Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting.

Importance: Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective: To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants: Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures: Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures: Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results: Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% [95% CI, -18.4% to 11.1%]; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance: Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Comparative efficacy and safety of daclatasvir/asunaprevir versus IFN-based regimens in genotype 1b hepatitis C virus infection.

AIM: Efficacy and safety comparison of daclatasvir/asunaprevir (DCV + ASV) versus peginterferon-α/ribavirin (A/R) alone or combined with telaprevir, boceprevir, simeprevir or sofosbuvir in chronic genotype 1b hepatitis C virus infection. METHODS: Network meta-analysis (NMA) and matching-adjusted indirect comparisons (MAICs). RESULTS: Among treatment-naive patients, DCV + ASV demonstrated higher sustained virologic response (SVR) rates than telaprevir + A/R, boceprevir + A/R and A/R in NMA and MAICs and simeprevir + A/R in NMA. DCV + ASV among treatment-experienced patients had higher SVR rates than telaprevir + A/R, boceprevir + A/R, simeprevir + A/R and A/R in MAICs. DCV + ASV had lower adverse events rates than comparators. CONCLUSION: DCV + ASV demonstrated superior efficacy and safety compared with A/R-based regimens.

Costs and Resource Utilization Associated With Anemia and Rash in Chronic Hepatitis C Patients Treated With Direct-Acting Antiviral Agents in the United States.

PURPOSE: The addition of 2 direct-acting antiviral (DAA) agents, telaprevir and boceprevir, to peginterferon and ribavirin therapy significantly improves sustained virologic response rates in patients treated for chronic hepatitis C virus (CHC) but is associated with a higher risk of adverse events (AEs), including anemia and rash. Using a large administrative claims database, this study compared the health care resource utilization and costs among CHC patients who developed anemia and/or rash while receiving DAA-based therapies (telaprevir and boceprevir) versus those who did not develop anemia or rash. Adjusted costs were compared by using regression analysis. METHODS: Adult patients with ≥1 CHC diagnosis and a prescription for boceprevir or telaprevir were selected from a US-based claims database. The date of the first DAA fill after May 13, 2011, was defined as the index date. Patients were required to have continuous eligibility and no claims for hepatitis B treatment during the 6 months before (baseline) and 12 months after (study period) the index date. Patients were categorized into 4 cohorts based on the development of anemia only, rash only, both anemia and rash (anemia/rash), or neither anemia nor rash (NAR) while receiving DAA-based therapies. Baseline characteristics and study period health care utilization and costs were compared by using univariate statistics between cohorts that developed anemia only, rash only, or anemia/rash and the cohort that did not develop anemia or rash. Adjusted costs were compared by using multivariable regressions. FINDINGS: A total of 2862 patients were identified and categorized into 4 cohorts: 1204 anemia only, 131 rash only, 188 anemia/rash, and 1339 NAR patients. During the study period, patients developing anemia and/or rash incurred significantly more outpatient, dermatologist, and total medical visits compared with the NAR cohort. The anemia-only and anemia/rash cohorts also had significantly more inpatient, emergency department, and hematologist visits, as well as significantly higher adjusted total medical costs ($18,285 and $21,435 vs $11,253), total drug costs ($76,723 and $79,689 vs $63,001), and non-CHC drug costs ($10,391 and $10,475 vs $2437). The rash-only cohort had comparable adjusted total medical and drug costs. IMPLICATIONS: CHC patients who developed anemia while receiving DAA-based therapies incurred significantly higher resource utilization and costs compared with those who did not. The study highlights the need for new CHC treatment regimens that are associated with fewer and less severe AEs, particularly anemia.

Treatment patterns, health care resource utilization, and costs in U.S. patients diagnosed with chronic hepatitis C infection who received telaprevir or boceprevir.

BACKGROUND: Chronic hepatitis C (CHC) is associated with substantial morbidity and mortality, with the future burden of disease predicted to significantly increase. The recent addition of 2 direct-acting antiviral (DAA) protease inhibitors, telaprevir and boceprevir, to peginterferon alfa (PEG) and ribavirin (RBV) therapy has been shown to significantly improve sustained virologic response rates and thus has become standard of care. While the efficacy and safety of DAAs has been assessed in the clinical trial setting, less is known about real-world use of these new therapies. OBJECTIVES: To (a) evaluate the treatment patterns, health care utilization, and costs of CHC patients receiving DAA-based therapies in the United States using a retrospective analysis of a large administrative claims database and (b) evaluate factors associated with therapy noncompletion using multivariable analyses. METHODS: Adult patients with ≥ 1 claim for CHC and a prescription filled for boceprevir or telaprevir were selected from a de-identified U.S.-based claims database. The date of the first fill for a DAA after May 13, 2011 (date of first DAA availability) was defined as the index date, and patients were categorized into either the telaprevir or boceprevir cohort. Patients were required to have continuous eligibility and no claims for hepatitis B during the 6 months before (baseline) and 12 months following (study period) the index date. Baseline characteristics and study period treatment patterns, health care utilization, and costs were described. Factors associated with therapy noncompletion were examined using multivariable logistic regression, and adjusted health care costs were compared between the DAA cohorts using multivariable analyses. RESULTS: A total of 871 telaprevir and 284 boceprevir patients were identified. DAA patients were aged 54 years on average and more often were male (60%, n = 688). Approximately 25% (n = 216) of telaprevir and 18% (n = 52) of boceprevir patients had cirrhosis, and 9% (n = 82) of telaprevir and 7% (n = 20) of boceprevir patients had decompensated cirrhosis at baseline. Less than 1% (n = 9) of patients were HIV co-infected. Approximately 54% (n = 470) of telaprevir and 74% (n = 210) of boceprevir patients did not complete the minimum duration of therapy as per the prescribing information (telaprevir: 12 weeks of triple + 12 weeks of dual; boceprevir: 3 weeks of lead-in + 24 weeks of triple). In multivariable analyses, females (vs. males) and patients taking boceprevir (vs. telaprevir) were more likely to not complete therapy (P = 0.011). CHC patients experienced high medical and drug-related resource utilization. Telaprevir patients had numerically higher study period unadjusted medical (boceprevir: $16,927; telaprevir: $19,519) and drug costs (boceprevir: $59,953; telaprevir: $76,497) than boceprevir patients; however, after adjusting for baseline characteristics, only drug costs remained significantly different (P less than 0.001).  CONCLUSIONS: These results indicate that a large proportion of CHC patients receiving telaprevir or boceprevir did not complete minimum duration of therapy as per the prescribing information. CHC patients on a DAA regimen also experienced high resource utilization and high medical and drug costs.

Healthcare resource use and costs of privately insured patients who switch, discontinue, or persist on anti-muscarinic therapy for overactive bladder.

OBJECTIVES: To compare the healthcare costs of patients with overactive bladder (OAB) who switch vs persist on anti-muscarinic agents (AMs), describe resource use and costs among OAB patients who discontinue AMs, and assess factors associated with persisting vs switching or discontinuing. METHODS: OAB patients initiating an AM between January 1, 2007 and March 31, 2012 were identified from a claims database of US privately insured beneficiaries (n ≈ 16 million) and required to have no AM claims in the 12 months before AM initiation (baseline period). Patients were classified as persisters, switchers, or discontinuers, and assigned a study index date based on their AM use in the 6 months following initiation. Baseline characteristics, resource use, and costs were compared between persisters and the other groups. Resource use and costs in the 1 month before and 6 months after the study index date (for switchers, the date of index AM switching; for persisters, a randomly assigned date to reflect the distribution of the time from AM initiation to switching among switchers) were also compared between persisters and switchers in unadjusted and adjusted analyses. Factors associated with persisting vs switching or discontinuing were assessed. RESULTS: After controlling for baseline characteristics and costs, persisters vs switchers had significantly lower all-cause and OAB-related costs in both the month before (all-cause $1222 vs $1759, OAB-related $142 vs $170) and 6 months after the study index date (all-cause $7017 vs $8806, OAB-related $642 vs $797). Factors associated with switching or discontinuing vs persisting included index AM, younger age, and history of UTI. CONCLUSION: A large proportion of OAB patients discontinue or switch AMs shortly after initiation, and switching is associated with higher costs.

The prevalence and economic impact of prescription opioid-related side effects among patients with chronic noncancer pain.

OBJECTIVES: To estimate the prevalence of opioid-related side effects among patients with chronic noncancer pain (CNCP) who initiated opioids and compare healthcare costs of patients with and without side effects using patient survey, medical charts, and claims data. PATIENTS, PARTICIPANTS: Patients initiating opioids, who were aged ≥18 years, had ≥1 pain diagnosis, and did not have cancer, were identified through claims data and medical records from a Central Massachusetts medical group practice and mailed surveys between October 2010 and July 2012. MAIN OUTCOMES MEASURES: Prevalence of opioid-related side effects was estimated from patient surveys, charts, and claims data within 90 days after opioid initiation (study period). Study period healthcare costs were compared between patients with and without side effects (self-reported problematic side effects or side effects recorded in medical charts or claims). RESULTS: Among patients with CNCP who initiated opioids and completed the survey (N = 167), the average age was 53 years, and 62.9 percent were women. Based on the survey, charts, and claims, 91.6 percent, 15.0 percent, and 19.2 percent of patients, respectively, had ≥1 opioid-related side effect. Overall, 59.3 percent of patients reported having ≥1 problematic side effect or side effect recorded in charts or claims. In the analysis that controlled for baseline characteristics and resource use, patients with versus without side effects had higher mean study period healthcare costs ($3,347 vs $2,521, p = 0.049). CONCLUSIONS: Prevalence of opioid-related side effects among patients with CNCP who initiated opioids was substantially higher based on patient survey than from charts or claims. Opioid-related side effects were associated with significantly higher healthcare costs.

Healthcare costs and utilization for privately insured patients treated for non-infectious uveitis in the USA.

BACKGROUND: The purpose of this study was to describe comorbidities, healthcare costs, and resource utilization among patients with chronic non-infectious uveitis initiating corticosteroid, immunosuppressants, or biologics.In this retrospective cohort study, patients with a non-infectious uveitis diagnosis and continuous insurance coverage during a 6-month baseline were selected from a privately insured claims database with 80.7 million enrollees. Index dates were defined as the first prescription/administration of a corticosteroid, immunosuppressant, or biologic between 2003 and 2009. Comorbidities, healthcare costs, and utilization were analyzed in a per-member-per-month (PMPM) framework to account for varying between-patient treatment periods, defined as continuous medication use within the same class. Wilcoxon rank-sum and chi-square tests were used for comparisons of costs and categorical outcomes. RESULTS: Patients on corticosteroids (N = 4,568), immunosuppressants (N = 5,466), and biologics (N = 1,694) formed the study population. Baseline PMPM inpatient admission rates were 0.029 for patients on corticosteroids, 0.044 for patients on immunosuppressants, and 0.045 for patients on biologics (p < 0.001 immunosuppressants or biologics versus corticosteroids); during treatment, PMPM inpatient admissions increased to 0.044 and 0.048 for patients taking corticosteroids and immunosuppressants, respectively, but decreased to 0.024 for patients taking biologics (p < 0.001 versus corticosteroids and p = 0.003 versus immunosuppressants). Baseline average PMPM costs for patients taking corticosteroids, immunosuppressants, and biologics were US$935, US$1,738, and US$1,439 (p < 0.001 between groups), while on-treatment PMPM costs excluding drug costs increased to US$1,129 for patients taking corticosteroids but lowered to US$1,592 for patients taking immunosuppressants, and US$918 for patients taking biologics (p < 0.001 versus corticosteroids or immunosuppressants). CONCLUSIONS: There is significant economic burden associated with existing treatments of uveitis. Corticosteroids may be overused as a treatment for uveitis.

Effects of care management and telehealth: a longitudinal analysis using medicare data.

OBJECTIVES: To evaluate mortality and healthcare utilization effects of an intervention that combined care management and telehealth, targeting individuals with congestive heart failure, chronic obstructive pulmonary disease, or diabetes mellitus. DESIGN: Retrospective matched cohort study. SETTING: Northwest United States. PARTICIPANTS: High-cost Medicare fee-for-service beneficiaries (N = 1,767) enrolled in two Centers for Medicare and Medicaid Services demonstration participating clinics and a propensity-score matched control group. INTERVENTION: The Health Buddy Program, which integrates a content-driven telehealth system with care management. MEASUREMENTS: Mortality, inpatient admissions, hospital days, and emergency department (ED) visits during the 2-year study period were measured. Cox-proportional hazard models and negative binomial regression models were used to assess the relationship between the intervention and survival and utilization, controlling for demographic and health characteristics that were statistically different between groups after matching. RESULTS: At 2 years, participants offered the Health Buddy Program had 15% lower risk-adjusted all-cause mortality (hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.74-0.98; P = .03) and had reductions in the number of quarterly inpatient admissions from baseline to the study period that were 18% greater than those of matched controls during this same time period (-0.035 vs -0.003; difference-in-differences = -0.032, 95% CI = -0.054 to -0.010, P = .005). No relationship was found between the Health Buddy Program and ED use or number of hospital days for participants who were hospitalized. The Health Buddy Program was most strongly associated with fewer admissions for individuals with chronic obstructive pulmonary disease and mortality for those with congestive heart failure. CONCLUSION: Care management coupled with content-driven telehealth technology has potential to improve health outcomes in high-cost Medicare beneficiaries.

Development and validation of a claims-based prediction model for COPD severity.

BACKGROUND: Administrative claims are an important data source for COPD research but lack a validated measure of patient COPD severity, which is an important determinant of treatment and outcomes. METHODS: Patients with ≥1 diagnosis of COPD and spirometry results from 01/2004-05/2011 were identified from an electronic health records database linked to healthcare claims. Patients were classified into 3 COPD severity groups based on spirometry and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines: GOLD-Unclassified, Mild/Moderate, and Severe/Very Severe. A multinomial logistic regression model was constructed using claims data from 3 months before and after (observation period) the most recent spirometry (index date) to categorize patient COPD severity. A random selection of 90% of patients in each severity level was selected to build the model, and the remaining 10% were used as a validation sample. Model predictions were evaluated for sensitivity, specificity, accuracy, and concordance. RESULTS: Among 2028 COPD patients who met sample selection criteria, 886, 683, and 459 patients were in the GOLD-Unclassified, Mild/Moderate, and Severe/Very Severe categories, respectively. The final model included age, sex, comorbidities (such as pulmonary fibrosis and diabetes), COPD-related resource utilization (such as oxygen use), and all-cause healthcare utilization. In the validation sample, the model correctly predicted COPD severity for 62.7% of all patients (accuracy for predicting GOLD-Unclassified: 73.5%; Mild/Moderate: 70.6%; Severe/Very Severe: 81.4%) with kappa = 0.41. CONCLUSIONS: The prediction model was developed using clinically measured COPD severity to provide researchers an approach to classify patients using claims data when clinical measures are not available.

Energy intake and energy expenditure among children with polymorphisms of the melanocortin-3 receptor.

BACKGROUND: Homozygosity for 2 protein-altering polymorphisms in the melanocortin-3 receptor gene (MC3R) coding sequence, C17A and G241A, has been reported to be associated with an obesity phenotype in children, yet how these polymorphisms affect energy homeostasis is unknown. Association between adult body weight and +2138InsCAGACC, another variant in the 3' untranslated region of MC3R, has also been described. OBJECTIVE: The objective of this study was to examine associations of C17A + G241A and +2138InsCAGACC MC3R variants with children's energy balance. DESIGN: Children aged 6-19 y were genotyped for MC3R C17A, G241A, and +2138InsCAGACC. Subjects underwent studies of energy intake from a 9835-kcal food array (n = 185), resting energy expenditure (REE) by using indirect calorimetry (n = 302), or total daily energy expenditure (TEE) by using doubly labeled water (n = 120). Linear regression was used to examine the associations between MC3R polymorphisms and the measures of energy balance. RESULTS: Body mass index and fat mass were greater in those with double homozygosity for C17A + G241A (P = 0.001). After accounting for covariates (including body composition), the number of minor C17A + G241A alleles was associated with significantly greater energy intake (beta = +0.15, P = 0.02) but not altered REE or TEE. No significant associations were observed between +2138InsCAGACC and measures of either fat mass or energy balance. CONCLUSIONS: C17A + G241A polymorphisms may be associated with pediatric obesity because of greater energy intake rather than because of diminished energy expenditure. +2138InsCAGACC does not appear to be associated with obesity or measures of energy balance in children.