Nicole M. Engel-Nitz, PhD

Lung cancer is the second-most common form of cancer in both men and women

 and is the leading cause of cancer-related mortality in the United States.

 It was estimated that more than 219,440 new cases of lung disease were diagnosed in 2009, with 159,690 deaths.

 Of the lung cancers, approximately 80% are non—small cell lung cancer (NSCLC) types.

 For patients with advanced NSCLC (stages IIIb and IV) for whom radiation and/or surgical resection are no longer a viable option, first-line treatment involves intravenous chemotherapy agents and may be combined with radiotherapy and/or other targeted biologic agents.

 However, approximately 30% to 40% of patients with advanced NSCLC fail to respond adequately to first-line chemotherapy and are candidates for second-line therapy.

 For patients who have locally advanced or metastatic NSCLC and have had failure of at least 1 prior chemotherapy regimen, erlotinib (Tarceva; Genentech, Inc, and OSI Pharmaceuticals, Inc) was approved in November 2004 as monotherapy.

 Erlotinib is an oral epidermal growth factor receptor tyrosine-kinase inhibitor (TKI), and in clinical trials, resulted in a 2-month increase in survival for lung cancer patients.

With the use of self-administered oral chemotherapy drugs, concern has been raised regarding patient adherence and persistence.

 In particular, underdosing due to either nonadherence or dose reductions/delays may result in lower plasma drug levels and subsequently increased risk of cancer relapse and progression.

 Furthermore, nonadherence has been associated with higher medical service utilization.

 Factors that have been found to modify medication adherence include patient characteristics (female sex

) and comorbid conditions (increased depression symptoms

or higher Charlson Comorbidity Index score

), medication dosing12 and type,14 clinician drug choice and patient education,

 and financial aspects of the healthcare system

 However, it is unclear whether these factors affect patients’ adherence to treatment for diseases such as lung cancer with high and rapid mortality as much as they influence medication use for the treatment of chronic diseases.

Most oral chemotherapy adherence research has been conducted on either breast cancer patients

 In one study of NSCLC patients, Greer and colleagues

 identified smoking behavior and anxiety as predictors of infusion-based chemotherapy regime dose delays/reductions; for the 14% of their patients who were also receiving an oral epidermal growth factor receptor TKI, adherence data were not presented. Furthermore, Ramsey and colleagues

 noted in their evaluation of lung cancer chemotherapy use within a large US insurance claims database that erlotinib prescriptions were increasingly filled and that erlotinib was the second most commonly used second- and third-line treatment for refractory lung cancer. These researchers also evaluated cost utilization and grouped oral erlotinib medication costs with other outpatient pharmacy costs. Erlotinib therapy resulted in pharmacy costs of $3888 and $1290 per-patient-per-month for second- and third-line outpatient therapy, respectively.

During the November 2004—December 2006 time frame of the study by Ramsey and colleagues,

 erlotinib was classified as a tier 3 drug on the prescription drug list for healthcare plan insurance reimbursement. However, this healthcare plan moved erlotinib to tier 2 starting on September 1, 2007.

This natural experiment provided the opportunity to examine whether the high copayments and other aspects of financial burden

that have been associated with adherence in other medication studies also affect adherence with erlotinib for patients with NSLC. The purpose of this retrospective study was to examine the impact of the erlotinib tier change on patient copayments and its impact on treatment behavior among patients with lung cancer.

This retrospective analysis used medical and pharmacy claims to identify patients from a large US healthcare claims database affi liated with OptumInsight who had evidence of lung cancer and had fi lled prescriptions for erlotinib. Medical and pharmacy claims, as well as enrollment information from May 1, 2004, to March 30, 2009, were used. A variable follow-up period (until the earliest of 1 year following index date, disenrollment, death, or March 30, 2009) was used to assess copayments, discontinuation, and adherence with erlotinib. The pharmacy benefit change that moved erlotinib from tier 3 to tier 2 occurred on September 1, 2007. A 6-month baseline period (baseline period) before the first filled prescription date (index date) was used to identify patient characteristics. The follow-up period was from the index date until either disenrollment from the health plan or March 30, 2009, whichever occurred earlier, and was used to assess erlotinib use and outcomes (

Eligible patients had erlotinib prescriptions filled from November 1, 2004, through December 31, 2008. Patients were also required to have continuous eligibility in a commercial healthcare plan with both medical and pharmacy benefits during the baseline period through the follow-up period. Patients were 18 years or older with no evidence of erlotinib use during the baseline period. Diagnostic evidence of lung cancer in the medical claims was based on

 International Classification of Diseases, Ninth Revision, Clinical Modification

 codes occurring at any time during the study period. Patients were further required to have either at least 2 qualifying medical claims for lung cancer with codes of 162.2-162.9 (malignant neoplasm of bronchus and lung) or 163.x (malignant neoplasm of pleura) in the primary position on separate service dates within the study period, or at least 1 qualifying medical claim for lung cancer with codes of 162.2-162.9 or 163.x in the primary position plus at least 1 qualifying medical claim for lung cancer with codes 231.2-231.9 (carcinoma in situ of bronchus and lung—other specified site, including pleura or unspecified site) in the primary position. All qualifying claims were required to occur on separate service dates within the study period. Patients were required to have evidence of chemotherapy use during the baseline period based on appropriate Healthcare Common Procedure Code System chemotherapy codes (

). Laboratory claims either at laboratory sites or for laboratory services were excluded.

Patients were categorized into 3 analytic cohorts based on the period of time when they initiated and ended erlotinib use. Patients who started (index date) and ended use of erlotinib before September 1, 2007, were designated as pre-tier patients. Patients with index dates occurring after September 1, 2007, were designated as post-tier patients. Patients starting use of erlotinib before September 1, 2007, and continuing erlotinib use beyond this same date were designated as crossover patients.

Patient demographics including age, sex, geographic location, and enrollment dates were used. Clinical characteristics were evaluated and included the following: Charlson Comorbidity Index score; diagnosis of additional disease and tumor types at baseline and follow-up; use of radiation, surgery, or other chemotherapy at baseline and follow-up; and mortality.

Erlotinib copayment was defined as the mean monthly prescription copayment cost (per 30 days) and was calculated as the total out-of-pocket cost divided by total number of 30-day prescriptions (accounting for mail order). For prescription counts, total number of prescriptions was counted, with prescriptions filled by mail order credited as multiple prescriptions based on days of supply.

Erlotinib adherence was defi ned as the total days of supply of all prescription fi lls between the first and last fill divided by the number of days between the first and last fill; adherence values of 

80% were used as a cutoff value (commonly used in the literature

). This definition excluded patients with just 1 prescription fill. Erlotinib persistence (or discontinuation) was defined as a 60-day gap in therapy between the run-out date of the medication fill and the subsequent refill.

Descriptive statistics were generated for baseline patient characteristics stratified by tier-change cohort. Comparisons of baseline characteristics among tier-change cohorts were assessed using the

 test for continuous variables and the χ2 test for categorical variables. Erlotinib mean copayments and mean adherence rates in the pre-tier and post-tier cohorts were compared by using

 tests; Wilcoxon rank-sum tests were used to compare median copayments. Paired 

tests were used to compare mean copayments, and Wilcoxon signed-rank tests were used to compare median copayments for the crossover cohort before and after the tier change. Rates of treatment discontinuation were compared by using χ2 tests.

Due to small sample size and difficulty in determining intake of oral doses before and after tier change, the differences within the crossover cohort for erlotinib use were not determined. The dichotomous measure of adherence (

80%) to treatment was assessed using multivariate logistic regression; persistence was assessed using Cox proportional hazards modeling. Both compared pretier and post-tier cohorts on risk of treatment use (either adherence or discontinuation) and were adjusted for age, sex, Charlson Comorbidity Index score, and prior surgery or radiation. For the primary analysis, the primary independent variables of interest were the cohort (pre-tier and post-tier) and patient copayment for erlotinib.

For sensitivity analysis, the sample was restricted to patients with similar follow-up times and included patients with 1 or more prescriptions. Prescription use (an alternative adherence measure) was defined as total supply divided by length of follow-up with adherence values of 

80% used as a cutoff. Multivariate logistic regression was used to assess prescription use, and treatment discontinuation was assessed using Cox proportional hazards modeling. Both models compared cohorts on risk of treatment utilization (use or discontinuation) and were adjusted for age, sex, Charlson Comorbidity Index score, and prior surgery or radiation. For the sensitivity analysis, the independent variable of interest was the cohort (pre-tier and post-tier).

We identified 1460 patients with lung cancer who had filled at least 1 erlotinib prescription from November 1, 2004, through December 31, 2008. Of these, 949 patients received erlotinib before the tier change (pre-tier cohort), 410 received erlotinib after the tier change (post-tier cohort), and 101 patients received erlotinib both before and after the tier change (crossover cohort).

, patients in the post-tier cohort were slightly older compared with the pre-tier cohort patients (60.91 years vs 59.49 years; 

 = .0212), although the difference in distribution of age groups was not significant. Sex distribution was similar between the pre-tier and post-tier cohorts. Patients in the post-tier cohort had significantly fewer other tumor types identified; across all cohorts, the most common type of other tumor was connective tissue/breast cancer (13.6%). By design, there were significant differences between the cohorts for index date. The post-tier group had signifi cantly fewer claims-based deaths compared with pre-tier cohort; however, this may be due to the longer follow-up period in the pre-tier cohort. During the baseline period, patients in the post-tier cohort had signifi cantly fewer other chemotherapies and radiation and more surgeries compared with the pre-tier cohort patients. Although post-tier patients had a significantly lower mean Charlson Comorbidity Index score (7.29 vs 7.58; 

= .0008), the difference of 0.29 was considered clinically insignificant.

) copayment levels were compared across years of erlotinib initiation. The overall difference between the mean copayment of post-tier patients and the mean copayment of pre-tier patients was not statistically signifi cant, although the overall median copayment was signifi cantly lower for post-tier patients than for pre-tier patients. For post-tier patients who initiated erlotinib in 2007, both mean and median copayments were signifi cantly lower compared with those for pre-tier patients. Median, but not mean, copayment differed for post- and pre-tier patients initiating erlotinib in 2004, 2005, or 2006. For patients in the crossover cohort, mean (

 <.001) copayments were significantly lower after the tier change compared with before the tier change.

) prescription counts were compared across years and by year of erlotinib initiation. The average number of erlotinib prescriptions appeared to vary across the pretier and post-tier cohorts when stratified by the year of erlotinib initiation, although differences were not statistically significant when all years were combined. The mean number of prescriptions was 3.37 for the pre-tier cohort and 3.41 for the post-tier cohort (median of 2 prescriptions for both the pre-tier and post-tier cohorts) when all years were combined. Among post-tier cohort patients who initiated erlotinib therapy in 2007, significantly more prescriptions were fi lled (3.41 prescriptions) compared with those for pre-tier cohort patients who initiated erlotinib in 2007 (2.39 prescriptions; 

Primary Adherence and Persistence Analysis

Pre-tier and post-tier patients had similar rates of adherence to erlotinib (84.45% and 83.75%, respectively; 

), compared with patients with copayments of 

$30, patients with copayments of $45 to <$65 had significantly decreased odds of adherence (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.30-0.96). Differences between the lowest-copayment group and patients with copayments of $30 to $45 (OR 0.67, 95% CI 0.0.40-1.12) or 

$65 (OR 0.52, 95% CI 0.26-1.06) were not statistically significant.

For erlotinib persistence (representing drug discontinuation), pre-tier patients were more likely than post-tier patients to discontinue erlotinib (44.78% vs 37.07%;

= .008) (Table 3). In multivariate analysis, post-tier patients were 21% less likely to discontinue treatment than pretier patients (hazard radio 0.79, 95% CI 0.65-0.95).

Sensitivity analysis of patients’ prescription use found that 41.94% of the pre-tier cohort and 47.56% of the post-tier cohort were adherent using this alternative definition (

), with no statistically significant difference in adherence between pre-tier and post-tier cohorts (

 = . 0551). After multivariate adjustment, the logistic regression model showed no statistically significant difference in adherence between pre-tier and post-tier cohorts (

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