Carolina M. Reyes, 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 (

Articles

Moving erlotinib from formulary tier 3 to tier 2 resulted in lower copayments and higher treatment persistence among lung cancer patients.

Lung Cancer: Copayments and Behavior Following Erlotinib Formulary Tier Change

Lung cancer is one of the most prevalent malignancies in developed countries.

 In the United States it has the highest incidence of any primary cancer site, accounting for 15% of all cancer diagnoses, and is the leading cause of cancer-relat

Prognosis is poor; the 5-year survival rate is estimated at

16% when factoring in all stages, and as low as 4% when

distant metastases are present at diagnosis.

cases are already at an advanced stage when diagnosed.

Lung cancer places a high economic burden on payers. Annual expenditures for lung cancer management in the United States have been estimated at $10.3 billion (2006 dollars).

 Furthermore, patients who experience lung cancer progression or treatment failure have significantly greater costs than patients with stable disease.

 Most of the economic analyses involving patients with lung cancer pertain to the first-line treatment setting, and many of them predate recent major advances in lung cancer treatment.

Claims-based analyses complement the previously published economic evaluations by depicting actual rates of healthcare utilization and costs.

 Such data can affect treatment provider decisions as well as payer decisions regarding coverage. In a claims-based study of Virginia Blue Cross and Blue Shield beneficiaries, Hillner et al

 reported direct costs of US $47,941 per patient for 2 years after diagnosis or until death in a commercially insured population with advanced lung cancer. Patients who undergo multiple lines of treatment have costs that are 2 to 3 times higher than those with treatment limited to first-line therapy.

 In another claims-based study (using data from MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits), patients who went on to receive second-line treatment accrued an additional US $10,370 per month in initial treatment phase costs and US $8779 more per month after starting second-line treatment and/or terminal care compared with those patients who underwent first-line treatment only.

Approximately 85% of lung cancers are classified as non—small cell lung cancer (NSCLC).

 First-line treatment for advanced NSCLC typically involves platinum-based chemotherapy.

 Current practice guidelines recommend the use of second-line therapy in patients with advanced or metastatic lung cancer who experienced disease progression either during or after first-line therapy and who have good performance status.

 Second-line therapy has been demonstrated in phase III trials to increase survival, reduce symptoms, and limit deterioration of quality of life for patients with metastatic lung cancer.

Specifically, docetaxel, pemetrexed, and erlotinib are recommended by the National Comprehensive Cancer Network for lung cancer patients after failure of first-line chemotherapy, and these agents are approved by the US Food and Drug Administration for use in this setting.

 Erlotinib and pemetrexed (which is approved only for nonsquamous NSCLC) are also approved as maintenance therapy for patients whose disease does not progress following first-line treatment. These 3 agents differ with regard to mechanism of action, method of administration, and adverse event (AE) profile.

 The cytotoxic agents docetaxel and pemetrexed are administered intravenously, whereas erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is an oral agent. While improved survival has been reported with each of these agents,

 no head-to-head clinical trials of efficacy and toxicity of docetaxel, pemetrexed, and erlotinib have been conducted.

Economic models and cost comparisons of erlotinib, docetaxel, and pemetrexed have been published,

 but 2 of these analyses were economic models based on clinical trial data available at the time of product launch and do not necessarily reflect real-world usage patterns.

 In recognition of the scarcity of economic analyses based on actual lung cancer treatment patterns, the present study was designed with the objective of comparing real-world total healthcare costs among lung cancer patients receiving docetaxel, pemetrexed, or erlotinib monotherapy as second-line treatment. Furthermore, because toxicities associated with cancer therapy often necessitate supportive care, AE-related costs were also assessed. Specifically, we provide estimates of costs among patients receiving each treatment regimen as second-line therapy, including pharmacy costs, the costs of office visits associated with medication administration, AE-related care, and total healthcare consumption.

In this retrospective claims analysis, data were obtained from a proprietary i3-affiliated claims database associated with a large US health plan. Approximately 14 million geographically diverse individuals with both medical and pharmacy benefit coverage were enrolled in the health plan during the study period. Data were deidentified and accessed in compliance with the Health Insurance Portability and Accountability Act

; approval by an institutional review board was therefore not required.

Patients were required to have at least 1 medical claim during the identification period of July 1, 2004, through December 31, 2006, with a diagnosis of lung cancer (

International Classification of Diseases, Ninth Revision,

] codes 162.xx, 163.xx, 231.xx) in any position (the service date of the first qualifying claim was defined as the initial diagnosis date); at least 2 medical claims with a lung cancer diagnosis on separate service dates within 6 months following the initial diagnosis date; and no more than 10 medical claims with diagnosis codes for other cancers on separate service dates in the period 30 days prior to and 6 months following the initial diagnosis date.

Patients were also required to be 18 years or older, to be continuously enrolled with both medical and pharmacy benefits from the initial diagnosis date through at least 60 days following the index date (defined as the service date on the first claim for a second-line agent), and to have received treatment with docetaxel monotherapy, erlotinib monotherapy, or pemetrexed monotherapy as secondline treatment (with or without third-line treatment).

First-line chemotherapy was identified as an anchor 

from which to identify second-line therapy with docetaxel,

 pemetrexed, or erlotinib. Medical and pharmacyclaims during the 30 days prior to and 6 months followingthe initial diagnosis date were examined for receiptof first-line chemotherapy. First-line chemotherapy wasdefined as the first chemotherapeutic agent received duringthe 213-day review period.

Second- and third-line agents were defined as agents different from the prior therapy. Docetaxel and pemetrexed were identified as second-line chemotherapy agents when they had an initial injectable administration date at least 28 days following the last delivery date of the first-line chemotherapy agent. Erlotinib, an oral medication, was counted as a second-line agent if the initial date on which the prescription was filled occurred on or after the last date of administration of first-line chemotherapy. The service date on the first claim (either pharmacy or medical) for one of the second-line agents was defined as the index date, and the identified agent was defined as the index therapy. Additional chemotherapy agents received within 8 days of the index therapy were considered part of the second-line treatment. Patients were assigned to 1 of 3 cohorts based on their index second-line treatment regimen: docetaxel monotherapy, erlotinib monotherapy, or pemetrexed monotherapy. Third-line therapy, identified in order to define the second-line treatment period, was defined as any new cancer therapy with an initial administration date at least 28 days following the last delivery of the second-line agent, with criteria analogous to those used to define second-line therapy.

All patients were enrolled for at least 6 months prior to and 2 months following the index date. The 6-month preindex period was defined as the baseline period and was used to assess patient demographic and baseline clinical characteristics, including age as of the index year, sex, geographic region, and Charlson-Deyo comorbidity score.

 Patients were followed until disenrollment from the health plan or December 31, 2007, whichever occurred earlier. The second-line treatment follow-up period was defined as the time period from the index date to the end of the follow-up period (for patients without third-line treatment) or the index date to the third-line treatment date (for patients with third-line treatment). A second claim for the index therapy during the follow-up period was required for a patient to be included in the analysis, but continuation with therapy was not a criterion defining the duration of follow-up.

Occurrence of toxicities commonly associated with cancer therapy (which may or may not have been directly caused by the medications) and related utilization were identified through AE-related diagnosis, procedure, and medication codes (including supportive care) on claims dated within the follow-up period. Twelve AEs were selected for study based on severity grade 3/4 incidence greater than or equal to 5% as reported in the prescribing information for docetaxel, pemetrexed, and erlotinib.

 These were nausea/emesis, anemia, neutropenia/leukopenia, selected pulmonary AEs, dyspnea, chest pain, dehydration, fatigue/asthenia, rash, anorexia, diarrhea, and febrile neutropenia. Codes indicative of these events were categorized according to the AE (

Erlotinib may confer an economic advantage for payers over docetaxel and pemetrexed for second-line treatment of lung cancer because of lower costs.