Real-World Patterns and Economic Burden Associated With Treatment Failure With Advanced Therapies in Patients With Moderate-to-Severe Ulcerative Colitis.

Background: Some patients lose response during treatment for moderate-to-severe ulcerative colitis (UC). We aimed to characterize real-world treatment failure patterns and associated economic burdens during use of first-line advanced therapies for UC. Methods: IBM MarketScan Commercial and Medicare Supplemental Databases were used to identify adults initiating ≥ 1 advanced therapy for UC (January 1, 2010-September 30, 2019). Treatment failure was defined as augmentation with non-advanced therapy, discontinuation, dose escalation/interval shortening, failure to taper corticosteroids, UC-related surgery, or UC-related urgent care ≤ 12 months after treatment initiation. The index date was the date of treatment failure (treatment failure cohort) or 12 months after treatment initiation (persistent cohort). Treatment failure rates were assessed using Kaplan-Meier analyses. All-cause and UC-related healthcare resource utilization (HCRU) and costs 12 months post-index were also assessed. Results: Analysis of treatment failure patterns included data from 6745 patients; HCRU and cost analyses included data from 5302 patients (treatment failure cohort, n = 4295; persistent cohort, n = 1007). In the overall population, 75% experienced treatment failure within the first 12 months (median: 5.1 months). Augmentation with non-advanced therapy (39%) was the most common first treatment failure event. The treatment failure cohort had significantly (P < .001) higher mean costs than the persistent cohort (all-cause, $74 995 vs $56 169; UC-related, $57 096 vs $47 347) mainly attributed to inpatient admissions and outpatient visits. Dose escalation/interval shortening accounted for the highest total costs ($101 668) across treatment failure events. Conclusions: Advanced therapies for moderate-to-severe UC are associated with high rates of treatment failure and significant economic burden. More efficacious and durable treatments are needed.

Unmet Needs in Real-World Advanced Therapy-Naïve and -Experienced Patients with Moderately to Severely Active Ulcerative Colitis in the United States.

INTRODUCTION: Despite availability of advanced therapies (ATs) for ulcerative colitis (UC), many patients fail to respond to treatment. This study examined real-world clinical and humanistic outcomes associated with current treatments in patients with UC. METHODS: This cross-sectional study used US data from the Adelphi Real World Disease Specific Programme for inflammatory bowel disease from before (2017-2018) and during the COVID-19 pandemic (2020-2021). Physicians (gastroenterologists) seeing > 5 patients/month reported patients' disease characteristics, current symptoms and treatments, and reasons for treatment choices for their next seven consecutive patients aged ≥ 18 years with moderately to severely active UC before current treatment. Patients were asked to complete the EQ-5D-5L health-related quality of life (HRQoL) measure. ATs included tumor necrosis factor inhibitors (TNFis), integrin receptor antagonists, interleukin-12/23 antagonists, and Janus kinase inhibitors. Patients were classified as AT-naïve or AT-experienced based on current treatment received for ≥ 8 weeks and further classified as responders or non-responders based on symptoms, disease flare status, and remission. Descriptive analyses are presented. RESULTS: The 2017-2018 cohort included 92 physicians and 539 patients (208 [38.6%] AT-experienced). The 2020-2021 cohort included 73 physicians and 448 patients (349 [77.9%] AT-experienced). TNFis were the most common ATs. In 2017-2018, 195 (58.9%) AT-naïve and 113 (54.3%) AT-experienced patients were non-responders; in 2020-2021 this was 57 (57.6%) and 182 (52.1%). Efficacy and induction of remission were physicians' most common reasons for AT choice. Dislike of injections/infusions was the most common reason for eligible patients not receiving biologic therapy. Numerically, non-responders (both AT-naïve and AT-experienced) had more symptoms, overall pain and fatigue, and lower HRQoL scores than responders. CONCLUSIONS: Before (2017-2018) and during the pandemic (2020-2021), over half of patients with UC did not respond to AT. Non-responders carried a high burden of disease. Alternative therapies are urgently needed to treat UC.

A Systematic Review of the Economic and Health-Related Quality of Life Impact of Advanced Therapies Used to Treat Moderate-to-Severe Ulcerative Colitis.

INTRODUCTION: The clinical benefits of advanced therapies (i.e., biologics and small-molecule drugs) in the treatment of moderate-to-severe ulcerative colitis (UC) have been demonstrated; however, there is less clarity regarding the economic and health-related quality of life (HRQoL) impact of these treatments. We conducted a systematic literature review to synthesize data on cost, healthcare resource utilization (HCRU), and HRQoL for patients who received approved advanced therapies for moderate-to-severe UC in the United States and Europe. METHODS: Databases including MEDLINE, Embase, the Database of Abstracts of Reviews of Effects (DARE), the National Health Service Economic Evaluation Database (NHS EED), and EconLit were searched systematically to identify observational studies published between January 1, 2010 and October 14, 2021 that assessed the impact of advanced therapies on cost, HCRU, and/or HRQoL in adults with moderate-to-severe UC. Supplementary gray literature searches of conference proceedings from the past 4 years (January 2018 to October 2021) were also performed. RESULTS: 47 publications of 40 unique cost/HCRU studies and 13 publications of nine unique HRQoL studies were included. Findings demonstrated that biologics have a positive impact on indirect costs (i.e., productivity, presenteeism, and absenteeism) and HRQoL. High costs of biologics were not always fully offset by reductions in cost and HCRU associated with disease management. For many patients, treatment switching and dose escalations were required, thus increasing drug costs, particularly when switching across treatment classes. CONCLUSION: These findings highlight a high unmet need for therapies for moderate-to-severe UC that can reduce the healthcare burden and impact on society. Further research is warranted, as the reported evidence was limited by the small sample sizes of some treatment groups within a study.

Although advanced therapies, such as biologics and small-molecule drugs, have shown clinical benefit in treating moderate-to-severe ulcerative colitis, their economic impact and effect on patients' quality of life is less clear. This study comprehensively reviewed the cost and use of healthcare resources associated with starting treatment with advanced therapies for ulcerative colitis, as well as the impact of these treatments on quality of life. We found that while biologics have a benefit on work productivity, work attendance, work absence, and quality of life, the high costs of biologics were not always fully met by reductions in disease management costs and healthcare resources. Many patients needed to switch treatments or required dose increases, which were expensive. There is a high unmet need for therapies for moderate-to-severe ulcerative colitis that can reduce healthcare costs, use of healthcare resources, and effect on society.

Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

INTRODUCTION: This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). METHODS: Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1 million USD fixed treatment budget. RESULTS: Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30 µg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95% CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30 µg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 with teriflunomide 7 mg, $4737 with teriflunomide 14 mg, $2178 with fingolimod, and $2793 with dimethyl fumarate. CONCLUSION: Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison.

BACKGROUND: Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS. METHODS: A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe. RESULTS: After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2 K/µL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes. CONCLUSION: The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

Identification of cognitive impairment, depression, and fatigue among multiple sclerosis patients in a large comprehensive care center: A mixed-methods, qualitative study.

BACKGROUND: Despite studies suggesting a high prevalence of cognitive impairment, depression, and fatigue (CDF) among patients with multiple sclerosis (MS), standardized CDF tools are used infrequently in clinical practice, potentially resulting in underdiagnosis. We documented the use of standardized tools to identify CDF in MS and sought to understand provider attitudes toward the tools and their use. METHODS: This mixed-methods study analyzed electronic health records (EHRs) from a large US urban MS center to determine the frequency and types of CDF screenings and numbers of MS treatment encounters (January 2018-December 2019). Participants included neurologists and nurse practitioners with ≥30 eligible patients and a convenience sample of adult MS patients (≥18 years) with at least outpatient encounters during the study period. Semistructured provider interviews (n = 6; the principal investigator and 1 provider were excluded) were conducted, transcribed, coded, and analyzed to characterize screening patterns. Assessments included proportions of encounters and patients who had standardized CDF screenings, positive screening results, and documentation of a treatment recommendation, as well as provider attitudes toward tools and reported barriers and facilitators for use. Bivariate analysis was used to evaluate the relationship between screening rates and patient and provider covariates for groups with sufficient sample size (n = 30). RESULTS: The final population included 260 unique patients, 489 outpatient encounters, and 8 providers. Of 260 patients (75% female, 83% aged <65 years), 24% (n = 63) were screened with a depression tool. Only 2% (n = 4) were screened with a tool measuring cognitive impairment, and none were screened with a tool measuring fatigue. Screening rates varied little by provider type. Higher depression screening rates were associated with white race (difference: 13.2%; 95% CI: 2.8-23.5%; P = .01), ≤2 visits during the study period (difference: 7.6%; 95% CI: 0.6-14.5%; P = .03), and provider experience >10 years (difference: 14.6%; 95% CI: 3.5-25.8%; P = .01). Lack of support staff and perception of limited treatment options were commonly cited barriers to standardized screening in provider interviews. The higher rate of depression screening is likely driven by institutional culture and priorities. CONCLUSION: Providers recognize the importance of CDF to patients, despite infrequent use of standardized screening. Integrating screening into institutional practices may enable ongoing tracking of assessment scores and provide a more comprehensive and longitudinal picture of symptom progression.

Real-World Effectiveness of Nivolumab Monotherapy After Prior Systemic Therapy in Advanced Non-Small-Cell Lung Cancer in the United States.

BACKGROUND: In phase 3 clinical trials, nivolumab prolonged overall survival (OS) compared to chemotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). This retrospective real-world study evaluated OS in patients receiving nivolumab for previously treated advanced NSCLC primarily in US community hospitals. PATIENTS AND METHODS: Patient data were taken from electronic health records in the Flatiron Health oncology database. OS was evaluated in patients receiving nivolumab monotherapy for nonsquamous or squamous advanced NSCLC after prior chemotherapy; subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), age, and other baseline characteristics. Cox analysis was used to determine OS predictors. RESULTS: Of 3019 included patients, 1968 (65%) had nonsquamous and 1051 (35%) had squamous histology. In both cohorts, approximately 20% of patients had a verified ECOG PS ≥ 2, and > 25% were aged ≥ 75 years. For all patients, median OS in the nonsquamous and squamous cohorts was 8.6 months (95% confidence interval [CI], 8.0-9.3) and 7.4 months (95% CI, 6.8-8.5), respectively; for those with ECOG PS 0-1, median OS was 10.8 months (95% CI, 9.8-11.8) and 8.7 months (95% CI, 7.6-9.7), respectively. In both cohorts, programmed death ligand 1 expression ≥ 1% and ECOG PS 0-1 were associated with longer OS (P < .05); the number of prior lines of therapy and age ≥ 75 years had no significant association with OS. CONCLUSIONS: This study confirmed the effectiveness of nivolumab monotherapy for previously treated advanced NSCLC in real-world clinical practice. Poor ECOG PS, but not advanced age, was associated with shorter OS.

Non-Small Cell Lung Cancer Patient Preferences for First-Line Treatment: A Discrete Choice Experiment.

Background. There has been much innovation in the treatment of non-small cell lung cancer (NSCLC) in recent years. In particular, use of immuno-oncology (IO) therapies has been growing. Methods. Patients with NSCLC in the United States were surveyed online using a discrete choice experiment to elicit first-line (1L) treatment preferences across six treatment attributes: survival, adverse events (AEs), mechanism of action (MOA), subsequent treatment options (STOs), genetic testing treatment delay, and out-of-pocket cost (OOPC). Preferences were estimated using a latent-class model. Preference shares were estimated for IO-IO, IO-chemo, and chemo-like regimens. Results. Of the 199 patients who completed the survey, 55% were male, 76% were white, 19% had not begun or were on 1L treatment, and the median age was 43 years. Based on a latent-class model with 3 preference classes, 53.0% of patients considered survival and OOPC alone and were less likely to choose an option with a higher OOPC and lower survival, 12.7% of patients were likely to choose the more expensive option, and for 34.3% of patients, survival, AE risk, and treatment delays all significantly influenced choices. MOA and STOs did not significantly influence treatment choices in any preference class. Approximately 53%, 27%, and 20% of patients preferred IO-IO-like, IO-chemo-like, and chemo-like regimens in 1L, respectively. Respondents were younger, more likely to be Caucasian, and more likely to speak English than the general NSCLC patient population. Conclusions. OOPC, effectiveness, treatment delays, and safety influenced NSCLC patients' 1L treatment decisions, and most patients preferred an IO-IO followed by IO-chemo-like regimen in 1L. Cancer treatment decisions are complex and patient preferences are unique; therefore, patients' treatment objectives should be discussed in shared treatment decision making.

Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma.

PURPOSE: Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points. METHODS: We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time. RESULTS: At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months). CONCLUSION: The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.

Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

INTRODUCTION: Nivolumab has been approved in patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. A pivotal trial compared nivolumab with ipilimumab; however, no head-to-head trial exists comparing nivolumab to observation, a common comparator in the adjuvant setting. Here, we compared the efficacy and cost-effectiveness of nivolumab with observation or ipilimumab as adjuvant therapies in resected stage IIIB/C melanoma. METHODS: Patient data were pooled from the EORTC 18071 and CheckMate 238 trials using propensity score weighting and adjusting for cross-trial differences. Number needed to treat (NNT) and costs per recurrence-free life-month (RFLM) at 12, 16, 18, and 24 months (as data allowed) were estimated. Costs included drug acquisition, administration costs, and direct medical costs. Sensitivity analyses including patients with stage IIIB/C and resected stage IV melanoma were conducted. RESULTS: A total of 1287 patients (278 nivolumab, 365 observation, and 644 ipilimumab) with resected stage IIIB/C melanoma were pooled. NNTs to achieve one additional recurrence-free survivor with nivolumab versus observation were 3.93 at 12 months and 3.42 at 24 months; NNTs for nivolumab versus ipilimumab were 7.97 at 12 months and 6.43 at 24 months. Mean drug costs per RFLM were lower for nivolumab at 12, 18, and 24 months, respectively (nivolumab: $13,447, $9462, and $7370; ipilimumab: $52,734, $40,484, and $33,875). Mean medical costs per RFLM were the lowest for nivolumab versus observation or ipilimumab at 12 months ($449 versus $674 or $1531) and 16 months ($383 versus $808 or $1316). The sensitivity analysis results were consistent with the base case. CONCLUSION: For resected melanoma, adjuvant nivolumab is both clinically effective and cost-effective compared with observation or ipilimumab. Adjuvant nivolumab was associated with a lower drug cost per RFLM compared with ipilimumab, and a lower medical cost compared with observation. Future analyses incorporating long-term follow-up data may help increase understanding of the economic impact of nivolumab in the adjuvant setting. FUNDING: Bristol-Myers Squibb Company.

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison.

AIM: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. METHODS: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed. RESULTS: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib. CONCLUSION: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.

Treatment patterns and outcomes for patients with unresectable stage III and metastatic melanoma in the USA.

Aim: To describe treatment patterns and outcomes of patients with unresectable stage III and metastatic/stage IV melanoma. Materials & methods: An observational retrospective chart review of patients diagnosed with advanced melanoma before 1 November 2015 who initiated a new line of therapy (LOT) from 1 January 2015 to 31 May 2016.  Results: Among 487 patients, ipilimumab monotherapy (27.5%) was the most common first line of therapy (1LOT) in 2015, surpassed by nivolumab monotherapy (21.5%) in 2016. 12-month survival was ≥80.1%; proportions were highest forpatients treated with nivolumab + ipilimumab (86.6%). All treatments relatively well tolerated in real-world setting and adverse events were consistent with the previously reported safety profiles. Conclusion: This study provides important insights into real-world advanced melanoma treatment patterns and demonstrates encouraging treatment safety and patient survival data.

Quality-adjusted survival of nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma: a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis.

PURPOSE: To compare the quality-adjusted survival of nivolumab plus ipilimumab combination and nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma based on a minimum 36-month follow-up from the CheckMate 067 trial. METHODS: Overall survival was partitioned into time without symptoms of progression or toxicity (TWiST), time with treatment-related grade ≥ 3 adverse events after randomization but before progression (TOX), and time from progression until end of follow-up or death (REL). Mean quality-adjusted TWiST (Q-TWiST) was calculated by multiplying the mean time spent in each health state by a utility of 1.0 for TWiST and 0.5 for TOX and REL. Sensitivity analyses included varying utilities of TOX and REL; Q-TWiST gains at different follow-up times were calculated using EQ-5D-3L utilities from the trial. Relative Q-TWiST gain of ≥ 10% was considered clinically important. RESULTS: Compared with ipilimumab-treated patients, those who received nivolumab + ipilimumab combination had significantly longer TWiST and TOX but shorter REL; nivolumab-treated patients had significantly longer TWiST, shorter REL, and shorter but statistically nonsignificant TOX. Mean Q-TWiST was highest for nivolumab + ipilimumab (23.5 months; 95% CI 21.9-25.2), followed by nivolumab (21.8 months; 95% CI 20.2-23.4) and ipilimumab (15.3 months; 95% CI 13.9-16.6). Relative Q-TWiST gains were favorable and clinically important for nivolumab + ipilimumab combination (+ 36.81%) and nivolumab alone (+ 29.18%) versus ipilimumab alone. Relative gains increased with follow-up from 3 to 40 months for all comparisons. These gains remained consistent in magnitude and direction in the different sensitivity analyses. CONCLUSIONS: Nivolumab + ipilimumab combination and nivolumab alone resulted in a statistically significant and clinically important improvement in quality-adjusted survival compared with ipilimumab alone.

Clinical and economic outcomes associated with treatment sequences in patients with BRAF-mutant advanced melanoma.

AIM: The cost-effectiveness of treatment sequences in BRAF-mutant advanced melanoma. MATERIALS & METHODS: A discrete event simulation model was developed to estimate total costs and health outcomes over a patient's lifetime (30 years). Efficacy was based on the CheckMate 067/069 trials and a matching-adjusted-indirect comparison between immuno-oncology and targeted therapies. Safety, cost (in US dollars; US third-party payer perspective) and health-related quality-of-life inputs were based on published literature. RESULTS: Estimated survival gain was higher for sequences initiating with anti-PD-1 + anti-CTLA-4 than for anti-PD-1 monotherapy or BRAF+MEK inhibitors. The incremental cost-effectiveness ratio per QALY gained for first-line anti-PD-1 + anti-CTLA-4 was US$54,273 versus first-line anti-PD-1 and $79,124 versus first-line BRAF+MEK inhibitors. CONCLUSION: Initiating treatment with anti-PD-1 + anti-CTLA-4 was more cost-effective than initiation with anti-PD-1 monotherapy or BRAF+MEK inhibitors.

Sequential treatment approaches in the management of BRAF wild-type advanced melanoma: a cost-effectiveness analysis.

AIM: To evaluate the cost-effectiveness of treatment sequences with checkpoint inhibitors in patients with BRAF wild-type melanoma. MATERIALS & METHODS: Using a discrete event simulation model, cost and health outcomes were estimated. Pooled data from CheckMate 067/069 trials were used to calculate survival outcomes including treatment-free interval extrapolated over a patient's lifetime. Costs accounted for treatment, administration, toxicity, and disease management. RESULTS: First-line anti-PD-1 + anti-CTLA-4 initiating sequences had the highest estimated mean survival gain (7.6-7.7 years), driven by a longer estimated mean treatment-free interval (5.3 years). Incremental costs per incremental quality-adjusted life year gained for anti-PD-1 + anti-CTLA-4 followed by chemotherapy were US$30,955 versus anti-PD-1 initiating sequences, within the willingness-to-pay threshold. CONCLUSION: Anti-PD-1 + anti-CTLA-4 initiating sequences for BRAF wild-type melanoma are cost-effective versus anti-PD-1.

Patterns of antiepileptic drug use in patients with potential refractory epilepsy in Texas Medicaid.

OBJECTIVES: Antiepileptic drug (AED) monotherapy is usually effective in 60% of the patients with epilepsy while the remaining patients have refractory epilepsy. This study compared treatment patterns (adherence, persistence, addition, and switching) associated with refractory and nonrefractory epilepsy. METHODS: Texas Medicaid claims from 09/01/07-12/31/13 were analyzed, and patients eligible for the study 1) were between 18 and 62 years of age, 2) had a prescription claim for an AED during the identification period (03/01/08-12/31/11) with no prior baseline AED use (6-month), and 3) had evidence of epilepsy diagnosis within 6 months of AED use. Based on AED use in the identification period, patients were categorized into "refractory" (≥3AEDs) and "nonrefractory" (<3AEDs) cohorts. The index date was the date of the first AED claim. Patients in both cohorts were matched 1:1 using propensity scoring and compared for adherence (proportion of days covered (PDC) ≥80% vs. <80%), persistence, addition (yes/no), and switching (yes/no) using multivariate conditional regression models. Conditional logistic regression and Cox proportional hazard models were used to address the study objectives. RESULTS: Of the 10,599 eligible patients, 2798 (26.5%) patients in the refractory cohort were matched to patients in the nonrefractory cohort. Patients in the refractory cohort had significantly higher (p < 0.005) mean (±Standard deviation (SD)) adherence (88.6% (±19.1%) vs. 77.0% ±â€¯(25.8%)) and persistence (328.0 (±87.3) days vs. 294.9 ±â€¯(113.4) days) as compared with patients in the nonrefractory cohort. Compared with patients with nonrefractory epilepsy, patients with refractory epilepsy were 3.6 times (odds ratio (OR) = 3.553; 95% confidence interval (CI) = 3.060-4.125; p < 0.0001) more likely to adhere to AEDs and had a 34.7% (hazard ratio (HR) = 0.653; 95% CI = 0.608-0.702; p < 0.0001) lower hazard rate of discontinuation of AEDs. Also, patients with refractory epilepsy were 3.7 times (OR = 3.723; 95% CI = 2.902-4.776; p < 0.0001) more likely to add an alternative AED and 3.6 times (OR = 3.591; 95% CI = 3.010-4.284; p < 0.0001) more likely to switch to an alternative AED. CONCLUSION: Patients with refractory epilepsy were significantly more likely to adhere and persist to AED regimen and were significantly more likely to add and switch to an alternative AED than patients with nonrefractory epilepsy.

Confirming the timing of phase-based costing in oncology studies: a case example in advanced melanoma.

AIMS: The utilization of healthcare services and costs among patients with cancer is often estimated by the phase of care: initial, interim, or terminal. Although their durations are often set arbitrarily, we sought to establish data-driven phases of care using joinpoint regression in an advanced melanoma population as a case example. METHODS: A retrospective claims database study was conducted to assess the costs of advanced melanoma from distant metastasis diagnosis to death during January 2010-September 2014. Joinpoint regression analysis was applied to identify the best-fitting points, where statistically significant changes in the trend of average monthly costs occurred. To identify the initial phase, average monthly costs were modeled from metastasis diagnosis to death; and were modeled backward from death to metastasis diagnosis for the terminal phase. Points of monthly cost trend inflection denoted ending and starting points. The months between represented the interim phase. RESULTS: A total of 1,671 patients with advanced melanoma who died met the eligibility criteria. Initial phase was identified as the 5-month period starting with diagnosis of metastasis, after which there was a sharp, significant decline in monthly cost trend (monthly percent change [MPC] = -13.0%; 95% CI = -16.9% to -8.8%). Terminal phase was defined as the 5-month period before death (MPC = -14.0%; 95% CI = -17.6% to -10.2%). LIMITATIONS: The claims-based algorithm may under-estimate patients due to misclassifications, and may over-estimate terminal phase costs because hospital and emergency visits were used as a death proxy. Also, recently approved therapies were not included, which may under-estimate advanced melanoma costs. CONCLUSIONS: In this advanced melanoma population, optimal duration of the initial and terminal phases of care was 5 months immediately after diagnosis of metastasis and before death, respectively. Joinpoint regression can be used to provide data-supported phase of cancer care durations, but should be combined with clinical judgement.

Economic Burden of Attention-Deficit/Hyperactivity Disorder among Pediatric Patients in the United States.

OBJECTIVES: To determine the adjusted incremental total costs (direct and indirect) for patients (aged 3-17 years) with attention-deficit/hyperactivity disorder (ADHD) and the differences in the adjusted incremental direct expenditures with respect to age groups (preschoolers, 0-5 years; children, 6-11 years; and adolescents, 12-17 years). METHODS: The 2011 Medical Expenditure Panel Survey was used as the data source. The ADHD cohort consisted of patients aged 0 to 17 years with a diagnosis of ADHD, whereas the non-ADHD cohort consisted of subjects in the same age range without a diagnosis of ADHD. The annual incremental total cost of ADHD is composed of the incremental direct expenditures and indirect costs. A two-part model with a logistic regression (first part) and a generalized linear model (second part) was used to estimate the incremental costs of ADHD while controlling for patient characteristics and access-to-care variables. RESULTS: The 2011 Medical Expenditure Panel Survey database included 9108 individuals aged 0 to 17 years, with 458 (5.0%) having an ADHD diagnosis. The ADHD cohort was 4.90 times more likely (95% confidence interval [CI] 2.97-8.08; P < 0.001) than the non-ADHD cohort to have an expenditure of at least $1, and among those with positive expenditures, the ADHD cohort had 58.4% higher expenditures than the non-ADHD cohort (P < 0.001). The estimated adjusted annual total incremental cost of ADHD was $949.24 (95% CI $593.30-$1305.18; P < 0.001). The adjusted annual incremental total direct expenditure for ADHD was higher among preschoolers ($989.34; 95% CI $402.70-$1575.98; P = 0.001) than among adolescents ($894.94; 95% CI $428.16-$1361.71; P < 0.001) or children ($682.71; 95% CI $347.94-$1017.48; P < 0.001). CONCLUSIONS: Early diagnosis and use of evidence-based treatments may address the substantial burden of ADHD.

Prospective Case-crossover Study Investigating the Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy and Phosphodiesterase Type 5 Inhibitor Exposure.

OBJECTIVE: To evaluate the association between intermittent phosphodiesterase type 5 inhibitor (PDE5i) exposure and risk of acute nonarteritic anterior ischemic optic neuropathy (NAION) using a case-crossover design. METHODS: Male adults with suspected NAION were enrolled at 41 US ophthalmology sites from 2010 to 2015 and were interviewed regarding risk factors for NAION, medical history, and PDE5i use before NAION onset (index date of onset [IDO]). An adjudication committee confirmed the NAION cases. The primary analysis, using the person-time method, examined the rate of PDE5i exposure within 5 half-lives of NAION onset relative to PDE5i exposure over a 30-day study period preceding the IDO in men exposed to PDE5i intermittently as a measure of NAION risk associated with PDE5i exposure. Rate ratios were estimated using the Mantel-Haenszel estimator. Secondary analyses included person-time analyses over the 12-months preceding the IDO and matched-interval analyses over 42 days preceding the IDO. RESULTS: Of 279 men with confirmed NAION, 22 were exposed to PDE5i intermittently within 30 days of IDO. The Mantel-Haenszel rate ratio for risk of NAION associated with PDE5i exposure within 5 half-lives of IDO was 2.27 (95% confidence interval [CI]: 0.99-5.20) over the 30-day period (n = 22) and 3.52 (95% CI: 1.59-7.79) over the 12-month period (n = 26). Sensitivity analyses showed similar results and were statistically significant. The matched-interval method found no association (hazard ratio = 1.64 [95% CI: 0.60-4.51]). CONCLUSION: Overall, the study suggests an increased risk of NAION associated with PDE5i use. Patients and health-care providers should continue to weigh the risks and benefits of PDE5i use, including the potential for NAION.

Adherence to Anticoagulant Therapy in Pediatric Patients Hospitalized With Pulmonary Embolism or Deep Vein Thrombosis: A Retrospective Cohort Study.

OBJECTIVES: The American College of Chest Physicians recommends anticoagulant therapy for at least 3 months in children hospitalized for venous thromboembolism. The objectives of the study were to evaluate the medication utilization patterns and predictors of adherence to anticoagulant therapy in pediatric population. METHODS: Texas Medicaid medical and prescription claims from September 1, 2007 to December 12, 2012 were extracted for children (<18 years) hospitalized for pulmonary embolism (PE) or deep vein thrombosis (DVT). The index date was defined as the date of the first prescription of an anticoagulant given within 14 days of discharge. Proportion of days covered (≥80% vs <80%) was used to assess adherence to anticoagulants while controlling for demographics, cause of hospitalization, history of nonsteroidal anti-inflammatory drug use, anticoagulant use, malignancy, drug type, and Charlson comorbidity index (CCI). KEY FINDINGS: The patients (n = 60) had a mean (± standard deviation [SD]) age of 14.2 (±4.8) years, were primarily female (56.7%), African American (55.0%), enoxaparin users (58.3%), and had a mean (±SD) CCI of 18.3 (±37.7). The mean (±SD) adherence rates for warfarin and enoxaparin were 85.5% (±22.7%) and 78.7% (±27.8%), respectively. Overall, 66.7% were adherent (≥80%) to anticoagulant therapy. Logistic regression showed that increasing age was significantly associated with adherence to anticoagulant therapy, after controlling for other covariates (odds ratio = 1.5, 95% confidence interval = 1.13-1.85). CONCLUSION: Nearly one-third of the pediatric patients on anticoagulant therapy after discharge from PE or DVT were still nonadherent. Further research is needed to highlight the factors responsible for nonadherence in pediatric patients.