Autoimmune comorbidities in patients with metastatic melanoma: a retrospective analysis of us claims data.

BACKGROUND: Immunotherapies have advanced the treatment of metastatic melanoma; however, they are associated with immune-related toxicities. Patients with pre-existing autoimmune comorbidities are commonly excluded from clinical trials investigating immunotherapies in metastatic melanoma. Since information on pre-existing autoimmune comorbidities in "real-world" patients with newly diagnosed metastatic melanoma is limited, we sought to estimate the prevalence of autoimmune comorbidities and its change over time. METHODS: Data were obtained from a large US claims database, MarketScan®, from 2004 to 2014. Records of patients with newly diagnosed metastatic or non-metastatic melanoma and of general population were analyzed. Autoimmune comorbidities were defined as presence of autoimmune disorders, which were obtained from the list of diseases at the American Autoimmune-Related Diseases Association web portal ( www.aarda.org ). The prevalence of pre-existing autoimmune comorbidities and its change over the 11-year period were calculated. Logistic regression analyses were performed to evaluate the relationship between clinical and demographic factors and pre-existing autoimmune comorbidities in patients with metastatic melanoma. RESULTS: This study assessed the prevalence and change of prevalence over a period of 11 years of 147 autoimmune comorbidities. Among 12,028 patients with newly diagnosed metastatic melanoma, the prevalence rate of pre-existing autoimmune comorbidities increased from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates of autoimmune comorbidities increased from 11.7% in 2004 to 19.8% in 2014 in patients with non-metastatic melanoma and 7.9% in 2004 to 9.2% in 2014 in the general population. In addition, patients with bone or gastrointestinal melanoma metastases, those with more comorbid diseases, or female patients, were found to have a higher risk of autoimmune comorbidities. CONCLUSIONS: The prevalence of pre-existing autoimmune comorbidities in patients with newly diagnosed metastatic melanoma was high, and increased over 11 years. In comparison, a lower prevalence of autoimmune comorbidities was seen in patients with newly diagnosed non-metastatic melanoma and in the general population. Increases in prevalence for these population groups were also observed over 11 years. Impact of autoimmune comorbidities on treatment decisions in patients with metastatic melanoma should be explored.

Management and treatment of relapsed or refractory Ph(-) B-precursor ALL: a web-based, double-blind survey of EU clinicians.

BACKGROUND: The prognosis for adult patients with Ph(-) B-precursor acute lymphoblastic leukaemia (ALL) who are refractory to treatment or experience relapse (R/R), is poor; over 90% of these patients die from the disease, typically within a few months. While there are some national guidelines published for the treatment of adult patients with ALL, and local working group recommendations do exist, there is very little detail and no preferred treatment regimens for adult patients with R/R Ph(-) B-precursor ALL. The aim of this study was to describe current real-world clinical practice in Europe for the management and treatment of adult R/R Ph(-) B-precursor ALL. METHODS: A web-based, double-blind survey was conducted in November/December 2013 in France, Germany, Italy, Spain, and the UK. The survey was developed following consultation with specialist clinicians and a critical review of published literature. Eligible clinicians (15 per country) were board-certified in haemato-oncology or haematology; had at least 4 years of experience in their current role and had treated at least five patients with adult ALL in the 36 months before the survey, including at least one with R/R Ph(-) B-precursor ALL. RESULTS: Clinicians across the five countries consulted 16 guidelines and local working group recommendations for the diagnosis and treatment of R/R Ph(-) B-precursor ALL. Thirty three regimens for salvage therapy were reported; the most frequently cited was augmented hyper-CVAD (15%), with vincristine the most commonly used agent. Salvage therapy regimens involved a range of agents, and most respondents reported using at least one cytotoxic agent; across respondents 10 different cytotoxic agents were cited. All respondents reported that toxicity was common for the regimens they used to treat R/R Ph(-) B-precursor ALL. CONCLUSIONS: This study provides evidence of current management and treatment patterns of R/R Ph(-) B-precursor ALL in the real-world clinical practice in Europe. The approach to the treatment of R/R Ph(-) B-precursor ALL is heterogeneous, reflecting the lack of any clearly superior chemotherapeutic option, thus it appears that clinicians are trying a wide variety of therapies. These findings show a clear need for effective, tolerable treatments for R/R Ph(-) B-precursor ALL.

Population preference values for health states in relapsed or refractory B-precursor acute lymphoblastic leukemia in the United Kingdom.

BACKGROUND: To date, reliable and comprehensive health-related quality of life data for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) have not been collected in clinical trials of the disease, and no utility studies have been published. The purpose of this study was to define and validate health states experienced by adults with relapsed/refractory B-precursor ALL, and to assign utility values to these health states using time-trade off methodology. METHODS: This study was conducted in the UK in three phases. In the first phase, five health state descriptions were developed based on a recent clinical trial. The second phase validated the health state descriptions with clinicians and patients with experience of relapsed/refractory B-precursor ALL. The third phase involved prospective health state valuation using time-trade off methodology in a sample of the general public. The study was approved by the UK National Health Service Research Ethics Committee. RESULTS: In total, 123 participants were recruited and included in the final analysis; all participants gave written, informed consent. Complete remission was the most preferred health state (mean utility [SEM], 0.86 [0.01]), followed by complete remission with partial hematological recovery (with minimal risk of bleeding or developing infection) (0.75 [0.02]); aplastic bone marrow (0.59 [0.02]); partial remission (0.50 [0.03]); and progressive disease (0.30 [0.04]). CONCLUSIONS: This is the first study to report utility values for health states associated with relapsed/refractory B-precursor ALL. It was designed and conducted to align with NICE guidance on alternative methods for generating health state utility values when EQ-5D data are either unavailable or inappropriate. These utilities can be applied in future cost-effectiveness analyses of treatment for relapsed/refractory B-precursor ALL.

Acute stress, depression, and anxiety symptoms among English and Spanish speaking children with recent trauma exposure.

A growing literature suggests the clinical importance of acute stress disorder symptoms in youth following potentially traumatic events. A multisite sample of English and Spanish speaking children and adolescents (N = 479) between the ages of 8-17, along with their caregivers completed interviews and self-report questionnaires between 2 days and 1 month following the event. The results indicate that children with greater total acute stress symptoms reported greater depressive (r = .41, p < .01) and anxiety symptoms (r = .53, p < .01). Examining specific acute stress subscales, reexperiencing was correlated with anxiety (r = .47, p < .01) and arousal was correlated with depression (r = .50, p < .01) and anxiety (r = .55, p < .01). Age was inversely associated with total acute stress symptoms (r = -.24, p < .01), reexperiencing (r = -.17, p < .01), avoidance (r = -.27, p < .01), and arousal (r = -.19, p < .01) and gender was related to total anxiety symptoms (Spearman's ρ = .17, p < .01). The current study supports the importance of screening acute stress symptoms and other mental health outcomes following a potentially traumatic event in children and adolescents. Early screening may enable clinicians to identify and acutely intervene to support children's psychological and physical recovery.

The impact of infusion reactions associated with monoclonal antibodies in metastatic colorectal cancer: a European perspective.

BACKGROUND AND OBJECTIVES: Published data on the clinical and economic impact of infusion reactions to monoclonal antibodies are limited. This study investigated oncologists' and oncology nurses' opinions about resource use associated with infusion reactions and the impact on patient management in Europe. METHODS: Eighty oncologists and nurses from Denmark, France, Germany, Greece, Italy, Spain, Sweden and the UK currently treating patients with metastatic colorectal cancer were interviewed by telephone using a 27-item questionnaire developed for this study. RESULTS: The mean estimated number of staff (physicians and nurses) involved in managing an infusion reaction was 1.97 for a grade 1, 2.35 for a grade 2, 3.6 for a grade 3 and 5.3 for a grade 4 reaction. In respondents' experiences, most patients with grade 3 infusion reactions (73.4%) were admitted to hospital for treatment; 82.5% of those with grade 4 infusion reactions were treated in intensive care. The estimated duration of hospital treatment was 13.3 ± 29 h for a grade 3 infusion reaction, increasing to 48.1 ± 43.7 h for a grade 4 infusion reaction. CONCLUSIONS: According to respondents, management of infusion reactions led to substantial resource use, which increased with the severity of the reaction. More severe reactions also led to anxiety in patients and distress to staff.

Neurocognitive functioning in children with obstructive sleep apnea syndrome: a pilot study of positive airway pressure therapy.

Studies of individuals with obstructive sleep apnea syndrome (OSAS) have shown impairment in neurocognitive function. This study investigated the neurocognitive function in children with OSAS before and after positive airway pressure (PAP) therapy. Twenty-one participants with suspected/documented OSAS were recruited, completing the Epworth Sleepiness Scale (ESS), the Child Sleep Habit Questionnaire (CSHQ), and/or the Pittsburgh Sleep Quality Index. Participants were administered sections of the Wechsler Intelligence Scale for Children-IV, the Delis Kaplan Executive Functioning Scales, the Test of Everyday Attention for Children, and the Wide Range Assessment of Memory and Learning--2nd Edition to assess neurocognitive function. The ESS and the CSHQ indicate that many participants had excessive daytime sleepiness and increased sleep-disordered breathing. Participants before therapy reflected neurocognitive deficiencies in all areas. Of the original 21 children, 4 completed the full PAP treatment and were reevaluated, demonstrating improvements in memory and motor speed. Children with OSAS reported sleep-disordered breathing, increased daytime sleepiness, and deficiencies in neurocognitive measures. Correcting these sleep impairments appeared to reduce global neurocognitive deficits while improving memory and processing speed.

Health-related quality of life and colorectal cancer-specific symptoms in patients with chemotherapy-refractory metastatic disease treated with panitumumab.

PURPOSE: Panitumumab monotherapy is approved for chemotherapy-refractory wild-type KRAS metastatic colorectal cancer (mCRC). Patient-reported outcomes-although important in the palliative setting-have not been reported in this patient population. METHODS: In a phase 3 trial (n = 463), patients with chemotherapy-refractory mCRC were randomized 1:1 to panitumumab plus best supportive care (BSC) or BSC alone. Patient-reported outcomes were assessed using the NCCN/FACT CRC Symptom Index (FCSI) and EQ-5D Index. KRAS tumor status was analyzed in a prospectively defined, retrospective analysis. Average difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models. RESULTS: KRAS tumor status and post-baseline patient-reported outcomes were available for 363 patients. Linear mixed models indicated significant differences in the FCSI score (difference in least-squares [LS] adjusted means [95% CI]; 5.62 [2.38, 8.86]) and the EQ-5D Index (difference in LS adjusted means [95% CI]; 0.22 [0.12, 0.32]) favoring panitumumab over BSC in patients with wild-type KRAS mCRC. By pattern-mixture analysis, the advantage of panitumumab over BSC was more pronounced in those patients with wild-type KRAS mCRC who did not drop out of the study early. In patients with mutant KRAS mCRC, no differences were observed between groups. CONCLUSIONS: Panitumumab-treated patients with wild-type KRAS mCRC maintained better control of CRC symptoms and quality of life compared with BSC alone, extending our understanding of the benefits of panitumumab treatment beyond improvements in progression-free survival.

Healthcare costs in patients with metastatic lung cancer receiving chemotherapy.

BACKGROUND: To characterize healthcare resource utilization and costs in patients with metastatic lung cancer receiving chemotherapy in the US. METHODS: Using data from a large private multi-payer health insurance claims database (2000-2006), we identified all patients beginning chemotherapy for metastatic lung cancer. Healthcare resource use (inpatient, outpatient, medications) and costs were tallied over time from date of therapy initiation ("index date") to date of disenrollment from the health plan (in most instances, presumably due to death) or the end of the study period, whichever occurred first. Healthcare utilization and costs were characterized using Kaplan-Meier sample average methods. RESULTS: The study population consisted of 4068 patients; mean (SD) age was 65 (11) years. Over a median follow-up of 334 days, study subjects averaged 1.5 hospital admissions, 8.9 total inpatient days, and 69 physician office and hospital outpatient visits. Mean (95% CI) cumulative total healthcare costs were $125,849 ($120,228, $131,231). Costs of outpatient medical services and inpatient care constituted 34% and 20% of total healthcare costs, respectively; corresponding estimates for outpatient chemotherapy and other medication were 22% and 24%. CONCLUSION: Our study sheds additional light on the burden of metastatic lung cancer among patients receiving chemotherapy, in terms of total cost thru end of life as well as component costs by setting and type of service, and may be useful in informing medical resource allocation in this patient population.

Pitfalls of Cost-Effectiveness Analysis in Practice: A TRD Case Example in the United States with Esketamine Versus Oral Antidepressants.

DISCLOSURES: The writing of this letter was supported by Janssen Scientific Affairs. The authors are employees of Janssen Scientific Affairs or Janssen Global Services (Johnson & Johnson).

Clinician Concepts of Cure in Adult Relapsed and Refractory Philadelphia-Negative B Cell Precursor Acute Lymphoblastic Leukemia: A Delphi Study.

INTRODUCTION: Despite the poor prognosis for adults with relapsed or refractory (RR) Philadelphia chromosome (Ph)-negative B cell precursor acute lymphoblastic leukemia (ALL), long-term survival is possible and may even be considered as "cure". METHODS: This study used a Delphi panel approach to explore concepts of cure in RR Ph-negative B cell precursor ALL. Ten European experts in this disease area participated in a survey and face-to-face panel meeting. RESULTS: Findings showed that clinicians conceptualize "cure" as a combination of three broad treatment outcomes that vary depending on the treatment stage: complete remission early in treatment (1-3 months) indicates initial success; eradicating cancer cells (minimal residual disease negative status) consolidates the early clinical response; leukemia-free survival is required in the long term. CONCLUSIONS: Although such terminology remains contested, clinicians would begin considering "cure" as early as 2 years provided the patient is off therapy, with most considering the term applicable by the third year. FUNDING: Amgen Inc.

Cost-effectiveness of early versus late cinacalcet treatment in addition to standard care for secondary renal hyperparathyroidism in the USA.

OBJECTIVES: The objective of this research was to estimate lifetime cost-effectiveness of treating patients with cinacalcet early (when parathyroid hormone [PTH] levels are in the range of 300-500 pg/ml) versus delaying treatment with cinacalcet (cinacalcet initiated when PTH levels are > 800 pg/ml) in patients with secondary hyperparathyroidism (SHPT) in the US setting. METHODS: A Markov model was developed to simulate the effects of early versus delayed use of cinacalcet (plus standard of care). Four different PTH ranges (< or = 300 pg/ml; 301-500 pg/ml; 501-800 pg/ml; > 800 pg/ml) were used to represent four different health states within the Markov model. Associated with each Markov state (PTH range) were varying risks of major SHPT complications, including cardiovascular disease (CVD), fracture (Fx), and parathyroidectomy (PTx). Baseline cohort characteristics and risks of CVD, Fx, and PTx by PTH category were derived from a large US renal database and published sources. Costs were estimated from the US Renal Data System database and reported in 2006 US Dollars ($). Clinical and economic outcomes were discounted at 3.0% per annum. RESULTS: Early treatment was projected to improve quality-adjusted life years (QALYs) by 0.337 years compared to delaying treatment. The incremental cost-effectiveness ratio was $17,275 per QALY gained. CONCLUSIONS: Early treatment with cinacalcet was associated with improvements in QALYs and would represent good value for money compared to delaying treatment with cinacalcet.

Relative Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor, Dacarbazine, and Glycoprotein 100 in Metastatic Melanoma: An Indirect Treatment Comparison.

INTRODUCTION: Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect. METHODS: A systematic literature review identified trials for inclusion in the meta-analysis. A valid network meta-analysis was not feasible: treatment-specific meta-analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB-IV M1c, stage IIIB-IV M1a, and stage IV M1b/c. RESULTS: One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups. CONCLUSION: The relative treatment effect of GM-CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies. FUNDING: Amgen Inc.

Economic burden of toxicities associated with treating metastatic melanoma in eight countries.

BACKGROUND: Information on costs of managing adverse events (AEs) associated with current treatments in metastatic melanoma is limited. This study estimates costs of AEs in eight countries: Australia (AU), Canada (CA), France (FR), Germany (GE), Italy (IT), the Netherlands (NL), Spain (ES), and the UK. METHODS: A literature search was conducted to identify grade 3/4 AEs from product label, published trials, conference abstracts, and treatment guidelines. Resource utilization for the management of each type of AE was determined via interviews with 5 melanoma clinicians in each country. Outpatient and inpatient costs were estimated for each type of AE using country-specific tariffs or government/published sources. RESULTS: In outpatient settings, the most costly AEs per incident included cutaneous squamous cell carcinoma (CSCC) (€1063, £720; NL/UK), anemia (€1443, €1329, €1285; ES/IT/FR), peripheral neuropathy (€1289; ES), and immune-related diarrhea (AUS$1,121; AU). In inpatient settings, the most costly AEs per hospitalization included hypophysitis (€10,265; €5316; CAN$9735; AUS$7231: ES/FR/CA/AU), dyspnea (€9077; GE), elevated liver enzymes (€6913, CAN$8030, AUS$6594; FR/CA/AU), CSCC (CAN$8934; CA), peripheral neuropathy (€6977, €4144, CAN$9472; NL/ES/CA), and diarrhea (£4284, €4113; UK/ES). CONCLUSIONS: Costs of managing AEs can be significant, and thus effective treatments with lower rates of severe AEs would be valuable.

Patterns of use of systemic therapies among patients with metastatic melanoma: a retrospective claims database analysis in the United States.

OBJECTIVES: This retrospective analysis of the IMS PharMetrics Plus claims database aimed to describe the current real-world treatment patterns for metastatic melanoma in the USA. METHODS: Included patients (aged ≥18 years) had ≥1 prescription for ipilimumab, vemurafenib, temozolomide or dacarbazine between 1 January 2011 and 31 August 2013; diagnosis of melanoma and metastasis before first use (index date); no index drug use prior to the index date; continuous health plan enrollment for ≥6 months before and ≥3 months after index date. Proportion of days covered (PDC) was defined as days exposed to index therapy divided by continuously enrolled days between index date and last prescription date. RESULTS: Overall, 1043 patients were included (median age 57 years, 63% male), of whom 39% received the index drug ipilimumab, 35% vemurafenib, 19% temozolomide and 7% dacarbazine. Mean treatment duration (days) was 174 (vemurafenib), 100 (temozolomide) and 64 (dacarbazine). Mean PDC was 81% (vemurafenib), 67% (temozolomide) and 51% (dacarbazine). For patients receiving ipilimumab, 58% had the full 4 doses, 20% 3 doses, 14% 2 doses and 9% 1 dose only for the first induction course; 4% received re-induction, and none had a second re-induction. CONCLUSIONS: This study provides insights into the treatment patterns for metastatic melanoma, including newer agents, in real-world clinical practice.

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data.

INTRODUCTION: Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years. METHODS: The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset. Conditional survival probabilities of blinatumomab-treated patients beyond month 60 were assumed to be the same as the US general population. RESULTS: At month 60, the estimated proportion of blinatumomab-treated patients alive was more than double that of historical patients (12.6% vs 5.4%). The mean overall survival was 76.1 months for blinatumomab patients and 39.8 months for historical patients. Sensitivity analyses including additional follow-up data from the clinical study showed consistent results. CONCLUSIONS: These findings suggest that blinatumomab provides substantial overall survival benefit to patients with (R/R) Ph(-) B-precursor ALL compared with salvage chemotherapy. FUNDING: Amgen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01466179 and NCT02003612.

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis.

INTRODUCTION: Isolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US). METHODS: Retrospective, observational study, using administrative claims data from the MarketScan(®) databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed. RESULTS: One hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (± SD) length of hospital stay was 5.6 (± 3.5) days and the mean (± SD) cost was US$36,758 (± 27,124) per ILP/ILI procedure. CONCLUSIONS: Isolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma. FUNDING: This study was funded by Amgen, Inc.

Years of life lost due to metastatic melanoma in 12 countries.

BACKGROUND: Regionally or distantly metastatic melanoma (stages IIIB/C and IV) place a high burden on society. To quantify this burden, this study estimated years of life lost (YLL) per patient for adults with metastatic melanoma in 12 countries in 2014. METHODS: General population growth and life expectancy were estimated from the Organization for Economic Co-operation and Development data and life tables for each country. Incidence of melanoma and mortality rates for the disease were based on GLOBOCAN and US registry data. The prevalence of metastatic melanoma was calculated using mortality rates and survival data from patients with melanoma. YLL per patient was estimated by the difference between the disease-free life expectancy and the life expectancy with metastatic melanoma. RESULTS: YLL per patient were as follows: Australia, men = 19.9 years, women = 22.7 years; Brazil, 16.3, 19.8; Canada, 19.4, 22.3; France, 18.8, 23.1; Germany, 18.3, 20.8; Italy, 19.3, 22.7; Mexico, 17.2, 19.0; the Netherlands, 18.5, 21.5; Spain, 19.2, 23.1; Sweden 19.4, 22.0; the UK, 18.7, 21.2; and the US, 17.9, 20.6. CONCLUSIONS: The burden of metastatic melanoma as measured by YLL is substantial in all 12 countries; although there is variation across countries and between men and women.

Indirect Treatment Comparison of Talimogene Laherparepvec Compared with Ipilimumab and Vemurafenib for the Treatment of Patients with Metastatic Melanoma.

INTRODUCTION: Few randomized controlled trials have compared new treatments for metastatic melanoma. We sought to examine the relative treatment effect of talimogene laherparepvec compared with ipilimumab and vemurafenib. METHODS: A systematic literature review of treatments for metastatic melanoma was undertaken but a valid network of evidence could not be established because of a lack of comparative data or studies with sufficient common comparators. A conventional adjusted indirect treatment comparison via network meta-analysis was, therefore, not feasible. Instead, a meta-analysis of absolute efficacy was undertaken, adjusting overall survival (OS) data for differences in prognostic factors between studies using a published algorithm. RESULTS: Four trials were included in the final indirect treatment comparison: two of ipilimumab, one of vemurafenib, and one of talimogene laherparepvec. Median OS for ipilimumab and vemurafenib increased significantly when adjustment was applied, demonstrating that variation in disease and patient characteristics was biasing OS estimates; adjusting for this made the survival data more comparable. For both ipilimumab and vemurafenib, the adjustments improved Kaplan-Meier OS curves; the observed talimogene laherparepvec OS curve remained above the adjusted OS curves for ipilimumab and vemurafenib, showing that long-term survival could differ from the observed medians. CONCLUSION: Even with limited data, talimogene laherparepvec, ipilimumab, and vemurafenib could be compared following adjustments, thereby providing a more reliable understanding of the relative effect of treatment on survival in a more comparable patient population. The results of this analysis suggest that OS with talimogene laherparepvec is at least as good as with ipilimumab and vemurafenib and improvement was more pronounced in patients with no bone, brain, lung or other visceral metastases. FUNDING: Amgen Inc.

Estimating healthcare resource use associated with the treatment of metastatic melanoma in eight countries.

Objectives Studies reporting healthcare resourse use (HRU) for melanoma, one of the most costly cancers to treat, are limited. Using consistent, robust methodology, this study estimated HRU associated with the treatment of metastatic melanoma in eight countries. Methods Using published literature and clinician input, treatment phases were identified: active systemic treatment (pre-progression); disease progression; best supportive care (BSC)/palliative care; and terminal care. HRU elements were identified for each phase and estimates of the magnitude and frequency of use in clinical practice were obtained through country-specific Delphi panels, comprising healthcare professionals with experience in oncology (n = 8). Results Medical oncologists are the key care providers for patients with metastatic melanoma, although in Germany dermato-oncologists also lead care. During the active systemic treatment phase, each patient was estimated to require 0.83-2 consultations with a medical oncologist/month across countries; the median number of such assessments in 3 months was highest in Canada (range = 3.5-5) and lowest in France, the Netherlands and Spain (1). Resource use during the disease progression phase was intensive and similar across countries: all patients were estimated to consult with medical oncologists and 10-40% with a radiation oncologist; up to 40% were estimated to require a brain MRI scan. During the BSC/palliative care phase, all patients were estimated to consult with medical oncologists, and most to consult with a primary care physician (40-100%). Limitations Panelists were from centers of excellence, thus results may not reflect care within smaller hospitals; data obtained from experts may be less variable than data from broader clinical practice. Treatments for metastatic melanoma are continually emerging, thus some elements of our work could be superseded. Conclusions HRU estimates were substantial and varied across countries for some resources. These data could be used with country-specific costs to elucidate costs for the management of metastatic melanoma.

Economic Burden of Toxicities Associated with Treating Metastatic Melanoma in the United States.

BACKGROUND: Little has been reported on the costs of managing the adverse events (AEs) associated with current therapies for patients with regional or distant metastatic melanoma. OBJECTIVES: To identify treatment-related AEs in patients with metastatic melanoma and to estimate the associated costs of treating these AEs in the United States. METHODS: A cost-estimation study for AEs associated with treatment of metastatic melanoma was conducted from 2012 to 2013 by identifying grades 3 and 4 AEs through the use of a comprehensive search of drug labels and English-language, published phase 2/3 studies in PubMed, conference abstracts, and the National Comprehensive Cancer Network guidelines. Resource utilization for the management of each type of AE in the outpatient setting was obtained via interviews with 5 melanoma specialists in the United States. Unit costs for an AE associated with melanoma treatment in the outpatient setting were assigned using Medicare reimbursement rates to obtain these costs. Hospitalization and length-of-stay costs were estimated for each associated AE using the large national claims database Optum Clinformatics Data Mart for the period of July 1, 2004, to November 30, 2012. RESULTS: The most common AEs associated with chemotherapies used for melanoma were neutropenia, vomiting, and anemia. The most common AEs associated with vemurafenib were cutaneous squamous-cell carcinoma or keratoacanthoma, rash, and elevated liver enzymes; the most common AEs associated with dabrafenib were cutaneous squamous-cell carcinoma and pyrexia. Trametinib was most often associated with hypertension and rash. The most common AEs with ipilimumab were immune-related diarrhea or colitis, dyspnea, anemia, vomiting, and, less frequently, hypophysitis. The most common grade 3/4 AE with talimogene laherparepvec was cellulitis. The highest treatment costs for an AE in the outpatient setting were for neutropenia ($2092), headache ($609), and peripheral neuropathy ($539). The highest mean inpatient costs for an AE were for acute myocardial infarction, sepsis, and coma, which ranged from $31,682 to $47,069. Colitis or diarrhea, cutaneous squamous-cell carcinoma, thrombocytopenia, hyponatremia, oliguria or anuria, hypertension, anemia, and elevated liver enzymes were associated with mean costs for hospitalization ranging from $19,122 to $26,861. CONCLUSION: The costs of managing treatment-related AEs in patients with metastatic melanoma are substantial. Effective treatments with improved safety profiles may help to reduce these costs. Until real-world evidence for the costs associated with treatment toxicity is available in the outpatient and inpatient settings, the costs estimated in this study can help inform decision makers about the cost-effectiveness of managing patients with metastatic melanoma.