Initial versus early switch to targeted therapy during first-line treatment among patients with biomarker-positive advanced or metastatic non-small cell lung cancer in the United States.

OBJECTIVES: This study compared outcomes between patients with biomarker-positive advanced/metastatic non-small cell lung cancer (a/mNSCLC) who initiated treatment with targeted therapy versus those who initiated chemotherapy-based treatment and switched to targeted therapy during the first ∼3 cycles (defined as the first 56 days) of first-line treatment. MATERIALS AND METHODS: This was an observational study of patients with a/mNSCLC who received targeted therapy from a nationwide electronic health record (EHR)-derived de-identified database. Outcomes were compared between those who initiated targeted therapy versus those who switched from chemotherapy to a targeted agent. Time-to-event outcomes were evaluated using Kaplan-Meier method; Cox proportional hazards models (adjusted for baseline covariates) were used to compare outcomes between groups. RESULTS: Of the 4,244 patients in this study, 3,107 (73.2%) initiated the first line with targeted therapy and 346 (8.2%) switched to targeted therapy. Patients who received initial targeted therapy were significantly more likely to be non-smokers, treated in an academic practice setting, and of slightly older age (all p < 0.05). Patients who received initial targeted therapy also had a significantly longer time to start of first-line treatment (35.8 vs 25.3 days, p < 0.001). No significant differences were observed for clinical outcomes between groups. CONCLUSION: In both unadjusted and adjusted analyses, there were no differences in the clinical outcomes observed among patients with a/mNSCLC in this study. This study found that initiating chemotherapy with an early switch to targeted therapy (within 56 days) of receiving biomarker positive results may be an acceptable strategy for a patient for whom immediate care is needed.

Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study.

This retrospective study using the nationwide de-identified Flatiron Health electronic health record-derived database was designed to evaluate clinical outcomes among patients with chronic lymphocytic leukemia (CLL) who previously received both a covalent Bruton's tyrosine kinase inhibitor (cBTKi) and B-cell lymphoma 2 inhibitor (BCL2i) in a real-world setting. Outcomes for the immediate next line of therapy following the latter of the cBTKi or BCL2i treatment included: real-world response rate of 34.4% (using methods most consistent with clinical trials); median duration of real-world response of 13.3 months; and median real-world progression-free survival of 9.2 months. Median overall survival was 25.5 months from the start of the immediate next line of therapy. There remains a need for more effective therapies after cBTKi and BCL2i therapy for patients with CLL.

Cardiac events among patients with sarcoma treated with doxorubicin by method of infusion: A real-world database study.

BACKGROUND: Administration of doxorubicin by continuous intravenous (CIV) infusion, versus bolus (BOL) administration, has been proposed to mitigate the risk of cardiac events. This study used real-world data to explore the association between mode of doxorubicin administration and duration of treatment, time-to-treatment failure (TTF), and cardiac events. METHODS: Occurrence of cardiac events after initiation of BOL versus CIV doxorubicin for sarcoma in the International Business Machines MarketScan claims database were compared. Duration of doxorubicin treatment, TTF, and time-to-first-cardiac event (TCE) were evaluated using Kaplan-Meier method and unadjusted and adjusted Cox regression models. RESULTS: A total of 196 patients were included in the BOL group and 399 in the CIV group. In unadjusted analyses, there were significant differences between BOL versus CIV for duration of doxorubicin treatment (median 1.4 vs. 2.1 months, p = .002), TTF (median 8.8 vs. 5.6 months, p = .002), and TCE (medians not reached, p = .03). Adjusting for baseline covariates, only TTF remained significant (hazard ratio: 0.71, 95% confidence interval 0.59-0.86, p = .0004), favoring BOL. CONCLUSIONS: While the risk of cardiac complications was higher with BOL in unadjusted analysis, the risk was no longer present in the adjusted analysis. While we cannot draw causal inferences due to the retrospective, nonrandomized study design, these data suggest that replacing BOL with prolonged CIV administration has not been effective as a strategy to mitigate cardiac events, given community standards of oncologic practice.

A real-world US study of recurrence risks using combined clinicopathological features in HR-positive, HER2-negative early breast cancer.

Aim: To assess invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, HER2-negative early breast cancer with combined clinicopathological criteria from monarchE, a phase III study of abemaciclib. Methods: US electronic health records were used to compare outcomes between high-risk (≥4 lymph nodes, or 1-3 lymph nodes and grade 3, tumor ≥5 cm or Ki-67 ≥20%) versus nonhigh-risk groups using Kaplan-Meier methods and Cox regression models. Results: The high-risk group (n = 557) was at higher risk for IDFS and DRFS events than the nonhigh-risk group (n = 3471). IDFS events (hazard ratio: 3.07; 95% CI: 2.45-3.83) and DRFS events (hazard ratio: 3.15; 95% CI: 2.49-3.97) were significantly higher for the high-risk group. Conclusion: Risk of recurrence was three-times greater in the high-risk group, highlighting the need for better therapies.

Breast cancer is frequently diagnosed early, at a stage when patients can be cured. However, some patients have breast cancers (tumors) with a high risk of recurrence. When cancers come back, a cure is often not possible. This study looks at multiple high-risk tumor features and the risk of cancer returning, in the most common breast cancer type, known as hormone receptor-positive, HER2-negative breast cancer. In patients with high-risk tumors, breast cancer returned in about 11.9% of patients within 2 years and in 29.8% of patients at 5 years. The risk of recurrence or death was three-times higher in patients with high-risk tumors compared to patients with nonhigh-risk tumors. These results suggest better treatments are needed to prevent breast cancers from coming back in patients at high risk of recurrence.

Study of patient characteristics, treatment patterns, EGFR testing patterns and outcomes in real-world patients with EGFRm+ non-small cell lung cancer.

OBJECTIVE: This retrospective, observational study examined patient characteristics, treatment patterns, testing patterns, and outcomes of US patients receiving first-/second- or third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). METHODS: This study used an electronic health record-derived de-identified database. Eligible patients had advanced EGFRm+ non-small cell lung cancer. Descriptive statistics were used to describe demographic, clinical, and treatment characteristics. Logistic regression models were used to identify patient characteristics that were associated with the use of osimertinib vs. a first-/second-generation EGFR TKI. Kaplan-Meier methods were used for survival analysis. RESULTS: Of the 782 patients who received first-line (1L) therapy with first-/second-generation EGFR TKIs in cohort A, erlotinib was the most common (58%), and osimertinib was the most widely prescribed second-line (2L) therapy (52%). Of the patients who received 1L therapy with osimertinib, a greater range of treatments were prescribed in 2L. A third of patients treated with first-/second-generation EGFR TKIs underwent EGFR testing near the end of 1L, and 44% of these patients had T790M positive disease. The median time on targeted therapy (TTT) of the cohort was 11.1 months (95% confidence interval [CI] 9.7, 12.3), and the median overall survival from the start of 1L therapy was 23.5 months (95% CI 20.7, 24.8). CONCLUSIONS: The majority of patients treated with first-/second-generation EGFR TKIs went on to receive osimertinib in the 2L setting, but overall, only a third of patients had received molecular testing at progression. Improved testing frequency is vital to inform treatment decisions.

Real-World Outcomes and Factors Associated With the Second-Line Treatment of Patients With Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma.

This retrospective observational study was designed to evaluate overall survival in a real-world patient population and to identify predictive factors associated with receipt of second-line therapy. A retrospective analysis of electronic medical records (Flatiron Health, New York) was conducted among patients initiating first-line therapy from January 1, 2013, through April 30, 2018. Eligible patients were diagnosed with advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma and ≥18 years of age at the time of treatment initiation. Patients alive 45 days after discontinuation of first-line therapy were considered potentially eligible for continued therapy and were categorized into those who received and those who did not receive second-line therapy. Survival analyses were conducted using Kaplan-Meier method and log-rank test without adjusting for any baseline covariates. Factors associated with further treatment were evaluated using logistic regression. A total of 3850 patients met eligibility criteria. Among the 2516 patients available to receive second-line therapy, 1515 (60.2%) received second-line therapy and 1001 (39.8%) did not receive further therapy. Among those potentially eligible to receive second-line therapy, median survival was 15.4 months (95% confidence interval [CI]: 14.6-16.0) from initiation of first-line therapy for those who received second-line therapy and 10.0 months (95% CI: 9.3-10.7) for those who did not. Longer duration of first-line therapy (≥169 vs ≤84 days), HER2-positive tumors, initially diagnosed with stage IV disease, less weight loss during first-line therapy, and younger age were associated with receipt of second-line therapy (all P < .001). Longer survival was associated with multiple lines of therapy; however, these results should be interpreted with caution, and no causal relationship can be inferred.

Challenges of Using ICD-9-CM and ICD-10-CM Codes for Soft-Tissue Sarcoma in Databases for Health Services Research.

Objectives: Soft-tissue sarcoma (STS) is a heterogeneous group of rare solid tumors that arise from various soft tissues in the body, such as muscle, fat, nerves, and blood vessels. Current International Classification of Diseases (ICD) coding systems include a set of nonspecific codes for malignancies of connective and soft tissue (ICD-9-CM code 171 and ICD-10-CM code C49). The goal of this study was to evaluate the use of these codes for health services research involving patients with a diagnosis of this rare malignancy. Methods: Two databases were utilized to explore ICD coding for STS: claims data from Truven MarketScan and electronic medical records (EMRs) from Flatiron Health. Eligible patients from claims data were those with at least two ICD-9-CM codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The treatment patterns of these cases were evaluated for consistency with known therapeutic approaches for STS. Eligible patients from the Flatiron EMR system were those who received olaratumab (a drug indicated only for use in patients diagnosed with STS) after its US Food and Drug Administration approval in October 2016 through the end of the data set (November 2017). ICD-10-CM codes were evaluated for this known STS cohort. Results: In claims data, 4,159 patients were eligible for inclusion. Although national treatment guidelines include only a limited number of drugs used to treat STS, 98 unique anticancer drugs were identified as being used to treat patients in a claims data cohort. Only 7.7 percent of patients had claims for doxorubicin-based therapy and 3.8 percent had claims for ifosfamide-based therapy as initial treatment for STS, despite these being a standard of care. In the EMR data, 350 patients were eligible; only 170 patients (48.6 percent) had any evidence in the database of a connective or soft-tissue ICD-10-CM malignancy code within 60 days before or after initiation of olaratumab. Conclusions: ICD coding for STS using the "Malignant neoplasm of connective and soft tissue" code is not reliable as a method to identify patients diagnosed with STS. Although codes reflecting the primary site of disease may have clinical relevance, lack of consistency in ICD coding for the diagnosis and treatment of this disease is a limiting factor in the ability to conduct real-world observational research of this rare disease. In the absence of consistent use of this code, an algorithm needs to be developed and validated to accurately identify patients with STS in these databases.

Fracture risk and healthcare resource utilization and costs among osteoporosis patients with type 2 diabetes mellitus and without diabetes mellitus in Japan: retrospective analysis of a hospital claims database.

BACKGROUND: Osteoporosis, osteoporosis-related fractures, and diabetes are considerable health burdens in Japan. Diabetes in patients with osteoporosis has been reported to be associated with increased fracture risk. This retrospective analysis of a Japanese hospital claims database investigated the real-world effect of type 2 diabetes mellitus (T2DM) on the incidence of clinical fractures, costs, and healthcare resource utilization in patients with osteoporosis and a subgroup of patients prescribed raloxifene. METHODS: Women aged ≥50 years diagnosed with osteoporosis who had a first prescription claim for osteoporosis treatment with a pre-index period ≥12 months and a post-index period of 30 months were selected from a database extract (April 2008-July 2013). Patients prescribed raloxifene were classed as a subgroup. Patients diagnosed with T2DM constituted the T2DM group; all other patients (excluding patients with type 1 diabetes mellitus) constituted the non-diabetes mellitus (non-DM) group. Groups were matched by exact matching, using selected baseline characteristics. Patient demographic and clinical characteristics were compared using chi-squared tests, t-tests, or Wilcoxon rank sum tests. Time to first fracture was examined using Kaplan-Meier survival analysis. RESULTS: Overall, the T2DM and non-DM groups had 7580 and 7979 patients, respectively; following matching, there were 3273 patients per group. In the raloxifene subgroup, the T2DM and non-DM groups had 668 and 699 patients, respectively; following matching, there were 239 patients per group. At baseline, the T2DM group (overall and raloxifene subgroup) had significantly higher healthcare resource utilization and comorbidities. During the post-index period, a similar pattern was observed in the overall group, even after matching; the T2DM group also had a higher incidence of fracture. In the raloxifene subgroup, after matching, there were no significant differences in fracture incidence or costs and fewer differences in healthcare resource utilization between the T2DM and non-DM groups. CONCLUSIONS: These findings suggest that comorbid T2DM increases fracture incidence in patients with osteoporosis, compared with patients without DM. Increases in fracture incidence were accompanied by greater costs and healthcare resource utilization, which are important considerations for clinical practice in Japan. Further research investigating the use of raloxifene for treatment of osteoporosis with comorbid T2DM may also be warranted.

Real-world clinical and economic outcomes for daily teriparatide patients in Japan.

A large medical and pharmacy claims database was used to evaluate outcomes in daily teriparatide (D-TPD) patients in Japan. 445 patients were identified (April 2008-July 2013) with 6+ months' pre- and 18+ months' post-index observation. D-TPD 20 µg subcutaneous injection is indicated for individuals at high risk of fracture. Descriptive analyses were conducted on clinical fractures, health care utilization, and costs. Adherence was measured by medication possession ratio (MPR) (High MPR > 0.8; 0.5 ≤ Medium MPR ≤ 0.8, Low MPR < 0.5). Adjusted analyses of Lower (Low + Medium) MPR vs. High MPR for fracture incidence and hospital admissions were performed using logistic and Poisson regression models; adjusted cost analyses used propensity bin bootstrapping methods. Baseline characteristics were: mean 74.7 years (standard deviation = 8.9); 90 % female; 20 % 1+ fracture. Post-index, 249 and 196 patients had High and Lower MPR, respectively. Mean incident fractures/1000 patient-years for Lower and High MPR patients were 77.4 and 57.7, respectively. Adjusted fracture risk was greater in Lower MPR patients [logistic odds ratio (OR) = 1.67, 95 % confidence interval 0.791-3.541; Poisson incidence rate ratio (IRR) = 1.505, 0.764-2.966]. Hospital admission risk was significantly greater in Lower than High MPR patients (OR = 1.85, 1.169-2.921; IRR = 1.47, 1.137-1.904). High MPR patients had numerically lower inpatient and total unadjusted costs than Lower MPR patients. Adjusted inpatient costs were significantly less in High MPR patients; outpatient and pharmacy costs were greater. Better adherence to D-TPD revealed a trend towards lower fracture risk, and significant reductions in hospital admissions and costs. The small sample size limited the robustness of these results.

Osteoporotic fractures and associated hospitalizations among patients treated with teriparatide compared to a matched cohort of patients not treated with teriparatide.

OBJECTIVE: To compare fractures and fracture-related resource utilization (RU) among patients with a recent fracture and treated with teriparatide (TPTD) to a matched cohort of patients not treated with TPTD (non-TPTD). RESEARCH DESIGN AND METHODS: Women aged 50 years or older initiating TPTD (N = 5314; index date between 1 January 2007 and 31 December 2012) were identified in an insurance claims database. Patients with fragility fracture (hip, pelvis, clavicle, humerus, wrist, leg or spine) during the 12 months prior to the index date (N = 1164) were selected to control for unmeasured confounding due to absence of bone mineral density test levels. TPTD patients were matched to the non-TPTD cohort using propensity score and exact matching (N = 912). Relative risk (RR) of fracture and fracture-related RU were estimated by Cox proportional hazard modeling, adjusted for potential fracture risk factors. RESULTS: Fractures were observed in 4.6%, 8.6%, 10.3%, and 11.3% of TPTD patients and in 9.2%, 15.2%, 19.2% and 21.7% of non-TPTD patients over 6, 12, 18, and 24 months, respectively. The adjusted RR reduction in TPTD was 36% (RR = 0.64, 95% CI: 0.44-0.94) during 6 months, 27% (RR = 0.73, 95% CI: 0.54-0.97) during 12 months, 28% (RR = 0.72, 95% CI: 0.55-0.93) during 18 months, and 28% (RR = 0.72, 95% CI: 0.56-0.92) during 24 months versus matched non-TPTD patients. Fracture-related RU followed a similar trend to that observed for fracture risk. CONCLUSIONS: This real-world study found TPTD to be more effective in reducing risk of fragility fractures as early as 6 months with continuous treatment benefit up to 24 months compared to a matched non-TPTD cohort. TPTD patients experienced lower rates of fracture-related RU than non-TPTD patients. Key study limitations include the inability to confirm reported diagnostic and procedural codes and the absence of uninsured and individually insured patients in the claims database.

Comparison of several multiple imputation strategies for repeated measures analysis of clinical scales: to truncate or not to?

We evaluated via a simulation study several strategies for imputing missing ordinal outcomes in a longitudinal clinical trial, contrasting methods that involve truncation of imputed values outside plausible ranges with those that do not. Our aim was to identify a preferred imputation strategy for estimating treatment difference at study endpoint. Plausible data were simulated via resampling of existing placebo data sets and adding treatment effect; then different imputation strategies were evaluated under missingness at random (MAR) and varying dropout rates. Our conclusion is that imputation methods based on rounding and truncation lead to larger bias than strategies based on simple methods based on (nontruncated) multivariate normal distribution.

Adherence and persistence with once-daily teriparatide in Japan: a retrospective, prescription database, cohort study.

Adherence and persistence with osteoporosis treatments are essential for reducing fracture risk. Once-daily teriparatide is available in Japan for treating osteoporosis in patients with a high risk of fracture. The study objective was to describe real-world adherence and persistence with once-daily teriparatide 20 µg during the first year of treatment for patients who started treatment during the first eight months of availability in Japan. This prescription database study involved patients with an index date (first claim) between October 2010 and May 2011, a preindex period ≥6 months, and a postindex period ≥12 months and who were aged >45 years. Adherence (medication possession ratio (MPR)) and persistence (time from the start of treatment to discontinuation; a 60-day gap in supply) were calculated. A total of 287 patients started treatment during the specified time period; 123 (42.9%) were eligible for inclusion. Overall mean (standard deviation) adherence was 0.702 (0.366), with 61.0% of patients having high adherence (MPR > 0.8). The percentage of patients remaining on treatment was 65.9% at 180 days and 61.0% at 365 days. Our findings suggest that real-world adherence and persistence with once-daily teriparatide in Japan are similar to that with once-daily teriparatide in other countries and with other osteoporosis medications.

Construct validity of 2 measures to assess reasons for antipsychotic discontinuation and continuation from patients' and clinicians' perspectives in a clinical trial.

BACKGROUND: Little is known about the specific reasons for antipsychotic discontinuation or continuation from patients' or clinicians' perspectives. This study aimed to assess the construct validity of 2 new measures of the Reasons for Antipsychotic Discontinuation/Continuation (RAD): RAD-I (a structured interview assessing the patient's perspective) and RAD-Q (a questionnaire assessing the clinician's perspective). METHODS: Data were used from a 12-week antipsychotic trial of schizophrenia patients in which the RAD was administered at study entry and at study completion (or discontinuation). Construct validity was assessed through comparisons of RAD responses, clinicians' responses to a standard patient disposition form identifying reasons for patient's study discontinuation, and several standard psychiatric measures. Percent agreement quantified the correspondence between patient and clinician scores. RESULTS: Patients indicating lack of improvement/worsening of positive symptoms as a 'somewhat' to 'primary' reason for medication discontinuation had statistically significantly less improvement in Positive and Negative Syndrome Scale positive score than patients not reporting these as a reason (concurrent validity). Similar results were observed for the RAD negative symptom, functional, social support, and adherence items, whereas the mood and cognitive items were not significantly associated with change scores on standard psychiatric measures. Responses to the RAD were also weakly associated with variables that theoretically should not be related to them (divergent validity). Level of agreement between the clinician- and patient-rated RAD scores was high (60%-100%). CONCLUSIONS: Initial validation of the RAD suggests that the instruments are valid tools for gathering detailed information regarding reasons for antipsychotic discontinuation and continuation from patients' and clinicians' perspectives.

Rehospitalization following percutaneous coronary intervention for commercially insured patients with acute coronary syndrome: a retrospective analysis.

BACKGROUND: While prior research has provided important information about readmission rates following percutaneous coronary intervention, reports regarding charges and length of stay for readmission beyond 30 days post-discharge for patients in a large cohort are limited. The objective of this study was to characterize the rehospitalization of patients with acute coronary syndrome receiving percutaneous coronary intervention in a U.S. health benefit plan. METHODS: This study retrospectively analyzed administrative claims data from a large US managed care plan at index hospitalization, 30-days, and 31-days to 15-months rehospitalization. A valid Diagnosis Related Group code (version 24) associated with a PCI claim (codes 00.66, 36.0X, 929.73, 929.75, 929.78-929.82, 929.84, 929.95/6, and G0290/1) was required to be included in the study. Patients were also required to have an ACS diagnosis on the day of admission or within 30 days prior to the index PCI. ACS diagnoses were classified by the International Statistical Classification of Disease 9 (ICD-9-CM) codes 410.xx or 411.11. Patients with a history of transient ischemic attack or stroke were excluded from the study because of the focus only on ACS-PCI patients. A clopidogrel prescription claim was required within 60 days after hospitalization. RESULTS: Of the 6,687 ACS-PCI patients included in the study, 5,174 (77.4%) were male, 5,587 (83.6%) were <65 years old, 4,821 (72.1%) had hypertension, 5,176 (77.4%) had hyperlipidemia, and 1,777 (26.6%) had diabetes. At index hospitalization drug-eluting stents were the most frequently used: 5,534 (82.8%). Of the 4,384 patients who completed the 15-month follow-up, a total of 1,367 (31.2%) patients were rehospitalized for cardiovascular (CV)-related events, of which 811 (59.3%) were revascularization procedures: 13 (1.0%) for coronary artery bypass graft and 798 (58.4%) for PCI. In general, rehospitalizations associated with revascularization procedures cost more than other CV-related rehospitalizations. Patients rehospitalized for revascularization procedures had the shortest median time from post-index PCI to rehospitalization when compared to the patients who were rehospitalized for other CV-related events. CONCLUSIONS: For ACS patients who underwent PCI, revascularization procedures represented a large portion of rehospitalizations. Revascularization procedures appear to be the most frequent, most costly, and earliest cause for rehospitalization after ACS-PCI.

Healthcare resource utilization and costs assessment of type 2 diabetes patients initiating exenatide BID or glargine: a retrospective database analysis.

OBJECTIVE: To examine resource utilization and healthcare costs associated with the use of exenatide versus glargine in type 2 diabetes (T2D) patients. METHODS: A retrospective analysis comprised of patients with T2D initiating exenatide (n = 7,255) or glargine (n = 2,819) between 04/01/2005 and 06/30/2007. Propensity score matching was used (2,506 matched pairs) to control for baseline demographic, clinical, resource use, and cost variables to balance treatment groups. Mean medical costs and other cost components were estimated using nonparametric bootstrapping. RESULTS: Exenatide-treated patients had 19% lower likelihood of all-cause hospitalizations (odds ratio [OR]: 0.81, p = 0.009) compared to glargine-treated patients. Exenatide-treated patients had significantly lower total medical costs of $2,597 (p = 0.008). Exenatide-treated patients had significantly lower inpatient costs of $1,968 (p = 0.004) and outpatient costs of $1,324 (p = 0.011), but higher prescription costs of $706 (p < 0.001). Exenatide-treated patients further incurred lower hospitalization costs of $1,910 (p = 0.005) and physician office visit costs of $608 (p = 0.008). KEY LIMITATIONS: Lack of availability of clinical measures including duration of diabetes, severity of T2D and lack of control for unmeasured confounding. CONCLUSIONS: Patients initiating exenatide treatment had significantly lower healthcare resource utilization and total medical costs. Cost offsets were observed in inpatient and outpatient costs despite higher prescription costs.