Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.

Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab.

PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

Benchmarking Maintenance Therapy Survival in First-Line Platinum-Based Chemotherapy-Treated Patients with Advanced Urothelial Carcinoma Using Simulated Disease Modeling.

Objective: First-line (1L) maintenance avelumab prolonged overall survival (OS) in patients with advanced urothelial carcinoma (aUC) in JAVELIN Bladder 100. OS was measured from maintenance initiation in patients with disease control following 1L platinum-based therapy (PBT). The OS impact of maintenance for the 1L PBT-treated population is unknown since it was not measured from 1L initiation, nor can it be benchmarked with other 1L therapies. To characterize the OS impact of maintenance avelumab, we used an oncology simulation model to estimate the OS of maintenance-eligible and -ineligible patients with aUC from 1L PBT initiation. Methods: We developed a simulated cohort of 1L PBT-treated patients with aUC, including those who did and did not receive maintenance avelumab. Eligibility was assessed at 5.6 months post 1L PBT initiation based on the JAVELIN trial design. Among the 1L-treated population, 58% (95% credible interval [CrI] 49-67%) were projected to be eligible (calculated from contemporary phase 3 trials); of those, 85% were assumed to receive maintenance. The model estimated median OS (mOS) among a maintenance-ineligible simulated cohort which when combined with the maintenance-eligible cohort yielded an estimated OS in the overall maintenance- intended population from 1L PBT initiation. Results: Approximately half of the modeled 1L PBT-treated population received maintenance. Estimated mOS was 10.1 months (95% CrI 7.5-13.5) for the maintenance-ineligible cohort, 29.3 months (95% CrI 24.8-33.9) for the maintenance-eligible, received maintenance cohort, and 15.9 months (95% CrI 13.2-19.1) in the overall maintenance-intended, 1L PBT-treated population, including those eligible and ineligible for maintenance. Conclusion: The model shows that maintenance avelumab has a modest impact on OS in the overall 1L PBT-treated population of patients with aUC. While maintenance avelumab improves OS for eligible patients, a large proportion of the maintenance-intended population may not receive maintenance due to ineligibility or physician/patient choice.

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

Health care resource utilization, quality metrics, and costs of bladder cancer within the Oncology Care Model.

OBJECTIVES: New and emerging therapies have significantly changed the bladder cancer (BC) treatment landscape and can potentially affect spending and patient care in CMS' Oncology Care Model (OCM), a service delivery and payment model for voluntarily participating practices. The objectives of this analysis were to estimate health care resource utilization (HCRU) and benchmark spending per OCM episode of BC, and to model spending drivers and quality metrics. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective cohort study was conducted of OCM episodes triggered by receipt of anticancer therapy among Medicare beneficiaries from 2016 to 2018. Based on this, an average performance estimation was conducted to assess the impact of hypothetical changes in novel therapy use by OCM practices. RESULTS: BC accounted for approximately 3% (n = 60,099) of identified OCM episodes. Relative to low-risk episodes, high-risk episodes were associated with greater HCRU and worse OCM quality metrics. Mean spending per high-risk episode was $37,857 (low-risk episode: $9204), with $11,051 spent on systemic therapies and $7158 on inpatient services. In the estimation, high- and low-risk BC exceeded the spending target by 1.7% and 9.4%, respectively. This did not affect payments to practices and no retrospective payments were necessary. CONCLUSIONS: As 3% of OCM episodes were attributed to BC, with only one-third classified as high-risk, controlling expenditure on novel therapies for advanced BC is unlikely to affect overall practice performance. The average performance estimation further emphasized the minimal impact that novel therapy spending in high-risk BC has on OCM payments to practices.

Real-world treatment patterns and clinical outcomes with first-line therapy in patients with locally advanced/metastatic urothelial carcinoma by cisplatin-eligibility.

INTRODUCTION: Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) have a poor prognosis. With recent therapeutic advances, data on real-world treatment patterns and overall survival (OS) in patients with la/mUC treated with first-line therapy are limited, particularly when comparing patients who are cisplatin-ineligible versus cisplatin-eligible. METHODS: This was a retrospective observational study of real-world first-line treatment patterns and OS in patients with la/mUC stratified by cisplatin-eligibility and treatment. Data were from a nationwide electronic health record-derived de-identified database. Eligible patients were adults diagnosed with la/mUC from May 2016 to April 2021 and followed until death or end of data availability in January 2022. OS stratified by first-line treatment and cisplatin eligibility was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. RESULTS: Of 4,757 patients with la/mUC, 3,632 (76.4%) received first-line treatment, with 2,029 (55.9%) cisplatin-ineligible and 1,603 (44.1%) cisplatin-eligible. Patients who were cisplatin-ineligible were older (mean age, 74.9 vs. 68.8 years) and had lower CrCl (median, 46.4 vs. 87.0 ml/min). Only 43.8% of patients receiving first-line treatment (37.6% cisplatin-ineligible vs. 51.6% cisplatin-eligible) received second-line therapy. Median OS in all patients receiving first-line treatment was 10.8 (95% CI, 10.2-11.3) months and was shorter in patients who were cisplatin-ineligible than cisplatin-eligible (8.5 [95% CI, 7.8-9.0] vs. 14.4 [13.3-16.1]; hazard ratio [HR], 0.9 [0.7-1.1]). Cisplatin-based therapy was associated with longer OS (17.6 [15.1-20.4] months) than other first-line treatments (the shortest OS was with PD-1/L1 inhibitor monotherapy; 7.7 [6.8-8.8] months), including among patients who were classified as cisplatin-ineligible. CONCLUSIONS: Outcomes for patients with newly diagnosed la/mUC are poor, particularly for patients who are cisplatin-ineligible and/or do not receive cisplatin-based therapy. Many patients with la/mUC did not receive first-line treatment and among those who did, fewer than half received second-line therapy. These data highlight the need for more effective first-line therapies for all patients with la/mUC.

Oncology Simulation Model: A Comprehensive and Innovative Approach to Estimate and Project Prevalence and Survival in Oncology.

Objective: We demonstrate a new model framework as an innovative approach to more accurately estimate and project prevalence and survival outcomes in oncology. Methods: We developed an oncology simulation model (OSM) framework that offers a customizable, dynamic simulation model to generate population-level, country-specific estimates of prevalence, incidence of patients progressing from earlier stages (progression-based incidence), and survival in oncology. The framework, a continuous dynamic Markov cohort model, was implemented in Microsoft Excel. The simulation runs continuously through a prespecified calendar time range. Time-varying incidence, treatment patterns, treatment rates, and treatment pathways are specified by year to account for guideline-directed changes in standard of care and real-world trends, as well as newly approved clinical treatments. Patient cohorts transition between defined health states, with transitions informed by progression-free survival and overall survival as reported in published literature. Results: Model outputs include point prevalence and period prevalence, with options for highly granular prevalence predictions by disease stage, treatment pathway, or time of diagnosis. As a use case, we leveraged the OSM framework to estimate the prevalence of bladder cancer in the United States. Conclusion: The OSM is a robust model that builds upon existing modeling practices to offer an innovative, transparent approach in estimating prevalence, progression-based incidence, and survival for oncologic conditions. The OSM combines and extends the capabilities of other common health-economic modeling approaches to provide a detailed and comprehensive modeling framework to estimate prevalence in oncology using simulation modeling and to assess the impacts of new treatments on prevalence over time.

Understanding Treatment Patterns and Outcomes among Patients with De Novo Unresectable Locally Advanced or Metastatic Urothelial Cancer: A Population-Level Retrospective Analysis from Alberta, Canada.

Despite a high disease burden, real-world data on treatment patterns in patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) in Canada are limited. This retrospective, longitudinal cohort study describes treatment patterns and survival in a population of patients with de novo unresectable la/mUC from Alberta, Canada, diagnosed between 1 January 2015 and 31 December 2019, followed until mid-2020. The outcomes of interest were systemic therapy treatment patterns and overall survival (OS). Of 206 patients, most (65.0%, n = 134) did not receive any systemic therapies. Of 72 patients (35.0%) who received first-line systemic therapy, the median duration of treatment was 2.8 months (IQR 3.3). Thirty-five patients (48.6% of those who received first-line therapy) received subsequent second-line therapy, for a median of 3.0 months (IQR 3.3). In all patients (n = 206), the median OS from diagnosis was 5.3 months (95% CI, 4.5-7.0). In patients who received treatment, the median OS from the initiation of first-line and second-line systemic therapy was 9.1 (6.4-11.6) and 4.6 months (3.9-19.2), respectively. The majority of patients did not receive first-line systemic therapy, and, in those who did, survival outcomes were poor. This study highlights the significant unmet need for safe and efficacious therapies for patients with la/mUC in Canada.

Clinical and Patient-Reported Outcomes of Advanced Urothelial Carcinoma Following Discontinuation of PD-1/L1 Inhibitor Therapy.

INTRODUCTION: The patterns of care and attrition of locally advanced or metastatic urothelial carcinoma (la/mUC) patients eligible for systemic therapy following PD-1/L1 inhibitors are unclear. The objective of this study was to evaluate the clinical characteristics and treatment patterns among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1 inhibitor therapy. METHODS: An ambispective, multisite, chart review study was conducted in the United States, including patients with la/mUC. Eligible patients had initiated and subsequently discontinued PD-1/L1 therapy in the 1L or 2L setting for la/mUC between May 2016 and July 2018; with follow-up through October 2019. Patient characteristics, treatments, and overall survival (OS) were described. Patients had the option to complete a 1-time patient reported outcomes (PRO) survey. RESULTS: Among 300 patients included in the chart review, 198 (66%) received 1L PD-1/L1 inhibitor and 102 (34%) received 2L PD-1/L1 inhibitor. Following discontinuation of PD-1/L1 inhibitor therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The median OS post-1L PD-1/L1 inhibitor was 9.4 (95% CI 8.6-NA) and 2.5 months (95% CI 2.24-3.50) for those who received and did not receive subsequent therapy, respectively. Following 2L PD-1/L1 inhibitor discontinuation, the median OS was 5.7 (95% CI 5.1-7.8) and 3.98 (95% CI 3.29-4.87) months for those who received and did not receive subsequent therapy, respectively. Among those with PRO data, 64% reported experiencing cancer-related pain and 29.6% received an opioid. Only 12.7% reported having a caregiver, requiring approximately 13 h/d of service. CONCLUSION: The symptom and caregiver burden are high among real-world patients with la/mUC who discontinued 1L or 2L PD-1/L1 inhibitors and outcomes are dismal, with a minority receiving subsequent therapy. Patterns of care in the setting of 1L maintenance avelumab and novel agents require further investigation.

Treatment with opioids in patients with locally advanced or metastatic urothelial carcinoma and matched non-cancer controls.

BACKGROUND: Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive disease with a poor long-term survival. While patients frequently report pain, there are limited data on the patient experience with pain and pain medication use. This study used real-world data to quantify treatment with opioids, as a proxy for pain, in patients with la/mUC compared with matched non-cancer controls. METHODS: This was a retrospective claims analysis, using the IBM® MarketScan® databases, of adults diagnosed with urothelial carcinoma and initiating ≥1 la/mUC therapy between May 2016 and June 2019. Index date was date of first systemic therapy claim for la/mUC; baseline was the 6 months pre-index; follow-up was from index until disenrollment or study end. Proportion with treatment with opioids, number of opioid prescriptions, and daily morphine-equivalent dose (MEQ; in morphine milligram equivalents/day) in patients with la/mUC and matched non-cancer controls from the same databases were assessed. RESULTS: We identified 1293 patients with la/mUC and matched 1:3 with 3862 non-cancer controls. Mean (SD) follow-up was 1.26 (0.74) years in patients with la/mUC and 1.29 (0.72) years in controls. A greater proportion of patients with la/mUC, compared with controls, used opioids during both baseline (63.6% vs. 19.4%) and follow-up (61.4% vs. 27.9%). Among those who used opioids, mean monthly prescriptions (number of medications claims/patient/month) were 0.55 both in patients with la/mUC and controls during baseline, and 0.49 and 0.39, respectively, at follow-up. Daily MEQ among those who used opioids was 53.6 and 45.7 during baseline, and 74.7 and 40.8 at follow-up, in patients with la/mUC and controls, respectively. In patients with la/mUC, mean opioid prescriptions and daily MEQ increased during later lines of therapy. CONCLUSION: In patients with la/mUC, pain requiring opioids is common at diagnosis, worsens as the patient progresses, and is consistently higher than in matched controls. Improvement in disease control with more effective therapies may reduce cancer pain in this population.

Health-related Quality of Life of Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin after Platinum and PD-1/PD-L1 Inhibitor Therapy: Results from Cohort 1 of the Phase 2 EV-201 Clinical Trial.

BACKGROUND: The EV-201 trial (NCT03219333) demonstrated a clinically meaningful and durable response rate and a tolerable safety profile with enfortumab vedotin (EV) in patients with locally advanced/metastatic urothelial carcinoma (LA/mUC) treated with prior PD-1/PD-L1 inhibitor therapy and platinum-containing chemotherapy (cohort 1). Patient-reported outcome (PRO) measures were included in EV-201 as exploratory endpoints. OBJECTIVE: To evaluate PRO data for cohort 1 of EV-201 to better understand the relationship between EV therapy and health-related quality of life (HRQoL). DESIGN, SETTING, AND PARTICIPANTS: Enrolled patients with LA/mUC who received EV were invited to electronically complete two HRQoL instruments (EORTC QLQ-C30 and EQ-5D-3L) at baseline and day 1 of each cycle until treatment discontinuation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient demographics, completion and compliance rates, and PRO scores were analysed using descriptive statistics. Selected EORTC QLQ-C30 scores were analysed post hoc using a repeated-measures mixed model. RESULTS AND LIMITATIONS: Among treated patients (n = 125), 95% completed both baseline questionnaires. Compliance rates were ≥86% throughout the study. Descriptive analyses showed that global health status, physical functioning, and symptom scores remained stable over time, with average scores similar at each cycle. Lower pain and fatigue scores were observed in responders at cycles following an objective response. Pain was lower at cycle 3 than at baseline in patients with bone metastases. Mean EQ-5D-3L utility score (0.80 at baseline; range from 0.77 at cycle 2 to 0.91 at cycle 10) and visual analogue scale scores (66.9 at baseline; range from 65.5 at cycle 2 to 78.4 at cycle 10) remained similar over time. Variability and the small sample size limited definitive conclusions. CONCLUSIONS: PRO scores remained stable throughout EV treatment, further supporting the overall value of EV in the treatment of patients with LA/mUC. The potential benefit of EV therapy on overall HRQoL and symptoms such as pain and fatigue is currently being explored. PATIENT SUMMARY: In this study of adult patients with advanced cancer of the urinary tract that progressed after previous medications, quality of life, ability to function, and symptoms did not worsen on treatment with enfortumab vedotin, which is an antibody + drug combination. Some improvements in pain and fatigue were reported by patients, but further research needs to be conducted. These data complement the efficacy and safety data from the EV-201 trial.

Real-world outcomes in locally advanced or metastatic urothelial carcinoma following platinum and PD-1/L1 inhibitor therapy.

Aim: To investigate real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) in locally advanced/metastatic urothelial carcinoma postplatinum and postprogrammed death receptor-1/death ligand 1 inhibitors. Patients & methods: Adult patients diagnosed with locally advanced/metastatic urothelial carcinoma from 1 January 2011 to 31 December 2018 and treated with taxane monotherapy or any therapy postplatinum and post-PD-1/L1 inhibitors were included from a nationwide electronic health record-derived oncology database. Results: Median rwOS among 72 patients treated with taxane monotherapy was 7.6 months (95% CI: 5.2-14.4) and rwPFS was 2.9 months (95% CI: 2.4-4.0). Among 208 patients treated with any therapy, median rwOS was 8.9 months (95% CI: 7.3-10.6) and rwPFS was 3.6 months (95% CI: 2.7-4.7). Conclusion: Short duration of rwOS and rwPFS were observed, highlighting the need for effective and safe treatments in this patient population.

Lay abstract Few studies have evaluated survival outcomes in patients with advanced urothelial cancer who have disease relapse after chemotherapy and PD-1/L1 inhibitor therapy in clinical practice. In this study, we used electronic health records from a nationwide cancer database to assess survival in adult patients who received further treatment in this setting from 2011 to 2018. Among 72 patients who were treated with taxane monotherapy after chemotherapy and a PD-1/L1 inhibitor, average overall survival was 7.6 months and progression-free survival was 2.9 months. Among 208 patients who were treated with any therapy, average overall survival was 8.9 months and progression-free survival was 3.6 months. These results highlight the need for safer and more effective therapies in patients with advanced urothelial cancer who have disease relapse after chemotherapy and PD-1/L1 inhibitor therapy.

Real-world burden of illness and unmet need in locally advanced or metastatic urothelial carcinoma following discontinuation of PD-1/L1 inhibitor therapy: A Medicare claims database analysis.

BACKGROUND: Several programmed death-1 or death-ligand 1 (PD-1/L1) inhibitors are approved first- or second-line therapies for locally advanced or metastatic urothelial carcinoma (la/mUC); however, clinical trials show that only ∼20% of patients respond and all ultimately progress. This study elucidated real-world treatment patterns, healthcare resource utilization (HRU), and economic burden among Medicare beneficiaries with la/mUC who discontinue PD-1/L1 inhibitor therapies. METHODS: We conducted a retrospective claims analysis of patients aged ≥65 years diagnosed with la/mUC (2015-2017) who initiated and subsequently discontinued PD-1/L1 inhibitor therapy (index=date of last administration) using Medicare Fee-for-Service Research Identifiable Files. Included patients had ≥12 months pre- and ≥3 months post-index continuous Medicare enrollment, and were followed until disenrollment, death, or data cutoff. RESULTS: Among 28,063 patients, 17% (n=4652) received ≥1 PD-1/L1 inhibitor following la/mUC diagnosis. Of these, 791 discontinued PD-1/L1 inhibitor therapy and met inclusion criteria (study cohort); 73% male, median age 76 years. Post-discontinuation, 3% received a different PD-1/L1 inhibitor, 46% chemotherapy, and 51% no further systemic treatment. HRU was high during follow-up: 97% had ≥1 outpatient visit and 52% ≥1 hospitalization. Healthcare costs per-patient-per-month were $7153 pre- and $7745 (adjusted) post-index; systemic therapy costs were higher pre- vs. post-index ($2978 vs. $1195) but other costs were higher post-index: hospitalization ($1120 vs. $2200), outpatient ($1437 vs. $2064), hospice ($3 vs. $536), skilled nursing facility ($106 vs. $384). CONCLUSIONS: Over half of Medicare beneficiaries with la/mUC received no disease-directed therapy post-PD-1/L1 inhibitor treatment. Patients who discontinued PD-1/L1 inhibitor therapy had intensive HRU unrelated to therapy costs, highlighting the significant burden of la/mUC and need for treatments that extend survival.

The direct and indirect economic burden of hypothyroidism in the United States: a retrospective claims database study.

OBJECTIVE: To examine direct and indirect economic burden associated with hypothyroidism in the United States. METHODS: Medical costs attributable to hypothyroidism were estimated for patients with hypothyroidism. Non-hypothyroid (euthyroid) controls were matched to patients with hypothyroidism based upon patient characteristics and availability of productivity data. Multivariable analyses examined resource utilization, annual medical costs, comorbidities, and productivity costs. RESULTS: Estimates of hypothyroidism-related total medical costs ranged from $460 to $2,555 per patient per year. Compared to euthyroid controls, patients with hypothyroidism had significantly higher all-cause medical costs and medical resource utilization. For the subset of patients with available productivity data, hypothyroidism was associated with significantly higher absenteeism and long- and short-term disability costs but significantly lower worker's compensation costs. CONCLUSIONS: Hypothyroidism is associated with significant direct and indirect economic burden among employed, commercially insured patients in the US. Clinical Significance: Despite the availability of relatively inexpensive generic therapies for hypothyroidism, this study found significant direct and indirect costs associated with the condition. The large number of patients diagnosed with hypothyroidism combined with increased costs associated with hypothyroidism result in a significant burden for patients, payers, and employers.

The Impact of Intestinal Complications on Health Care Costs Among Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Therapies.

BACKGROUND: Although there is evidence that anti-tumor necrosis factor (TNF) utilization earlier in the inflammatory bowel disease (IBD) course and before the onset of disease-related complications leads to improved patient outcomes, the health care costs and utilization impact have not been well defined. This study assessed differences in health care utilization and costs among patients with IBD treated with anti-TNFs. METHODS: Patients with a diagnosis of ulcerative colitis (UC) or Crohn disease (CD) between January 1, 2001, and December 31, 2014, were identified from a claims database. Patients were required to have ≥1 claim for a 5-aminosalicylic acid, corticosteroid, or immunomodulator after the IBD diagnosis and ≥1 anti-TNF drug claim after the first IBD treatment. Complication and noncomplication cohorts were identified based on disease-related complications and IBD-related hospitalizations or emergency department visits for 6 months before anti-TNF initiation. Generalized linear models were used to compare health care costs and utilization for the 12 months after anti-TNF initiation (follow-up). RESULTS: The study included 6329 patients with CD and 4451 patients with UC. In patients with CD with complications, >33.7% had intestinal strictures and 6% had enteroenteric fistula before anti-TNF treatment. Patients with CD with complications incurred significantly higher IBD-related and all-cause health care costs during follow-up, and patients with UC experienced the same trends. CONCLUSIONS: These results suggest that anti-TNF treatment after, rather than before, a patient develops complications leads to a higher economic burden. However, these findings could also result from patients with more severe disease having early complications that are more difficult to treat.

Epidemiology and treatment patterns for locally advanced or metastatic urothelial carcinoma: a systematic literature review and gap analysis.

BACKGROUND: Several immuno-oncology (IO) agents targeting programmed death-1 or programmed death-ligand 1 (PD-1/L1) are approved second-line therapy options for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) previously treated with platinum-based chemotherapy or first-line options in patients ineligible for cisplatin whose tumors express PD-L1 or for any platinum-based chemotherapy regardless of PD-L1 expression levels. However, literature on the epidemiology of la/mUC is limited, and real-world treatment patterns are not well established, especially with respect to therapies used following IO. OBJECTIVES: To (a) report the epidemiology of urothelial carcinoma (UC) and la/mUC; (b) identify and summarize the published literature on la/mUC treatment patterns, including IO and post-IO treatment; and (c) identify evidence gaps. METHODS: A systematic literature review was conducted using Cochrane dual-reviewer methodology and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. Literature databases and selected congress abstracts (2017-2018) were searched for retrospective studies published January 2013-August 2018 in English reporting epidemiological and treatment data (all lines of therapy) for adult patients with la/mUC. RESULTS: Among 6,584 database references and 1,832 congress abstracts screened, 45 publications (29 manuscripts, 1 poster, 15 abstracts; reporting 37 unique studies) were retained. All studies related to treatment patterns, and the majority were from the United States (n = 17), Japan (n = 8), and the United Kingdom (n = 5). Epidemiological data were not identified among the searches thus online registries were leveraged. Among the identified publications, 21 (20 unique) reported on cisplatin versus non-cisplatin regimens, 14 (8 unique) on IO, and 9 (7 unique) on vinflunine. Cisplatin use varied both within and among countries (ranging from 18.4% in 1 U.S. study to 87.9% in 1 Japanese study). The use of IO was higher in later lines of therapy, ranging from 1.4% to 7.9% as first-line therapy to 57.8% as second-line and 64.4% as third-line therapy. Among studies reporting IO discontinuation rates, 41.4%-71% of patients were reported to discontinue IO across the studies, and the median time to discontinuation ranged from 2.7 to 5.8 months. Only 25%-35.5% of patients received subsequent therapy following IO discontinuation; post-IO treatments varied widely. CONCLUSIONS: Additional published data on the country-specific epidemiology of UC and la/mUC are needed, including rates of progression from early-stage disease to la/mUC. There was large variation in treatment rates, particularly cisplatin use, within and across countries. The few published real-world IO studies reported high levels of discontinuation with only a small percentage of patients receiving subsequent therapy. As IO therapies continue to be granted regulatory approval in countries outside the United States and novel therapies gain approval in the post-IO setting, the treatment paradigm for patients with la/mUC is shifting, and future studies with more recent data will be required. DISCLOSURES: This study was funded by Astellas/Seagen. Hepp is an employee of and owns stock in Seagen. Shah was a contractor for Astellas Pharma at the time of the study and owns stock in Pfizer. Smoyer is an employee and shareholder of Envision Pharma Group, paid consultants to Seagen. Vadagam was an employee of Envision Pharma Group, paid consultants to Seagen, at the time of the study. Parts of these data have been presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 Annual Meeting; May 18-22, 2019; New Orleans, LA.

Hypothyroidism Treatment Among Older Adults: Evidence from a Claims Database.

INTRODUCTION: Hypothyroidism is a common but often unrecognized condition associated with significant morbidity in the older adult population. This study characterizes a large population of older adults diagnosed with hypothyroidism and examines concordance of their treatment with recommendations from expert bodies, e.g., the American Thyroid Association and American Association of Clinical Endocrinologists. METHODS: Individuals seen in general and/or specialty practices who were age ≥ 65 years and diagnosed with hypothyroidism were included in this observational, retrospective cohort study using a large US claims database. Analyses describe the population and examine the prevalence of hypothyroidism, treatment with levothyroxine and, among those treated, whether TSH laboratory values are within a guideline-recommended target range. RESULTS: Prevalence of hypothyroidism in this older adult population increased from 5.62% to 8.24% over the 2007-2015 period. Among older adults diagnosed with hypothyroidism (N = 4025), a substantial proportion (28.0%) did not receive levothyroxine therapy, and, of those who were receiving such therapy (N = 2899), 32.9% did not have evidence of being monitored to determine whether the dosage was appropriate. Moreover, the laboratory results of those who were treated suggest that a significant proportion (17.4%) had a TSH level above the recommended target range, while TSH levels for a smaller proportion (3.7%) were below target. CONCLUSIONS: Many older adults diagnosed with hypothyroidism may not have received medical care complying with clinical practice guidelines. Results of this study reveal a number of areas to target to potentially improve the treatment of older adults with hypothyroidism.

Levothyroxine Treatment of Pregnant Women with Hypothyroidism: Retrospective Analysis of a US Claims Database.

BACKGROUND: Approximately 2-4% of women of reproductive age have hypothyroidism. This study characterizes pregnant women with hypothyroidism and examines adherence to guidelines during pregnancy. METHODS: Women age 18 to 49 who were pregnant in 2014 and identified with hypothyroidism (N = 3448) were included in the retrospective study. The analyses examined differences in characteristics and comorbidities between pregnant women treated with levothyroxine and untreated women and adherence to guidelines by measuring thyroid-stimulating hormone (TSH) target achievement for women treated with levothyroxine. RESULTS: The average age was 32.76 years, and the median TSH value was 1.97 mIU/l. Compared with untreated pregnant women, pregnant women treated with levothyroxine were significantly younger, had a lower Charlson Comorbidity Index score and had lower rates of comorbid type 2 diabetes and migraines. Among women treated with levothyroxine, 52.61% had a last recorded TSH value consistent with American Thyroid Association (ATA) guidelines, 23.85% were undertreated, 1.03% were overtreated, and 22.52% did not have TSH monitored during their pregnancy. CONCLUSIONS: A large percentage of pregnant women, including many treated with levothyroxine, was not treated in a manner consistent with clinical guidelines. Additionally, there were significant differences in general health and comorbidities between pregnant women treated with levothyroxine and those untreated.

Adherence to thyroid hormone replacement therapy: a retrospective, claims database analysis.

OBJECTIVE: The objective of this analysis was to compare adherence at 6 months and 12 months across levothyroxine formulations for patients with hypothyroidism. METHODS: This retrospective analysis utilized insurance claims data from a commercially insured population from January 1, 2000 through March 31, 2016. Patients were included if they were diagnosed with hypothyroidism and initiated treatment with generic levothyroxine, Levoxyl, Synthroid, Unithroid, or Tirosint. Patients were excluded if they were younger than age 18, were diagnosed with thyroid cancer, received a prescription for liothyronine, or did not have continuous insurance coverage over the study period. Adherence, defined by the proportion of days covered (PDC) ≥ 80%, was examined using multivariable analyses for both 6 and 12 months post-initiation on therapy Results: The study identified 580,331 patients who fit the study criteria. At 6 months, 40.3% of patients were found to be non-adherent, while 51.9% were non-adherent at 12 months. Synthroid was associated with significantly higher adherence compared to all other levothyroxine formulations at both 6 and 12 months. Compared to generic levothyroxine, the likelihood of being adherent at 12 months was highest for Synthroid (OR = 1.44; 95% CI = 1.43-1.46), followed by Levoxyl (OR = 1.20 95% CI = 1.17-1.23). Tirosint and Unithroid were associated with significantly lower adherence at 12 months compared to generic levothyroxine (OR = 0.65; 95% CI = 0.57-0.75 and OR = 0.79; 95% CI = 0.71-0.89, respectively). CONCLUSIONS: This large, retrospective real-world study demonstrated that adherence to levothyroxine remains a concern among patients with hypothyroidism, and that differences in adherence may exist across levothyroxine formulations.

The association between adherence to levothyroxine and economic and clinical outcomes in patients with hypothyroidism in the US.

OBJECTIVE: To evaluate outcomes associated with adherence to levothyroxine (LT4) in the US adult hypothyroidism population. METHODS: We used data from Truven's MarketScan databases from 1 July 2011 through 31 December 2015. Patients aged 18 or older were diagnosed with hypothyroidism (confirmed at least twice) and prescribed LT4. Patients were excluded if they did not have continuous insurance coverage or if they received a diagnosis of thyroid cancer or pregnancy during the study period. Multivariable analyses on a matched cohort of adherent and nonadherent patients examined the relationships among patient outcomes and adherence, defined as the proportion of days covered ≥80%. Outcomes included all-cause and hypothyroidism-related medical costs and resource utilization and comorbid diagnoses measured over the 1 year post-period following the first prescription for LT4. The analyses controlled for patient age, sex, region of residence, type of insurance coverage, diagnosing physician and pre-period general health status as proxied by the Charlson Comorbidity Index. RESULTS: Prior to matching, there were 168,457 patients identified as adherent and 198,443 patients identified as nonadherent. The matched cohort consisted of 318,628 individuals, with equal numbers of adherent and nonadherent patients (n = 159,314). Patients who were adherent used significantly fewer resources and had significantly lower all-cause ($14,136 vs. $14,926; p < .0001) and hypothyroidism-related ($1672 vs. $1709; p < .0001) total costs, although the costs of drugs were higher in the adherent group. Furthermore, adherent patients, compared to nonadherent patients, were significantly less likely to be diagnosed with comorbid Addison's disease, bipolar disorder, chronic kidney disease, depression, migraine, obesity, type 1 diabetes or type 2 diabetes during the follow-up period. CONCLUSIONS: Compared to nonadherence, adherence to LT4 among patients with hypothyroidism was associated with a significant reduction in all-cause and hypothyroidism-related costs and resource utilization as well as significantly lower rates of many comorbid diagnoses.