Targeted Cancer Therapy: From Bench to Bedside to Patient
Authors: Walid F. Gellad
Journal: Journal of Clinical Oncology (2013)

The decades of research that finally brought imatinib to the bedside make for a tremendous story of scientific discovery. 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)—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, and 20% to 30% of prescription medications are never filled. 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. The clinical consequences of nonadherence to cancer therapy are also well described. Nonadherence, in fact, has been identified as a critical factor in nonresponse, and loss of response, to imatinib. The barriers to optimal medication adherence in chronic disease are numerous, 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. 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. Patients discharged after myocardial infarction were randomly assigned to receive their cardiovascular medications for free 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. It is in this context that Dusetzina et al 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). This gap in knowledge is where Dusetzina et al 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 E D I T O R I A L VOLUME 32 NUMBER 4 FEBRUARY 1 2014