-week cycle, patients faced the following possibilities: one, continuing on therapy; two, stopping therapy with stable disease; three, progression of disease and starting subsequent therapy; four, progression of disease and receiving BSC alone; and five, death. Platinum doublet chemotherapy with gemcitabine/cisplatin was administered for up to four cycles, and pemetrexed therapy was administered for four cycles based on median treatment duration in previous randomized trials.15 Crizotinib and erlotinib were administered until disease progression or treatment discontinuation for adverse events (Fig 2). Economic Assumptions We performed a cost-utility analysis from the perspective of the provincial government single-payer system, the Ontario Ministry of Health and Long-Term Care. Both benefits and direct medical costs were discounted at 5% per annum based on Canadian guidelines.16 Health benefits were expressed as life-years and quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental cost difference between strategies by the incremental difference in health outcomes (life-years and QALYs). A lifetime horizon was used for the model (4.2 years). Probabilities The frequency of the EML4-ALK fusion gene in Canadian patients with advanced nonsquamous NSCLC has been estimated at 3.4%, the test failure rate resulting from inadequate tissue at 10%, and rebiopsy frequency at 15%, obtained from expert opinion and an ongoing pan-Canadian study17 (Table 1). The probability of patients with cancer accepting pharmacogenomic testing is 95% based on a recent study.22 Progression during first-line crizotinib therapy was estimated from a phase I study of 82 patients with EML4-ALK– positive advanced NSCLC receiving the recommended crizotinib dose of 250 mg twice per day.6 A Weibull model was fitted to the Kaplan-Meier PFS curve to estimate transition probabilities for each 3-week cycle. The mortality rate during first-line crizotinib therapy was estimated from a retrospective analysis of crizotinib therapy versus observation in patients with JOURNAL OF CLINICAL ONCOLOGY
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
FISH test confirmed
[+] EML4-ALK fusion positive
M
FISH test not confirmed
M
Tissue adequate EML4-ALK fusion negative and unknown (failure)
Accept IHC test
M Rebiopsy
[+]
Fig 1. Decision tree. M indicates movement into the Markov model, depicted in Figure 2. FISH, fluorescent in situ hybridization; IHC, immunohistochemistry.
Yes Tissue inadequate
No rebiopsy
M M
IHC test not accepted
EML4-ALK fusion testing
No
M
EML4-ALK fusion–positive advanced NSCLC.23 It was estimated that 70% of patients experiencing progression with crizotinib would be eligible for subsequent chemotherapy, whereas 30% would receive BSC alone, based on clinical expert opinion (Canadian investigators participating in crizotinib trials). Transition probabilities and mortality rates for platinum doublet therapy with gemcitabine/cisplatin, pemetrexed therapy, and BSC were calculated based on median time to next treatment or death from a review of 8,113 patients obtained from the Cancer Care Ontario New Drug Funding Program– and Activity Level Reporting–linked databases from 2005 to 2009.24 Probabilities for erlotinib progression were obtained from two clinical trials with 513 patients. To assess the validity of the model, we verified outcomes generated by the model at 20 and 40 weeks with reported trial outcomes for PFS.18 Utility Estimates Utility scores were derived from a mixed-model regression analysis for different stages of NSCLC and grade 3 to 4 toxicities commonly associated with chemotherapy treatments,20 using as inputs estimates of clinical response and main toxicities for conventional treatments19 and crizotinib18 (Table 1). Cost The costs for EML4-ALK fusion testing using IHC and FISH were obtained from the University Health Network laboratory medicine program. The cost of repeat biopsy was obtained from the Ontario Case Costing Initiative.21 The direct medical cost of each treatment included drug costs, administration costs, management of adverse events, and usual medical care. The costs of intravenous drugs were obtained from the Cancer Care Ontario New Drug Funding Program and oral medications from the outpatient pharmacy at the www.jco.org
Princess Margaret Cancer Centre (Toronto, Ontario, Canada), including 10% markup per current pharmacy practice. All estimated costs were adjusted to 2012 Canadian dollars using the consumer price index for Ontario (Table 1). ALK Testing Specificity and Sensitivity The specificity and sensitivity of FISH testing for EML4-ALK fusion are presumed to be 100%, because they are the current gold standard. Using the most commonly used IHC antibodies, we found from systematic review a weighted average of 93% sensitivity and 99% specificity for IHC (Appendix Table A1, online only). Because clinical opinion and unpublished results from the IHC testing studies suggest that IHC can be optimized beyond the results of the systematic review, the final inputs for the model were 95% sensitivity and 100% specificity. Assumptions We assumed that the benefit from crizotinib in pretreated EML4-ALK fusion–positive patients18 would be similar to that from crizotinib use in the first-line setting. Although this is a conservative estimate of benefit, data from ongoing first-line trials are not yet available. In addition, transition probabilities for progression and mortality rates for each treatment were deemed similar in the molecular testing versus standard care strategies. Sensitivity Analysis We varied all parameters separately in one-way and selected two-way sensitivity analyses. For crizotinib, we used the 95% CIs of parameters from regression as the upper and lower limits. For other parameters, we varied probabilities and utilities by 20% and costs by 30% (ranges listed in Table 1). © 2014 by American Society of Clinical Oncology
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EML4-ALK positive only
Crizotinib
EML4-ALK negative and unknown
Best supportive care
Platinum doublet
Best supportive care
Pemetrexed
Death
Post-treatment “stable”
Fig 2. Markov model.
Post-treatment “stable”
Best supportive care
Erlotinib
Best supportive care
We also conducted scenarios to assess the impact of our assumptions about testing and treatment.
RESULTS
The use of EML4-ALK fusion testing and targeted crizotinib treatment for EML4-ALK–positive advanced NSCLC results in added benefits (0.011 QALYs) as well as extra costs ($2,725; costs given in Canadian dollars throughout) for the average patient with NSCLC (Table 2). Of these extra costs, $60 was attributed to the cost of molecular testing. EML4-ALK fusion molecular testing and targeted crizotinib treatment in advanced NSCLC cost an additional $255,970 per QALY gained compared with standard care with no testing and no crizotinib treatment. From the supplementary analysis for treatment, the extra cost for a patient receiving treatment with crizotinib was $95,043, and the resulting ICER was $250,632 per QALY gained for patients with EML4-ALK–positive NSCLC treated with crizotinib instead of standard care. The results of the one-way sensitivity analysis indicated that the primary drivers of the ICER were the relative treatment-related utility with crizotinib and the cost of crizotinib treatment (Fig 3). The large impact of treatment-related utility resulted from its benefit or harm 4
© 2014 by American Society of Clinical Oncology
relative to the comparator. The base value for crizotinib utility was 0.03 higher than that for platinum doublet, and the ICER increased if the utility with crizotinib decreased (tested to 0.08 ⬍ platinum doublet in sensitivity analysis). The model was also sensitive to progression with crizotinib; if crizotinib performed less effectively in the real world compared with the trial, the ICER would increase. The model was not sensitive to the costs of molecular testing. The relationship between the ICER and EML4-ALK frequency in NSCLC is shown in Appendix Figure A1 (online only). The impact of biomarker frequency on cost effectiveness was minimal, whereas the ICER was moderately sensitive to lower biomarker frequencies. The ICER remained high with higher EML4-ALK frequencies, because the high drug costs offset the health gains (ie, finding more people who benefit means more people using an expensive treatment). The ICER had a linear relationship with the cost of crizotinib treatment (Appendix Fig A2, online only). In a scenario in which the crizotinib cost was zero, EML4-ALK fusion molecular testing and targeted crizotinib treatment was cost saving, indicating high sensitivity to crizotinib pricing. With potential payer concerns about the adoption of testing, we explored scenarios examining different testing strategies. If, instead of JOURNAL OF CLINICAL ONCOLOGY
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
Table 1. Transition Probabilities, Utilities, and Costs Variable
Value
Lower Limit
Upper Limit
0.017
0.014
0.020
Kwak et al18
0.199 0.155 0.22
0.159 0.124 0.176
0.239 0.186 0.264
CCO NDFP CCO NDFP CCO NDFP
0.0051
0.004
0.006
Kwak et al18
0.146 0.170
0.117 0.136
0.175 0.204
CCO NDFP CCO NDFP
0.015
0.012
0.018
Shaw et al5
0.05 0.069 0.074 0.107
0.040 0.055 0.059 0.086
0.060 0.083 0.089 0.128
Chen19 Chen19 Chen19 Chen19
0.5668
0.453
0.680
Author calculations, Nafees et al20
0.5353
0.428
0.642
Chen,19 Nafees et al20
0.6166
0.493
0.740
Chen,19 Nafees et al20
0.4537 0.5704 0.4798 0.4734
0.363 0.456 0.384 0.379
0.544 0.684 0.576 0.568
Chen,19 Chen,19 Chen,19 Chen,19
Source
Transition probabilities Progression Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Mortality rates Crizotinib Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC Utilities Crizotinib Platinum doublet (cisplatin and gemcitabine) during treatment Platinum doublet (cisplatin and gemcitabine) after treatment Pemetrexed during treatment Pemetrexed after treatment Erlotinib BSC Costs IHC test FISH test Rebiopsy Crizotinib
$40 $388 $712 $7,000
$28 $272 $498 $4,900
$52 $504 $926 $9,100
UHN Molecular Diagnostics Laboratory UHN Molecular Diagnostics Laboratory Ontario Case Costing Initiative21 PMH Pharmacy (Sandjar Djalalov, personal communication, August 2012)
Platinum doublet (cisplatin and gemcitabine) Pemetrexed Erlotinib BSC
$1,527 $5,900 $2,229 $582
$1,069 $4,130 $1,560 $407
$1,985 $7,670 $2,898 $757
Chen19 Chen19 Chen19 Chen19
Nafees Nafees Nafees Nafees
et et et et
al20 al20 al20 al20
NOTE. All treatment costs are for 3-week cycle and given in Canadian dollars. Abbreviations: BSC, best supportive care; CCO NDFP, Cancer Care Ontario New Drug Funding Program; IHC, immunohistochemistry; PMH, Princess Margaret Hospital; UHN, University Health Network.
IHC molecular testing, all patients were tested with the more expensive FISH test, the ICER increased by 11% to $284,511 per QALY gained. If only IHC testing was used without FISH confirmation for EML4-ALK–positive patients, the ICER decreased only slightly to $254,939 per QALY gained. Finally, if the health care system bore none of the costs related to testing, the ICER would decrease to $250,632 per QALY gained. DISCUSSION
This study examined the cost effectiveness of EML4-ALK fusion testing with targeted crizotinib treatment for patients with NSCLC www.jco.org
using a Markov model and Ontario administrative data. We estimated that for patients with stage IV nonsquamous NSCLC at initiation of therapy, the incremental cost-effectiveness ratio of a targeted pharmacogenomic strategy using EML4-ALK fusion testing and targeted crizotinib therapy versus standard care was $255,970 per QALY gained. Although the acceptability of an ICER value is subjective as well as dependent on jurisdiction, societal values, and total budget, among other things, this estimate is likely not considered cost effective in the current setting. This can be explained in part by the low prevalence of EML4-ALK fusion in patients with NSCLC and more importantly by the high cost of crizotinib. A similar effect was seen in an exploratory analysis of © 2014 by American Society of Clinical Oncology
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Table 2. Cost-Utility and Cost-Effectiveness Analysis Cost Strategy Screening and treatment model for advanced NSCLC Standard care EML4-ALK fusion testing Treatment model among EML4-ALK–positive patients Standard care Crizotinib first line
QALY
LY
ICER
Total
Incremental
Total
Incremental
Total
Incremental
Cost per QALY
Cost per LY
$14,912 $17,638
$2,725
0.302 0.313
0.011
0.62 0.64
0.018
$255,970
$160,583
$14,912 $109,955
$95,043
0.302 0.681
0.379
0.62 1.26
0.642
$250,632
$148,011
NOTE. Standard care was as follows: no testing; treatment with platinum doublet as first line, pemetrexed as second line, and erlotinib as third line. New strategy was: EML4-ALK fusion testing with crizotinib treatment as first line for EML4-ALK–positive patients, followed by conventional treatments for NSCLC. Abbreviations: ICER, incremental cost-effectiveness ratio; LY, life-year; NSCLC, non–small-cell lung cancer; QALY, quality-adjusted life-year.
ALK molecular testing, which used hypothetic life-year gains based on PFS with crizotinib to evaluate ALK molecular testing modalities and the effects of testing parameters such as cost and frequency of the biomarker on cost-effectiveness estimates.25 The use of genomic testing facilitates personalized treatment for smaller targeted populations, which may provide less incentive for pharmaceutical companies to develop drugs in small populations and in turn may drive up costs. Of approximately 8,000 new patient cases of lung cancer diagnosed in Ontario annually,26 an estimated 6,880 patients (86%) have nonsquamous NSCLC,24 and most would have advanced disease (approximately 5,160) and be
eligible for EML4-ALK fusion molecular testing. On the basis of EML4-ALK fusion frequency in this population, approximately 175 patients would be eligible for crizotinib treatment. The annual cost of ALK IHC testing with FISH confirmation in Ontario is estimated at $308,052, whereas the total cost of crizotinib treatment for patients with EML4-ALK–positive NSCLC in Ontario would be approximately $20 million at the current list price. Sensitivity analyses demonstrated the large impact of crizotinib cost on the cost effectiveness of the targeted pharmacogenomic strategy. At the current EML4-ALK fusion frequency (3% to 7%), substantial cost reductions might be needed to lower the ICER to a more
Parameters
Cycle cost for crizotinib Treatment-related utility on crizotinib Outcome discount rate Mortality on crizotinib Cost discount rate Treatment-related utility on platinum doublet Mortality from best supportive care Utility of best supportive care Cycle cost of pemetrexed Mortality on platinum doublet During-treatment utility on pemetrexed Probability of progression on platinum doublet Probability of progression on crizotinib Mortality on pemetrexed During-treatment utility on erlotinib Cycle cost for platinum doublet IHC test cost EML4-ALK fusion frequency Specificity of IHC test Mortality on erlotinib Probability of progressing to BSC on crizotinib Probability of progressing to BSC on platinum doublet Post-treatment utility on platinum doublet Cycle cost for erlotinib Cycle cost for best supportive care Post-treatment utility on pemetrexed FISH test cost $150,000
Fig 3. One-way sensitivity analysis. BSC, best supportive care; FISH, fluorescent in situ hybridization; ICER, incremental cost-effectiveness ratio; IHC, immunohistochemistry.
$200,000
$250,000
$300,000
$350,000
Magnitude of Change in ICER
6
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EML4-ALK Prevalence
Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
0.01 0.05
Base Case
0.10 0.15 0.20 ICER: ≤ $50,000/QALY gained ≤ $100,000/QALY gained ≤ $150,000/QALY gained
0.25 0.30 0.35 0.40 1,000
2,000
3,000
4,000
5,000
6,000
7,000
Cycle Cost ($CAD) Fig 4. Two-way sensitivity analysis of crizotinib cost versus ALK prevalence. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
acceptable value (Fig 4). In addition to lower drug costs, more targeted molecular testing or improved effectiveness would make this strategy more economically feasible. Introducing genomic testing to the larger NSCLC population as efficiently as possible remains a challenge. Selecting patients for genomic testing on the basis of ⱖ two clinical characteristics (younger age, female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology) would increase the prevalence of EML4-ALK fusion to 13% among 141 tumors evaluated,27 which would improve the cost effectiveness of the molecular testing and targeted treatment strategy. Recent studies have also found EML4-ALK, EGFR, and KRAS mutations to be mutually exclusive.28,29 Considering only never/light smokers without EGFR mutation, the frequency of EML4-ALK fusion could increase to as high as 33%, although this estimate is based on small numbers.27 Alternatively, multiplex testing, or testing for several genomic abnormalities in parallel, could be used to efficiently identify patient subgroups who would benefit from existing targeted therapies4,30 and spare the majority of patients from receiving noneffective treatments with associated toxicity and costs. In the future, economic evaluations of multiplex testing to guide treatment for patients with NSCLC could help inform decision makers. This study has several limitations. This evaluation was not conducted from head-to-head clinical data but was instead based on clinical and population-based studies. The probability of progression during crizotinib treatment was obtained from a single-arm phase I clinical trial including relatively young patients with good performance status. Probabilities for other lines of therapies were obtained from a review of an older population with nonsquamous NSCLC with poorer performance status. Because these data are noncomparative, the magnitude of benefit with crizotinib compared with conventional treatments is uncertain. Second, the utility score for each model state was estimated from a previous study,20 based on a formula derived from multivariable regression analysis for patients with NSCLC to REFERENCES 1. American Cancer Society: Cancer Facts and Figures 2013. http://www.cancer.org/acs/groups/content/ @epidemiologysurveilance/documents/document/acspc036845.pdf 2. Herbst RS, Heymach JV, Lippman SM: Lung cancer. N Engl J Med 359:1367-1380, 2008 www.jco.org
differentiate by clinical response and toxicities associated with drugs. This approach has not yet been validated. Finally, the external generalizability of these figures may be limited by the perspective taken for the analysis. A central public health care payer such as the province of Ontario commonly has lower administrative and drug costs relative to other jurisdictions, such as the United States.31,32 In conclusion, this is the first study to our knowledge investigating the cost effectiveness of targeted crizotinib therapy for treatment of advanced NSCLC with a Markov model. The results of our study suggest that EML4-ALK fusion molecular testing and targeted crizotinib treatment for patients with advanced nonsquamous NSCLC are currently not likely to be considered cost effective. Lower drug costs, more targeted molecular testing, or improved effectiveness would be required to make this strategy more economically feasible. The results of our study are preliminary, because they are based on noncomparative data; thus, future head-to-head clinical trials will provide valuable insight into the optimal treatment of advanced NSCLC. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jean-Claude Cutz, Pfizer (C) Stock Ownership: None Honoraria: Ming-Sound Tsao, Pfizer; Jean-Claude Cutz, Pfizer Research Funding: Ming-Sound Tsao, Pfizer; Jean-Claude Cutz, Pfizer Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Conception and design: Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, Natasha B. Leighl Financial support: Jeffrey S. Hoch Administrative support: Jeffrey S. Hoch, Ming-Sound Tsao Provision of study materials or patients: Ming-Sound Tsao, Jean-Claude Cutz, Natasha B. Leighl Collection and assembly of data: Sandjar Djalalov, Ming-Sound Tsao, Jean-Claude Cutz, Natasha B. Leighl Data analysis and interpretation: Sandjar Djalalov, Jaclyn Beca, Natasha B. Leighl Manuscript writing: All authors Final approval of manuscript: All authors
3. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 4. Dienstmann R, Martinez P, Felip E: Personalizing therapy with targeted agents in non-small cell lung cancer. Oncotarget 2:165-177, 2011 5. Shaw AT, Kim DW, Nakagawa K, et al: Phase III study of crizotinib ves pemetrexed or docetaxel
chemotherapy in patients with advanced ALKpositive NSCLC (profile 1007). Presented at the 37th European Society for Medical Oncology Congress, Vienna, Austria, September 28-October 2, 2012 (abstr 2862) 6. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol 13:1011-1019, 2012
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7. Kim DW, Ahn MJ, Shi Y, et al: Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 30:499s, 2012 (suppl; abstr 7533) 8. Crystal AS, Shaw AT: New targets in advanced NSCLC: EML4-ALK. Clin Adv Hematol Oncol 9:207-214, 2011 9. Takeuchi K, Choi YL, Togashi Y, et al: KIF5BALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:31433149, 2009 10. Mino-Kenudson M, Chirieac LR, Law K, et al: A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561-1571, 2010 11. Paik JH, Choe G, Kim H, et al: Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: Correlation with fluorescence in situ hybridization. J Thorac Oncol 6:466-472, 2011 11a. McLeer-Florin A, Moro-Sibilot D, Melis A, et al: Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: A French study. J Thorac Oncol 7:348-354, 2012 12. Yi ES, Boland JM, Maleszewski JJ, et al: Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 6:459-465, 2011 13. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131:1843, 2007
14. Leighl NB: Treatment paradigms for patients with metastatic non-small-cell lung cancer: First-, second-, and third-line. Curr Oncol 19:S52-S58, 2012 (suppl 1) 15. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 16. Guidelines for the Economic Evaluation of Health Technologies: Canada (ed 3). Ottawa, Ontario, Canada, Canadian Agency for Drugs and Technologies in Health, 2006 17. Tsao MS, Craddock K, Brandao G, et al: Canadian ALK (CALK): A pan-Canadian multicenter study to optimize and standardize ALK immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) for ALK gene rearrangements. J Clin Oncol 31, 2013 (suppl 15; abstr 8096) 18. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010 19. Chen W: Cost-Effectiveness of Epidermal Growth Factor Receptor Gene Mutation Testing For Patients With Advanced Non-Small Cell Lung Cancer Living in Ontario. http://old_theta.phm.utoronto. ca/papers/theta_EGFR-testing-for-lung-cancer.pdf 20. Nafees B, Stafford M, Gavriel S, et al: Health state utilities for non small cell lung cancer. Health Qual Life Outcomes 6:84, 2008 21. Ontario Case Costing Initiative (OCCI). http:// www.occp.com/mainPage.htm 22. Hon H, Qiu X, Tobros K, et al: Cancer patient acceptance, understanding, and willingness to pay for pharmacogenetic testing (PGT). J Clin Oncol 30:383s, 2012 (suppl; abstr 6005) 23. Shaw AT, Yeap BY, Solomon BJ, et al: Effect of crizotinib on overall survival in patients with
advanced non-small-cell lung cancer harbouring ALK gene rearrangement: A retrospective analysis. Lancet Oncol 12:1004-1012, 2011 24. Sacher AG, Le LW, Lau A, et al: Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer agents. J Clin Oncol 30:505s, 2012 (suppl; abstr 7606) 25. Atherly AJ, Camidge DR: The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. Br J Cancer 106:1100-1106, 2012 26. Canadian Cancer Society Steering Committee on Cancer Statistics: Canadian Cancer Statistics 2011. Toronto, Ontario, Canada, Canadian Cancer Society, 2011 27. Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with non– small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009 28. Wong DW, Leung EL, So KK, et al: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723-1733, 2009 29. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-smallcell lung cancer. Nature 448:561-566, 2007 30. Janku F, Garrido-Laguna I, Petruzelka LB, et al: Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 6:1601-1612, 2011 31. Woolhandler S, Campbell T, Himmelstein DU: Costs of health care administration in the United States and Canada. N Engl J Med 349:768-775, 2003 32. Sguires D: Explaining High Health Care Spending in the United States: An International Comparison of Supply, Utilization, Prices, and Quality. http://www.commonwealthfund.org/Publications/IssueBriefs/2012/May/High-Health-Care-Spending.aspx
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Cost Effectiveness of Crizotinib in ALK-Rearranged NSCLC
Acknowledgment We thank the peer reviewers for their comments. Appendix
Table A1. Weighted Average of Sensitivity and Specificity for IHC EML4-ALK Fusion Testing Antibody
Sensitivity (%)
Specificity (%)
Source
ALK1; Dako (Carpinteria, CA) 5A4; Abcam (Cambridge, United Kingdom) Polyclonal anti-ALK; Invitrogen (Carlsbad, CA) D5F3; Cell Signaling Technology (Danvers, MA) Overall
91 100 100 100 93
99 100 NA 99 99
Yi et al,12 Mino-Kenudson et al,10 Boland et al,ⴱ Rodig et al† Takeuchi et al9 Wong et al28 Mino-Kenudson et al10
Abbreviations: IHC, immunohistochemistry; NA, not applicable. ⴱ Boland JM, et al: Hum Pathol 40:1152-1158, 2009 †Rodig SJ, et al: Clin Cancer Res 15:5216-5223, 2009
ICER ($/QALY gained)
268,000
264,000
262,000
256,000
252,000 Baseline value
248,000 0
3.4
10
20
30
40
ALK Frequency in NSCLC (%) Fig A1. One-way sensitivity analysis of ALK frequency in non–small-cell lung cancer (NSCLC). ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
400,000
ICER ($/QALY gained)
350,000 300,000 250,000 200,000 150,000 Baseline value
100,000 50,000
0
2,000
4,000
6,000
8,000
10,000
Crizotinib per Cycle ($CAN) Fig A2. One-way sensitivity analysis of cost of crizotinib per cycle. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
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9
