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Targeted Cancer Therapy: From Bench to Bedside to Patient Walid F. Gellad, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System; University of Pittsburgh, Pittsburgh, PA See accompanying article on page 306

The decades of research that finally brought imatinib to the bedside make for a tremendous story of scientific discovery.1 Before imatinib was introduced, the median survival for patients with chronic myeloid leukemia (CML) was 4 to 6 years, and the main therapy was interferon, which prolonged life modestly, but made patients quite sick. In contrast, overall survival was 89% after 5 years among CML patients treated initially with imatinib in an analysis of data from the pivotal IRIS study (International Randomized Study of Interferon and STI571)2—an incredible statistic for a cancer that had been uniformly fatal. This remarkable progress in cancer treatment has been accompanied by a paradigm shift in medication delivery; namely, the advent of effective oral treatment for cancer and the shift in treatment away from the oncologist’s office and into the patient’s home. While the focus of drug development research has been to bring scientific discoveries like imatinib to the bedside, there has traditionally been little emphasis on making sure patients subsequently take the medications correctly once prescribed—the final step in the bench to bedside to patient pathway. The success of oncologic treatment, however, will increasingly depend on the patient’s adherence to home-administered, rather than office-administered, medication regimens. Medication nonadherence is an enormous public health challenge with important clinical consequences. It has been estimated that up to half of chronic disease medications are not taken as prescribed,3,4 and 20% to 30% of prescription medications are never filled.5 Estimates for the costs of medication nonadherence exceed $100 billion annually, due to increased health services utilization, hospital admission, and adverse drug events associated with nonadherence.6 The clinical consequences of nonadherence to cancer therapy are also well described.7,8 Nonadherence, in fact, has been identified as a critical factor in nonresponse, and loss of response, to imatinib.9-12 The barriers to optimal medication adherence in chronic disease are numerous,13,14 and they are relevant for patients with chronic cancers like CML. One of the most studied barriers to adherence is cost, and most studies come to the same conclusion— higher cost sharing for drugs is associated with worsened medication adherence.15,16 The largest, and perhaps only, randomized trial of a policy intervention to lower cost sharing was reported in 2012: The PostMyocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial.17 Patients discharged after myocardial infarction were randomly assigned to receive their cardiovascular medications for free 268

© 2013 by American Society of Clinical Oncology

or for their usual copay. Rates of adherence were 4 to 6 percentage points higher in the free-drug group compared with usual care. Although there was no significant between-group difference in the primary outcome of time to first major vascular event, the rates of total major vascular events were lower in the intervention group (HR 0.89, 95% CI 0.80 to 0.99), and the elimination of copayments did not increase total spending.17 It is in this context that Dusetzina et al18 describe the relationship between cost sharing and adherence to tyrosine kinase inhibitors (TKIs) in the article accompanying this editorial. Using 10 years of data on commercially insured adults age 18 to 64 years, the authors examined adherence to TKIs among 1,541 patients who newly initiated imatinib for their CML. The median cost for patients for a 30-day supply of imatinib was $30, but ranged from $0 to $4,792. In analyses accounting for a range of possible confounders, the authors found a 70% increase in risk of discontinuing TKIs among patients in the upper 75th percentile of cost sharing compared with those below the 75th percentile (risk ratio 1.70, 95% CI 1.30 to 2.22). Among these new imatinib users, 10% of patients with lower copayments and 17% of those with higher copayments stopped their medication during the first 6 months after treatment initiation. At first glance, the findings are not surprising given the large extant literature on the effect of costs on adherence. But this prior literature has focused on the traditional chronic diseases (diabetes, hypertension, hyperlipidemia), and not on new chronic diseases like CML (with rare exceptions, including a prior analysis published in Journal of Clinical Oncology examining the association between cost and nonadherence to aromatase inhibitors in patients with breast cancer).19 This gap in knowledge is where Dusetzina et al18 add valuable data, incorporating the most sophisticated adjustments for unmeasured confounders, which challenge every study of this type. The authors thus set the stage for what surely will be a robust future literature on the relationship between cost sharing and adherence to targeted cancer therapy. What is most striking from their analyses is not so much that cost is associated with nonadherence, but that there were high rates of discontinuation of these drugs in the first 6 months of treatment. At least one prior study that used similar data (through 2008) found that 41% of newly initiated imatinib users had low adherence, defined as a medication possession ratio of under 85% after 1 year. This study, Journal of Clinical Oncology, Vol 32, No 4 (February 1), 2014: pp 268-270

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Editorial

however, did not disentangle whether patients discontinued medications or they simply missed doses over the course of the year.20 A much smaller study (ADAGIO [Adherence Assessment with Glivec: Indicators and Outcomes]) that measured adherence over only a 90-day period reported one third of patients as nonadherent.9 There remain important questions about adherence and TKIs that are not answered by the Dusetzina et al18 study, and they mirror unanswered questions in the general adherence literature. The first relates to long-term adherence. Imatinib and related TKIs are meant for lifelong treatment, and although understanding rates of discontinuation and adherence in the first 6 months are critically important, rates later in the course of treatment are not known. For example, in a study of adherence to tamoxifen among women with early-stage breast cancer, rates of adherence among eligible women decreased from 80% in the first year to 50% by year four.21 Second, there is uncertainty about the most appropriate threshold when measuring adherence. Do patients need to be 100% adherent to their medications (namely, take 100% of the pills in a given time period) to receive the benefit, or can they take 95%, or 90%? The Dusetzina et al study used a threshold of 80%, but in sensitivity analyses also examined 85% and 90% thresholds. One prior study measuring TKI adherence over a 3-month period suggested that rates below 85% were associated with emergence of resistance and treatment failure in the long term.12 Finally, there is evidence in the chronic disease literature that overadherence, or consuming more medication than prescribed, can have deleterious effects.22 The prevalence of overadherence to TKIs and other targeted cancer therapy is unknown and needs to be better understood,8,23 particularly as patient-administered cancer therapies proliferate. There are a number of new, innovative solutions being proposed to address adherence, but it is unclear if they can be applied to TKIs. The MI FREEE trial is one of several versions of value-based insurance design interventions that lower cost sharing of medications viewed to be valuable. Aetna, the sponsor of the MI FREEE trial, actually implemented the policy of no cost sharing after myocardial infarction after reviewing the results of the trial. TKIs, however, are much more expensive than cardiovascular medications, many of which are generic with copays of $5 or less. In the Dusetzina et al18 study, although the median copayment was $30, 6% of patients had copays over $500 for a 30-day supply. Whether insurance companies would be willing to cover the cost of copayment is unclear. Although not focusing specifically on cost, there are also novel approaches using behavioral and financial incentives to improve adherence that are the subject of clinical trials outside of oncology,24 and there are a number of new mobile adherence technologies being developed and targeted to consumers.25 On a search of clinicaltrials.gov, however, there was only one study focused on improving adherence to TKIs in CML; the TAKE-IT trial is a small, prospective observational study recruiting patients in Israel for a behavioral intervention to improve adherence. Whatever solution is developed for improving adherence to TKIs, whether addressing cost or one of the other numerous barriers to adherence, it is clear that assessments of adherence will need to become routine in oncology offices. Imatinib and the other TKIs for the treatment of CML are the first of what will be many targeted therapies that oncology patients will take chronically. Small-molecule orally administered therapies targeting Bruton’s tyrosine kinase in chronic lymphocytic leukemia and mantle-cell lymphoma are being developed,26,27 and a number of oral small-molecule drugs are enterwww.jco.org

ing the market for advanced cancers to replace intravenous chemotherapy (eg, crizotinib in non–small-cell lung cancer).28 Oncologists will not be able to rely on a visit to their office to ensure that treatment is taken. Drug development, as well, will need to pay more attention to the issue of adherence, to ensure that scientific discoveries actually reach patients and are used optimally. ACKNOWLEDGMENT

Supported by a VA Career Development Award (CDA 09-207). The contents represent the views of the author only and not necessarily those of the Department of Veterans Affairs or the US Government. AUTHOR’S 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: None Stock Ownership: None Honoraria: None Research Funding: Walid F. Gellad, Express Scripts Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Mauro MJ, O’Dwyer M, Heinrich MC, et al: STI571: A paradigm of new agents for cancer therapeutics. J Clin Oncol 20:325-334, 2002 2. Druker BJ, Guilhot F, O’Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New Engl J Med 355:2408-2417, 2006 3. DiMatteo MR, Giordani PJ, Lepper HS, et al: Patient adherence and medical treatment outcomes: A meta-analysis. Med Care 40:794-811, 2002 4. Sabate E: Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland, World Health Organization, 2003 5. Fischer MA, Stedman MR, Lii J, et al: Primary medication non-adherence: Analysis of 195,930 electronic prescriptions. J Gen Intern Med 25:284-290, 2010 6. IMS Institute for Healthcare Informatics: Avoidable costs in U.S. healthcare: The $200 billion opportunity from using medicines more responsibly. http:// www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/ IMS%20Institute/RUOM-2013/IHII_Responsible_Use_Medicines_2013.pdf 7. Gebbia V, Bellavia G, Ferrau F, et al: Adherence, compliance and persistence to oral antineoplastic therapy: A review focused on chemotherapeutic and biologic agents. Expert Opin Drug Saf 1:S49-S59, 2012 (suppl) 8. Partridge AH, Avorn J, Wang PS, et al: Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 94:652-661, 2002 9. Noens L, van Lierde MA, De Bock R, et al: Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood 113:5401-5411, 2009 10. Marin D, Bazeos A, Mahon FX, et al: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28:2381-2388, 2010 11. Sandoval C, Giamelli J, Jayabose S: Imatinib mesylate noncompliance simulating chronic myeloid leukemia resistance. J Pediatr Hematol Oncol 25:507508, 2003 12. Ibrahim AR, Eliasson L, Apperley JF, et al: Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 117:3733-3736, 2011 13. Gellad WF, Grenard JL, Marcum ZA: A systematic review of barriers to medication adherence in the elderly: Looking beyond cost and regimen complexity. Am J Geriatr Pharmacother 9:11-23, 2011 14. Gellad WG, Grenard JL, McGlynn EA: A Review of Barriers to Medication Adherence: A Framework for Driving Policy Options. RAND Technical Report TR-765-MVC. 2009 15. Gibson TB, Ozminkowski RJ, Goetzel RZ: The effects of prescription drug cost sharing: A review of the evidence. Am J Manag Care. 11:730-740, 2005 16. Goldman DP, Joyce GF, Zheng Y: Prescription drug cost sharing: Associations with medication and medical utilization and spending and health. JAMA 298:61-69, 2007

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17. Choudhry NK, Avorn J, Glynn RJ, et al: Full coverage for preventive medications after myocardial infarction. New Engl J Med 365:2088-2097, 2011 18. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2014 19. Neugut AI, Subar M, Wilde ET, et al: Association between prescription co-payment amount and compliance with adjuvant hormonal therapy in women with early-stage breast cancer. J Clin Oncol 29:2534-2542, 2011 20. Wu EQ, Johnson S, Beaulieu N, et al: Healthcare resource utilization and costs associated with non-adherence to imatinib treatment in chronic myeloid leukemia patients. Curr Med Res Opin 26:61-69, 2010 21. Partridge AH, Wang PS, Winer EP, Avorn J: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602606, 2003 22. Thorpe CT, Bryson CL, Maciejewski ML, et al: Medication acquisition and self-reported adherence in veterans with hypertension. Med Care 47:474-481, 2009

23. Spoelstra SL, Given BA, Given CW, et al: Issues related to overadherence to oral chemotherapy or targeted agents. Clin J Oncol Nurs A1-A6, 2013 24. Kimmel SE, Troxel AB: Novel incentive-based approaches to adherence. Clin Trials 9:689-695, 2012 25. Granger BB, Bosworth HB: Medication adherence: Emerging use of technology. Curr Opin Cardiol 26:279-287, 2011 26. Byrd JC, Furman RR, Coutre SE, et al: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New Engl J Med 369:32-42, 2013 27. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. New Engl J Med 369:507-516, 2013 28. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. New Engl J Med 368:2385-2394, 2013

DOI: 10.1200/JCO.2013.53.8413; published online ahead of print at www.jco.org on December 23, 2013

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Targeted cancer therapy: from bench to bedside to patient.

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