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Understanding Total Cost of Care in Advanced Non-Small Cell Lung Cancer Pre- and Postapproval of Immuno-Oncology Therapies
Beata Korytowsky, MA; Janna Radtchenko, MBA; Esmond D. Nwokeji, PhD; Kenneth W. Tuell, RPh, BCGP; Jonathan K. Kish, PhD, MPH; and Bruce A. Feinberg, DO

Understanding Total Cost of Care in Advanced Non-Small Cell Lung Cancer Pre- and Postapproval of Immuno-Oncology Therapies

Beata Korytowsky, MA; Janna Radtchenko, MBA; Esmond D. Nwokeji, PhD; Kenneth W. Tuell, RPh, BCGP; Jonathan K. Kish, PhD, MPH; and Bruce A. Feinberg, DO
This study assesses resource utilization and total direct medical cost among patients in the United States starting systemic antineoplastic therapy (ST) pre- and postapproval of immuno-oncology (IO) agents for advanced non–small cell lung cancer. Adults diagnosed with lung cancer initiating first-line ST within 6 months of diagnosis during either the pre- (March 2013-March 2014) or post-IO (March 2015-December 2016) approval period were identified in a US-based multipayer administrative claims database. Excluded were patients with small cell lung cancer, secondary malignancies, less than 1 month follow-up, and those in clinical trials. Total cost (TC) was calculated from the date of initiation of treatment until the last follow-up. Propensity score matching was adjusted for differences in patient cohorts, including follow-up time. Binary multiple logistic regression assessed predictors of high TC (above mean) pre- and post IO. Mean TC per patient was higher pre-IO versus post IO in both unmatched ($165,548 vs $95,715) and matched analyses ($129,977 vs $113,177). Hospitalization and emergency department (ED) visit rates were higher pre-IO versus postapproval. Predictors of high TC pre-IO included use of first-line combination therapy, radiation, targeted therapy, maintenance therapy, biomarker testing, more comorbidities, longer follow-up, first-line hospitalization, first-line cost above mean, and age 65 years and older. In the post-IO period, additional predictors of higher TC included use of IO, having mild liver disease or hemiplegia, and longer time to ST initiation. Early data show lower ED visit and hospitalization rates and associated lower TC in the post-IO era.
Am J Manag Care. 2018;24:-S0
Lung cancer is the second most common cancer and the leading cause of cancer-related mortality in the United States, with approximately 234,030 new cases and 154,050 deaths expected in 2018.1 Approximately 85% of all lung cancer cases are classified as non–small cell lung cancer (NSCLC), and more than half (57%) of incident cases present at an advanced stage.1-2 The prognosis for patients with advanced NSCLC (aNSCLC) has been historically poor. Five-year relative survival is less than 5% on standard treatments including surgery, radiation, and systemic antineoplastic therapy (ST), primarily in the form of platinum-based chemotherapy.1,3

The development of mutation-targeting and immuno-oncology (IO) drugs is revolutionizing the treatment and prognosis of NSCLC. Since 2011, 4 agents targeting anaplastic lymphoma kinase and 5 agents targeting the epidermal growth factor receptor have been approved by FDA for NSCLC.4-12 Each agent received a salvage indication, and 6 of those received a frontline indication. The March 2015 approval of the first IO agent, nivolumab, for patients with aNSCLC, heralded a new era in treatment. Since 2015, 2 additional IO agents have been approved for patients with NSCLC with a salvage indication: pembrolizumab as frontline therapy and durvalumab as an adjuvant therapy.13-19 In 2016, the Institute of Clinical and Economic Review (ICER) commenced a cost-effectiveness analysis that demonstrated the value of novel therapies, such as IO, in both frontline and second-line NSCLC. ICER did note higher-than-acceptable cost per quality-adjusted life-year (QALY) gained. In the same report, cost per QALY for targeted therapies was considered acceptable in their approved indications.20

The published literature suggests that NSCLC is the fifth costliest tumor in the United States, with an estimated 2016 national expenditure of approximately $13.6 billion.21 Although much attention has been paid to drug costs, particularly costs of IO therapies, there has been no research to understand the real-world healthcare resource utilization (HRU) and associated total cost of care in the period prior to IO approval in NSCLC compared with the period when IO agents have emerged as effective treatment options. Most of the published real-world evidence in NSCLC is based on older data reporting patterns of care and costs prior to the approval of targeted and IO therapies. In addition, many of the published findings are not generalizable, as they represent a single institution, focus on a patient subgroup such as elderly or early-stage patients with NSCLC, or include patients not treated with ST.22-26 Many studies also focus on chemotherapy costs alone, with little information presented regarding broader treatment patterns, resource use, and costs for other services incurred by patients with NSCLC.25-27 Current real-world studies are needed to evaluate the relative impact of new drug treatment strategies on total cost and HRU among patients with aNSCLC to understand the value of various treatment choices for this difficult-to-treat population.

To address this knowledge gap, the primary objective of this research is to evaluate HRU rates and total cost (TC) of care from a US payer perspective among patients with aNSCLC treated with ST in the time periods before and after approval of these agents for treatment (pre-IO and post-IO periods, respectively). The secondary objective is to identify predictors of high treatment costs among patients with aNSCLC treated in the pre- and post-IO approval periods.


Study Design

The target population for the study included patients diagnosed with lung cancer who initiated treatment with NSCLC-specific ST between March 1, 2013, and December 31, 2016, and followed through March 2017, with history back to March 2012. Two independent, mutually exclusive patient cohorts were selected based on the time of initiation of ST for aNSCLC: cohort 1 (pre-IO period) included patients initiating first-line treatment between March 1, 2013, and February 28, 2014; cohort 2 (post-IO period) included patients initiating first-line treatment between March 1, 2015, and December 31, 2016. The index period for the post-IO period was longer than that for the pre-IO period to increase the number of patients who had received IO therapy. Patients initiating first-line treatment between March 1, 2014, and February 28, 2015, were excluded. This 1-year washout period was used to isolate the period before the introduction of IO and to minimize the effect of patient crossover between the 2 cohorts. Patients with aNSCLC were identified within the Medical Outcomes Research for Effectiveness and Economics Registry Research database, composed of multipayer claims data from 243 million unique patients since 2000.2 The information represents adjudicated medical and pharmacy claims from traditional fee-for-service commercial plans, Medicare Advantage, Managed Medicare, Medicaid, and dual-eligible plans.28 A dataset containing records from March 2012 through March 2017 was available at the time of data acquisition.

Patient Selection Criteria

All individuals with at least 1 nondiagnostic inpatient or outpatient claim for lung cancer (International Classification of Diseases, Ninth Revision [ICD-9] and Tenth Revision [ICD-10] codes: 162.XX/ C34.XX) who were 18 years or older at the time of the first lung cancer claim or diagnosis date were selected. Patients were considered to have developed advanced disease (IIIB or IV) if they received their first ST within 6 months of the lung cancer diagnosis or had secondary metastases codes at diagnosis (ICD-9: 196.XX, 197.XX, 198.XX; ICD-10: C77.XX, C78.XX, C79.XX). Next, a longitudinal record of patient treatment history was constructed from pharmacy and medical claims using National Drug Codes (NDC) numbers and J codes. Only patients who had newly initiated (no treatment in the prior 12 months) NSCLC treatment with a regimen recommended by the National Comprehensive Cancer Network (NCCN) during the pre- or post-IO index periods were included. Treatment regimens and a line of therapy assignment were based on group-administered chemotherapies using administration dates. Line of therapy determination was made using the following process: antineoplastic agents administered within 30 days of each other were considered combination therapy; change in regimen (use of new agents, addition of an agent, or discontinuation of an agent in a regimen for at least 60 days), or a regimen gap of more than 12 weeks triggered a line-of-therapy increment. Maintenance therapy was defined per NCCN guidelines as erlotinib, bevacizumab, pemetrexed, docetaxel, or gemcitabine within 6 weeks of first-line ST initiation, provided first-line was a platinum-based or pemetrexed-based combination given for at least 4 cycles. All patients were required to have a minimum of 1 month follow-up from the date of initiation of the first-line treatment.

As ICD-9/10 codes do not distinguish between NSCLC and small cell lung cancer (SCLC), patients were excluded from the analysis if they received a treatment consistent with NCCN guidelines for SCLC (eg, topotecan, temozolomide, cranial irradiation). Additionally, patients with a second primary cancer diagnosis or those who received care as part of a clinical trial (ICD-9: V70.7; ICD-10: Z00.6) were excluded.

Resource Utilization and Costs

Acute care interventions were identified using admission codes for hospitalizations and emergency department (ED) visits. The average wholesale price for drugs coded with NDC codes and CMS and the average sales price for drugs coded with J, Q, or C codes were used to calculate standardized cost per administration of any antineoplastic agent or other pharmaceutical. The CMS clinical laboratory fee schedule, Medicare physician fee schedule, and hospital outpatient prospective payment system were used to standardize procedure costs. Facility fees for acute care admissions per day for each evaluation period were calculated using actual paid amounts and multiplied by length of stay. All costs were adjusted to 2017 US dollars.

Data Analysis

HRU, TC, and TC per patient per month (PPPM) were compared between the pre-IO and post-IO cohorts for all lines of therapy combined and per line of therapy. TC, TC PPPM, and HRU by line of therapy were calculated from the first administration of ST for a given line until the beginning of the next line of therapy or last available claim if there was no subsequent treatment. Costs and HRU for third-line treatment or higher were presented as third-line-plus. Mean costs were reported for those patients utilizing the resource (ie, inpatient, ED, and ST), whereas mean TCs were calculated across all patients.

Comparisons between pre-IO and post-IO HRU costs were conducted between all patients (unmatched) and a subgroup of propensity score matched (PSM) patients. The PSM method was used to control the differences in demographic and clinical characteristics of the patient cohorts, such as age, gender, site(s) of metastases, geographic region, comorbidities, smoking status, payer type, and the length of follow-up. The χ2 test or Fisher Exact test were used to assess differences between cohorts for categorical variables, and the t test was used to evaluate differences in continuous variables. Multivariable binary logistic regression was used to assess predictors of high TC in each of the pre- and post-IO cohorts. Since the introduction of IO was expected to influence TC in the treatment lines where it is used most frequently, predictors of TC in second-line treatment were also assessed. For the predictive model, high cost was defined as TC above the mean per period. Evaluated predictors included:
  • Gender
  • Payer type
  • First-line combination therapy (vs monotherapy)
  • Maintenance therapy
  • Radiation therapy
  • Surgery
  • Biomarker testing
  • History of smoking or smoking cessation (receipt of smoking counseling, chronic obstructive pulmonary disease or emphysema diagnosis, or use of smoking cessation drugs)
  • Presence of individual comorbidities included from the Charlson Comorbidity Index (CCI)
  • CCI score >2
  • Age at time of treatment start (<65 or ≥65 years)
  • Drug class (targeted therapy, chemotherapy, or IO)
  • Hospitalization or ED visit in first-line
  • Cost above mean in first-line
  • Hospitalization or ED visit in any line of therapy
  • Time to treatment start (months)
  • Time to first-line discontinuation (months)
  • First-line adverse event count
  • Length of follow-up (months)
All analyses were conducted using SPSS (version 22.0, IBM Corporation, Armonk, New York); P <.05 was considered significant.


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