Budget impact of tepotinib in the treatment of adult patients with metastatic non-small cell lung cancer harboring METex14 skipping alterations in the United States.

AIMS: To estimate the budget impact of adding tepotinib to United States (US) health plans for treating adult patients with metastatic non-small cell lung cancer (mNSCLC) harboring mesenchymal-epithelial transition exon 14 (METex14) skipping alterations. METHODS: The base-case analysis was conducted from the perspective of a hypothetical Medicare plan of 1 million members. Scenarios were analysed for other US health plans. Treatments included tepotinib, capmatinib, crizotinib, and standard of care (SoC). Patients eligible for tepotinib were estimated from published epidemiological data and literature, and real-world evidence. Clinical inputs were derived from the phase II VISION trial, US prescribing information, and published literature. Tepotinib uptake and projected testing rates for METex14 skipping alterations were based on market research. Unit costs (2020 US dollars (USD)) and resource utilization associated with drug acquisition and administration, treatment monitoring, disease and adverse event (AE) management, and subsequent treatment were derived primarily from public sources. RESULTS: In the base-case, 38-65 patients were eligible for tepotinib each year over the three-year time horizon. The cumulative net budgetary impact of tepotinib was -$692,541 (-2.6%); $26,531,670 in the scenario without tepotinib and $25,839,129 in the scenario with tepotinib. A negligible net budget impact was observed per member per month (PMPM) at $0.2457 and $0.2393, respectively, before and after tepotinib's introduction. Results were most sensitive to variability in unit costs of capmatinib and tepotinib and their corresponding median treatment durations. Sensitivity and scenario analyses support the conclusion that introducing tepotinib will have minimal budgetary impact for Medicare health plans. Similar results were obtained for other US health plans. LIMITATIONS: Assumptions and expert opinion were applied to address data gaps in key model inputs. CONCLUSIONS: The estimated budgetary impact of tepotinib for the treatment of adult patients with mNSCLC harboring METex14 skipping alterations is minimal from the perspective of US health plans.

Health-related quality of life (QoL) in patients with advanced melanoma receiving immunotherapies in real-world clinical practice settings.

BACKGROUND: Pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are approved advanced melanoma (AM) immunotherapies. To address limited health-related quality of life (QoL) real-world evidence with immunotherapies in AM, we compared QoL in AM patients receiving either treatment in clinical practice. METHODS: A prospective US observational study enrolled adult AM patients initiating first-line PEMBRO or IPI + NIVO between June 2017 and March 2018. Endpoints included the QLQ-C30 global health score (GHS) and EuroQol visual analog scale (EQ-VAS) scores. Mean changes were compared using repeated measures mixed-effects models and are presented covariate adjusted. RESULTS: 225 PEMBRO and 187 IPI + NIVO patients were enrolled. From baseline through week 24, PEMBRO was associated with 3.2 mean GHS score increase (95% CI 0.5, 5.9; p = .02), while no change was observed with IPI + NIVO; 0.2 (95% CI - 2.6, 3.0; p = 0.87). Among objective treatment-responders, GHS scores associated with PEMBRO increased 6.0 (95% CI 3.1, 8.8; p < .0001); IPI + NIVO patients increased 3.8 (95% CI 0.8, 6.9; p = .01). In treatment non-responders, IPI + NIVO was associated with GHS/QoL deterioration of - 3.7 (95% CI - 6.8, - 0.6; p = .02), PEMBRO non-responders demonstrated no change; 0.7 (95% CI - 2.3, 3.7; p = 0.6). Between treatments, PEMBRO patients increased 2.6 greater in EQ-VAS (95% CI 0.6, 4.5; p = .01) vs IPI + NIVO at 24 weeks. CONCLUSIONS: PEMBRO was associated with better 24-week QoL compared to IPI + NIVO in actual clinical practice settings. Real-world data has known limitations, but with further confirmation these results may have implications for treatment selection.

Hospitalization and emergency department utilization in patients with advanced melanoma receiving pembrolizumab versus ipilimumab plus nivolumab in US academic centers.

Background: Both pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are FDA-approved immunotherapy regimens for advanced melanoma (AM). Each regimen has different toxicity profiles potentially impacting healthcare resource utilization (HCRU). This study compared real-world hospitalization and emergency department (ED) utilization within 12 months of therapy initiation of each regimen.Methods: A retrospective cohort study was conducted in AM patients ≥18 years old initiating PEMBRO or IPI + NIVO between January 1, 2016-December 30, 2017. Patients were identified from 12 US-based academic and satellite centers. All-cause hospitalization ED visits were identified. These events were used to calculate rates per 1,000 patient months. Utilization between groups was compared using multivariate logistic regression.Results: In total, 400 patients were included (200 PEMBRO, 200 IPI + NIVO). PEMBRO vs IPI + NIVO patients had poorer Eastern Cooperative Group (ECOG) performance status, 29% 2-4, vs 12% (p < .001); more diabetes, 21% vs 13% (p = .045); were more often PD-L1 expression positive, 77% vs 63% (p = .011); and less likely BRAF mutant, 35% vs 50% (p = .003). The proportion with more than one hospitalization over 12 months was 17% PEMBRO vs 24% IPI + NIVO. Less than 2% had more than one admission and none had more than two. Unadjusted mean (SD) hospitalizations per 1,000 patient-months were 16 (37) and 20 (38), PEMBRO and IPI + NIVO, respectively. Adjusted odds ratio for hospitalization was 0.6 (95% CI = 0.3-0.9; p = .027) for PEMBRO vs IPI + NIVO. ED visits occurred in 18% vs 21%, PEMBRO and IPI + NIVO, respectively, 0.7 (p = .186).Conclusions: PEMBRO patients had a significantly lower probability of hospitalization through 12 months vs IPI + NIVO. The probability of ED visits did not differ.

An indirect treatment comparison of the efficacy of pembrolizumab versus competing regimens for the adjuvant treatment of stage III melanoma.

Objective: To determine the efficacy of pembrolizumab relative to other treatments used in stage III melanoma by conducting a systematic literature review (SLR) and network meta-analysis (NMA). Methods: A SLR was conducted to identify randomized clinical trials (RCTs) evaluating approved adjuvant treatments including interferon-containing regimens, BRAF-inhibitors, and PD-L1 inhibitors in stage III melanoma patients. Relative treatment effects for recurrence-free survival (RFS) were synthesized with Bayesian NMA models that allowed for hazard ratios (HRs) to vary over time. Results: Included studies formed a connected network of evidence composed of eight trials. In high-risk stage III patients, the HR for pembrolizumab vs observation decreased significantly over time with the superiority of pembrolizumab over observation becoming statistically meaningful before 3 months. By 9 months, the HR for pembrolizumab vs observation was statistically significantly lower than the HR for most other treatments vs observation, with the exception of ipilimumab and biochemotherapy due to overlapping 95% credible intervals. In BRAF + patients, pembrolizumab was statistically significantly better than observation after 3 months. The HR for both BRAF-inhibitors vs observation increased significantly over time and pembrolizumab was statistically superior to both BRAF-inhibitors after 15 months. Conclusions: Pembrolizumab results in statistically significantly improved RFS compared to all competing regimens after 9 months, except ipilimumab and biochemotherapy, for the adjuvant treatment of stage III melanoma. However, point estimate HRs vs observation for pembrolizumab are much lower than those for ipilimumab. In BRAF + patients, the advantage of pembrolizumab versus competing interventions increases over time with respect to RFS.

Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).

Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ≥2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.

Real-world experience with pembrolizumab in patients with advanced melanoma: A large retrospective observational study.

Pembrolizumab has been approved in the United States for treating advanced melanoma for >4 years. We examined real-world pembrolizumab use and associated outcomes in US oncology clinical practices, including patients who would not be eligible for clinical trials.Flatiron Health longitudinal database was used to identify adult patients with advanced melanoma initiating ≥1 dose of pembrolizumab from September 4, 2014, through December 31, 2016, with follow-up through December 31, 2017. Patients in any clinical trial during the study period were excluded. Overall survival (OS) and time on treatment from pembrolizumab initiation were analyzed using the Kaplan-Meier (KM) method. Subgroup analyses were conducted to examine OS for several patient characteristics including Eastern Cooperative Oncology Group (ECOG) performance status >1, brain metastases, and corticosteroids before pembrolizumab initiation.Pembrolizumab was administered to 315 (59%), 152 (29%), and 65 (12%) patients as first-, second-, and third-line/later therapy. Median age at pembrolizumab initiation was 68 years (range, 18-84); most patients were male (66%) and white (94%). Of those with available data, 38% had BRAF-mutant melanoma, 21% had elevated lactate dehydrogenase (LDH) level, and 23% had ECOG >1. Overall, 18% had brain metastases, and 23% were prescribed corticosteroids <3 months before initiating pembrolizumab. Median study follow-up was 12.9 months (range, 0.03-39.6). Median OS was 21.8 months (95% confidence interval [CI] 16.8-29.1); KM 1-year and 2-year survival rates were 61% and 48%, respectively; and median time on pembrolizumab treatment was 4.9 months (95% CI 3.7-5.5). Median OS for first-line pembrolizumab was not reached, and for second-line and third-line/later was 13.9 and 12.5 months, respectively (log-rank P = .0095). Significantly better OS (all P ≤.0014, log-rank test) was evident for patients with ECOG performance status (PS) of 0 to 1 (vs >1), normal (vs elevated) LDH level, and no (vs yes) corticosteroid prescription <3 months before. No difference was recorded in OS by brain metastases (log-rank P = .22) or BRAF mutation status (log-rank P = .90).These findings support effectiveness of pembrolizumab in the real-world clinical setting and provide important insights into patient characteristics and outcomes associated with pembrolizumab therapy for a heterogeneous patient population with advanced melanoma, including patients who would not be eligible for clinical trials.

Health Care Resource Utilization and Costs in First-Line Treatments for Patients with Metastatic Melanoma in the United States.

BACKGROUND: The treatment landscape for patients with metastatic melanoma has changed dramatically with the introduction of novel therapies, such as targeted therapies and immunotherapies, in recent years. Health care resource utilization (HCRU) and cost data are needed to further evaluate these treatments in a value-based health care system. OBJECTIVE: To examine HCRU and total cost of care among U.S. metastatic melanoma patients treated with first-line systemic therapies, including immunotherapies, targeted therapies, and chemotherapy. METHODS: A retrospective observational study was conducted using a U.S. claims database. Adults with ≥ 2 claims for melanoma and ≥ 1 claim for metastasis between January 1, 2012, and June 30, 2017, were identified. Patients had pharmacy and medical enrollment ≥ 6 months before and ≥ 3 months following first-line treatment start. Per patient per month (PPPM) HCRU and costs were calculated by first-line treatment drug class: PD-1 inhibitors, CTLA-4 inhibitors, CTLA-4 + PD-1 combination, BRAF monotherapy, BRAF + MEK combination, and chemotherapy. Adjusted odds ratios (ORs) for HCRU were estimated by logistic regressions and adjusted costs were estimated by generalized linear models using log-link with gamma distribution to control for differences in patient characteristics across groups. RESULTS: Among 1,599 metastatic melanoma patients (PD-1, n = 255; CTLA-4, n = 555; CTLA-4 + PD-1, n = 88; BRAF, n = 210; BRAF + MEK, n=102; chemotherapy=389), mean age ranged from 59-68 years, and the majority were male (62%). Any hospitalization during first-line treatment was less frequent among PD-1-treated patients (25.9%) compared with 34.7%-45.5% of all other groups (all P < 0.05). PPPM hospitalizations were lowest in PD-1 (0.06) compared with 0.09-0.16 across all other groups (all P < 0.05), and PPPM emergency department (ED) visits were lowest in PD-1 (0.09) compared with 0.13-0.18 across all other groups (all P < 0.05), except for BRAF + MEK (0.14, P = 0.08). CTLA-4, CTLA-4 + PD-1, and BRAF + MEK had increased odds of hospitalization compared to PD-1 (adjusted ORs = 2.10, 2.35, 2.15, respectively; all P < 0.05). Total adjusted PPPM costs were significantly lower for PD-1 ($13,059) compared with CTLA-4 ($25,583), CTLA-4 + PD-1 ($31,310), and BRAF + MEK ($21,517) and higher compared to BRAF ($8,158) and chemotherapy ($6,361). CONCLUSIONS: Hospitalizations and ED visits represent important HCRU for metastatic melanoma patients and were lowest among PD-1-treated patients compared with any other systemic therapies (except for ED visits when compared with BRAF + MEK). Total monthly costs varied substantially across first-line regimens and were significantly lower in PD-1-treated patients compared with patients treated with CTLA-4, CTLA-4 + PD-1, and BRAF + MEK. DISCLOSURES: This study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. Klink, Feinberg, and Nero are employees of Cardinal Health Specialty Solutions, which received funding from Merck to conduct this study. Chmielsowki is a consultant to Merck but received no funding for the development of this manuscript. Ahsan and Liu are employees of Merck. Chmielowski reports advisory board/speaker fees from Bristol-Myers Squibb, Merck, Genentech/Roche, Iovance Biotherapeutics, HUYA Bioscience International, Compugen, Array BioPharma, Regeneron, Biothera, Janssen, and Novartis. Ahsan has a patent (US20160008380A1) pending.

Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States.

Aims: To evaluate the cost-effectiveness of adjuvant pembrolizumab relative to observation alone following complete resection of high-risk stage III melanoma with lymph node involvement, from a US health system perspective. Materials and methods: A Markov cohort model with four health states (recurrence-free, locoregional recurrence, distant metastases, and death) was developed to estimate costs, life-years, and quality-adjusted life-years (QALYs) associated with pembrolizumab vs observation over a lifetime (46-year) horizon. Using a parametric multi-state modeling approach, transition probabilities starting from recurrence-free were estimated based on patient-level data from KEYNOTE-054 (NCT02362594), a direct head-to-head phase 3 trial. Post-recurrence transition probabilities were informed by real-world retrospective data and clinical trials in advanced melanoma. Health state utilities and adverse event-related disutility were derived from KEYNOTE-054 trial data and published literature. Costs of drug acquisition and administration, adverse events, disease management, and terminal care were estimated in 2018 US dollars. Deterministic and probabilistic sensitivity analyses were conducted to assess robustness. Results: Over a lifetime horizon, adjuvant pembrolizumab and observation were associated with total QALYs of 9.24 and 5.95, total life-years of 10.54 and 7.15, and total costs of $489,820 and $440,431, respectively. The resulting incremental cost-effectiveness ratios (ICERs) for pembrolizumab vs observation were $15,009/QALY and $14,550/life-year. Across the range of input values and assumptions tested in deterministic sensitivity analyses, pembrolizumab ranged from being a dominant strategy to having an ICER of $57,449/QALY vs observation. The ICER was below a willingness-to-pay threshold of $100,000/QALY in 90.2% of probabilistic simulations. Limitations: Long-term extrapolation of outcomes was based on interim results from KEYNOTE-054, with a median follow-up of 15 months. Conclusions: Based on common willingness-to-pay benchmarks, pembrolizumab is highly cost-effective compared with observation alone for the adjuvant treatment of completely resected stage III melanoma in the US.

Patient and Oncology Nurse Preferences for the Treatment Options in Advanced Melanoma: A Discrete Choice Experiment.

BACKGROUND: Understanding the perceptions of patients and oncology nurses about the relative importance of benefits and risks associated with newer treatments of advanced melanoma can help to inform clinical decision-making. OBJECTIVES: The aims of this study were to quantify and compare the views of patients and oncology nurses regarding the importance of attributes of treatments of advanced melanoma. METHODS: A discrete choice experiment (DCE) was conducted in US-based oncology nurses and patients diagnosed with advanced melanoma. Patients and nurses were enlisted through online panels. In a series of scenarios, respondents had to choose between 2 hypothetical treatments, each with 7 attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (DoT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3 or 4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to estimate preference weights. RESULTS: A total of 200 patients with advanced melanoma and 150 oncology nurses participated. The relative importance estimates of attributes by patients and nurses, respectively, were as follows: OS, 33% and 28%; AEs, 29% and 26%; ORR, 25% and 27%; PFS, 12% and 15%; DS, 2% and 3%; DoT, 0% and 0%; and MoA, 0% and 0%. CONCLUSION: Both patients and oncology nurses valued OS, ORR, and AEs as the most important treatment attributes for advanced melanoma, followed by PFS, whereas DS, DoT, and MoA were given less value in their treatment decisions. IMPLICATIONS FOR PRACTICE: Oncology nurses and patients have similar views on important treatment considerations for advanced melanoma, which can help build trust in shared decision-making.

Treatment patterns and outcomes for patients with advanced melanoma in US oncology clinical practices.

AIM: To describe recent evolution in treatment patterns and outcomes for advanced melanoma (AMel). METHODS: This retrospective observational study analyzed de-identified electronic health record data from the Flatiron Health database for 1140 adult patients who initiated first-line therapy for AMel from 1 January 2014 to 30 June 2016 with follow-up through 28 February 2017. RESULTS: The most common first-line regimens were ipilimumab-based therapies (34%), anti-PD-1 monotherapy (26%) and BRAF/MEK inhibitor(s) (20%). First-line ipilimumab-based and BRAF inhibitor regimens decreased after the third quarter of 2014 (3Q2014), and by 2Q2016, 55 and 91% of BRAF-mutant and BRAF wild-type cohorts, respectively, received a first-line anti-PD-1 regimen. Median overall survival from first-line initiation for all patients was 18.8 months (95% CI: 16.3-23.3). CONCLUSION: Results illustrate changing paradigms of therapy and real-world patient outcomes for AMel.

Factors associated with immunotherapy selection in patients with advanced melanoma.

AIM: To explore factors associated with pembrolizumab (PEMBRO) versus ipilimumab + nivolumab (IPI+NIVO) selection in advanced melanoma. MATERIALS & METHODS: Total of 12 academic and satellite clinics contributed to this study. Descriptive and logistic regression analyses were conducted to explore associations between clinical characteristics and treatment choice.  Results: Total of 400 patients were included: 200 PEMBRO and 200 IPI+NIVO. Patients were significantly more likely to receive PEMBRO versus IPI+NIVO if they had poorer Eastern Cooperative Oncology Group score, 2-4 versus 0-1 (odds ratio [OR]: 6.6; 95% CI: 3.0-14.7), if they were PD-L1 positive (OR: 4.5; 95% CI: 1.9-10.4) or had BRAF wild-type tumor (OR: 2.2; 95% CI: 1.4-3.6). CONCLUSION: Patient factors are significantly associated with treatment selection in advanced melanoma. Outcomes comparisons should take this into consideration.

Real-world PD-L1 testing and distribution of PD-L1 tumor expression by immunohistochemistry assay type among patients with metastatic non-small cell lung cancer in the United States.

BACKGROUND: The anti-programmed death receptor-1 (anti-PD-1) pembrolizumab is approved as first-line monotherapy for metastatic non-small cell lung cancer (mNSCLC) with PD-ligand 1 (PD-L1) tumor expression ≥50%. Most studies comparing PD-L1 results by immunohistochemistry (IHC) assay type have been conducted by prespecified and, in most cases, highly experienced, trained pathologists; however, knowledge is limited regarding the current use and concordance of PD-L1 assays in the real-world clinical setting. Our aim was to study the distribution of PD-L1 tumor expression by IHC assay type among patients with mNSCLC in US oncology practices. METHODS: This retrospective observational study utilized de-identified, longitudinal data from a large US electronic medical record database. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of metastatic or recurrent NSCLC from October 2015 through December 2017. We determined PD-L1 testing trends and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type. RESULTS: The 12,574 eligible patients (mean age, 69 years) included 6,620 (53%) men and 86% with positive smoking history. Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28-8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of ≥50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (χ2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28-8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017. CONCLUSIONS: In the real-world clinical setting, we observed that measured PD-L1 tumor expression is concordant using the 22C3 and 28-8 assays; however, the SP142 assay and LDTs appear discordant and could underestimate high PD-L1 positivity. Further study is needed to evaluate the association between PD-L1 tumor expression and response to therapy.

Direct costs associated with adverse events of systemic therapies for advanced melanoma: Systematic literature review.

BACKGROUND: Treatments for advanced melanoma are associated with different adverse events (AEs), which may be costly to manage. This study aimed to evaluate direct costs associated with managing treatment-related AEs for advanced melanoma through a systematic literature review. METHODS: Systematic searches were conducted of the PubMed, Embase, Cochrane, BIOSIS, and EconLit medical literature databases to identify studies providing estimates of direct costs and health care resource utilization for the management of AEs of melanoma treatments, published between January 1, 2007, and February 23, 2017. Gray literature searches also were conducted. Studies reporting direct costs for patients with advanced melanoma that were published in English between 2007 and 2017 were eligible. Studies were systematically screened in 2 phases by 2 independent reviewers. Study design details and data on direct costs by country were extracted. RESULTS: Seven studies evaluating the cost of AEs in patients with advanced melanoma were included; most estimated the costs for grade 3 or 4 events. In a United States study, monthly AE costs constituted 36.9% of overall health care costs for dacarbazine, 30.3% for paclitaxel, 9.2% for temozolomide, 6.4% for vemurafenib, and 4.0% for ipilimumab. A multicountry study found the greatest cost per event to be for grade 3 or 4 AEs associated with ipilimumab, including colitis (A$1471 [Australia]-&OV0556;3313 [France]) and diarrhea (£2836 [United Kingdom]), and chemotherapy (neutropenia/leukopenia in Germany [&OV0556;1744] and Italy [&OV0556;804]). Across studies, cost drivers for the most expensive AEs to manage were requiring hospitalization or use of expensive outpatient medications and/or procedures (eg, erythropoietin and blood transfusions for anemia). Some currently available therapies were not available during the research period, and their associated AEs are not reflected. Results may not be comparable across countries. For some studies, resource-use estimates reflect practice patterns from a limited number of centers, limiting generalizability. CONCLUSION: Costs for managing each type of AE associated with the treatment of advanced melanoma are substantial. Effective treatments with improved safety profiles may help reduce total AE management costs.

Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices.

The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P<0.01) of decreased survival. Treatment-related toxicity was a discontinuation reason for 25% (29/117) of patients, and for 10 of these 29 patients (6% of the full-study cohort) treatment-related toxicity was the only reported reason. The real-world effectiveness and safety of pembrolizumab for advanced melanoma are consistent with clinical trial findings.

Patient and oncologist preferences for attributes of treatments in advanced melanoma: a discrete choice experiment.

PURPOSE: To examine and compare patient and oncologist preferences for advanced melanoma treatment attributes and to document their trade-offs for benefits with risks. MATERIALS AND METHODS: A discrete choice experiment (DCE) was conducted among advanced melanoma patients and oncologists. Qualitative pilot testing was used to inform the DCE design. A series of scenarios asked stakeholders to choose between two hypothetical medications, each with seven attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (MDT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3-4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to determine patients' and oncologists' choice-based preferences, analysis of variance models were used to estimate the relative importance of attributes, and independent t-tests were used to compare relative importance estimates between stakeholders. RESULTS: In total, 200 patients and 226 oncologists completed the study. OS was most important to patients (33%), followed by AEs (29%) and ORR (25%). For oncologists, AEs were most important (49%), followed by OS (34%) and ORR (12%). An improvement from 55% to 75% in 1-year OS was valued similar in magnitude to a 23% decrease (from 55% to 32%) in likelihood of AEs for oncologists. CONCLUSION: Patients valued OS, AEs, and ORR sequentially as the most important attributes in making a treatment decision, whereas oncologists valued AEs most, followed by OS and ORR. In comparison, patients differed significantly from oncologists on the importance of ORR, AEs, and PFS, but were consistent in OS and the rest of attributes.

Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First-Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States.

OBJECTIVES: Our objectives were to evaluate the cost effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy as first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) that expresses high levels of programmed death ligand-1 (PD-L1) [tumour proportion score (TPS) ≥50%], from a US third-party public healthcare payer perspective. METHODS: We conducted a partitioned-survival model with a cycle length of 1 week and a base-case time horizon of 20 years. Parametric models were fitted to Kaplan-Meier estimates of time on treatment, progression-free survival and overall survival from the KEYNOTE-024 randomized clinical trial (patients aged ≥18 years with stage IV NSCLC, TPS ≥50%, without epidermal growth factor receptor (EGFR)-activating mutations or anaplastic lymphoma kinase (ALK) translocations who received no prior systemic chemotherapy) and validated with long-term registry data. Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, year 2016 values) for drug acquisition/administration, adverse events and clinical management were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: In the base-case scenario, pembrolizumab resulted in an expected gain of 1.31 life-years (LYs) and 1.05 QALYs and an incremental cost of $US102,439 compared with SoC. The incremental cost per QALY gain was $US97,621/QALY and the incremental cost per LY gain was $US78,344/LY. CONCLUSIONS: Pembrolizumab is projected to be a cost-effective option compared with SoC platinum-based chemotherapy as first-line treatment in adults with metastatic NSCLC expressing high levels of PD-L1.

Cost-Effectiveness of Pembrolizumab Versus Ipilimumab in Ipilimumab-Naïve Patients with Advanced Melanoma in the United States.

BACKGROUND: Recent clinical trials have shown that pembrolizumab significantly prolonged progression-free survival and overall survival compared with ipilimumab in ipilimumab-naïve patients with unresectable or metastatic melanoma. However, there has been no published evidence on the cost-effectiveness of pembrolizumab for this indication. OBJECTIVE: To assess the long-term cost-effectiveness of pembrolizumab versus ipilimumab in ipilimumab-naïve patients with unresectable or meta-static melanoma from a U.S. integrated health system perspective. METHODS: A partitioned-survival model was developed, which divided overall survival time into progression-free survival and postprogression survival. The model used Kaplan-Meier estimates of progression-free survival and overall survival from a recent randomized phase 3 study (KEYNOTE-006) that compared pembrolizumab and ipilimumab. Extrapolation of progression-free survival and overall survival beyond the clinical trial was based on parametric functions and literature data. The base-case time horizon was 20 years, and costs and health outcomes were discounted at a rate of 3% per year. Clinical data-including progression-free survival and overall survival data spanning a median follow-up time of 15 months, as well as quality of life and adverse event data from the ongoing KEYNOTE-006 trial-and cost data from public sources were used to populate the model. Costs included those of drug acquisition, treatment administration, adverse event management, and disease management of advanced melanoma. The incremental cost-effectiveness ratio (ICER) expressed as cost difference per quality-adjusted life-year (QALY) gained was the main outcome, and a series of sensitivity analyses were performed to test the robustness of the results. RESULTS: In the base case, pembrolizumab was projected to increase the life expectancy of U.S. patients with advanced melanoma by 1.14 years, corresponding to a gain of 0.79 discounted QALYs over ipilimumab. The model also projected an average increase of $63,680 in discounted perpatient costs of treatment with pembrolizumab versus ipilimumab. The corresponding ICER was $81,091 per QALY ($68,712 per life-year) over a 20-year time horizon. With $100,000 per QALY as the threshold, when input parameters were varied in deterministic one-way sensitivity analyses, the use of pembrolizumab was cost-effective relative to ipilimumab in most ranges. Further, in a comprehensive probabilistic sensitivity analysis, the ICER was cost-effective in 83% of the simulations. CONCLUSIONS: Compared with ipilimumab, pembrolizumab had higher expected QALYs and was cost-effective for the treatment of patients with unresectable or metastatic melanoma from a U.S. integrated health system perspective. DISCLOSURES: This study was supported by funding from Merck & Co., which reviewed and approved the manuscript before journal submission. Wang, Pellissier, Xu, Stevinson, and Liu are employees of, and own stock in, Merck & Co. Chmielowski has served as a paid consultant for Merck & Co. and received a consultant fee for clinical input in connection with this study. Chmielowski also reports receiving advisory board and speaker bureau fees from multiple major pharmaceutical companies. Wang led the modeling and writing of the manuscript. Chmielowski, Xu, Stevinson, and Pellissier contributed substantially to the modeling design and methodology. Liu led the data collection work and contributed substantially to writing the manuscript. In conducting the analysis and writing the manuscript, the authors followed Merck publication polices and the "cost-effectiveness analysis alongside clinical trials-good research practices and the CHEERS reporting format as recommended by the International Society for Pharmacoeconomics and Outcomes Research.

Cost-effectiveness of pembrolizumab versus docetaxel for the treatment of previously treated PD-L1 positive advanced NSCLC patients in the United States.

OBJECTIVES: This analysis aimed to evaluate the cost-effectiveness of pembrolizumab compared with docetaxel in patients with previously treated advanced non-squamous cell lung cancer (NSCLC) with PD-L1 positive tumors (total proportion score [TPS] ≥ 50%). The analysis was conducted from a US third-party payer perspective. METHODS: A partitioned-survival model was developed using data from patients from the KEYNOTE 010 clinical trial. The model used Kaplan-Meier (KM) estimates of progression-free survival (PFS) and overall survival (OS) from the trial for patients treated with either pembrolizumab 2 mg/kg or docetaxel 75 mg/m2 with extrapolation based on fitted parametric functions and long-term registry data. Quality-adjusted life years (QALYs) were derived based on EQ-5D data from KEYNOTE 010 using a time to death approach. Costs of drug acquisition/administration, adverse event management, and clinical management of advanced NSCLC were included in the model. The base-case analysis used a time horizon of 20 years. Costs and health outcomes were discounted at a rate of 3% per year. A series of one-way and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: Base case results project for PD-L1 positive (TPS ≥50%) patients treated with pembrolizumab a mean survival of 2.25 years. For docetaxel, a mean survival time of 1.07 years was estimated. Expected QALYs were 1.71 and 0.76 for pembrolizumab and docetaxel, respectively. The incremental cost per QALY gained with pembrolizumab vs docetaxel is $168,619/QALY, which is cost-effective in the US using a threshold of 3-times GDP per capita. Sensitivity analyses showed the results to be robust over plausible values of the majority of inputs. Results were most sensitive to extrapolation of overall survival. CONCLUSIONS: Pembrolizumab improves survival, increases QALYs, and can be considered as a cost-effective option compared to docetaxel in PD-L1 positive (TPS ≥50%) pre-treated advanced NSCLC patients in the US.

Budget Impact Analysis of Peritoneal Dialysis versus Conventional In-Center Hemodialysis in Malaysia.

OBJECTIVES: To investigate the 5-year health care budget impact of variable distribution of adult patients treated with peritoneal dialysis (PD) and in-center hemodialysis (ICHD) on government funding in Malaysia. METHODS: An Excel-based budget impact model was constructed to assess dialysis-associated costs when changing dialysis modalities between PD and ICHD. The model incorporates the current modality distribution and accounts for Malaysian government dialysis payments and erythropoiesis-stimulating agent costs. Epidemiological data including dialysis prevalence, incidence, mortality, and transplant rates from the Malaysian renal registry reports were used to estimate the dialysis patient population for the next 5 years. The baseline scenario assumed a stable distribution of PD (8%) and ICHD (92%) over 5 years. Alternative scenarios included the prevalence of PD increasing by 2.5%, 5.0%, and 7.5% or decreasing 1% yearly over 5 years. All four scenarios were accompanied with commensurate changes in ICHD. RESULTS: Under the current best available cost information, an increase in the prevalent PD population from 8% in 2014 to 18%, 28%, or 38% in 2018 is predicted to result in 5-year cumulative savings of Ringgit Malaysia (RM) 7.98 million, RM15.96 million, and RM23.93 million, respectively, for the Malaysian government. If the prevalent PD population were to decrease from 8% in 2014 to 4.0% by 2018, the total expenditure for dialysis treatments would increase by RM3.19 million over the next 5 years. CONCLUSIONS: Under the current cost information associated with PD and HD paid by the Malaysian government, increasing the proportion of patients on PD could potentially reduce dialysis-associated costs in Malaysia.

Cost-Effectiveness of High Dose Hemodialysis in Comparison to Conventional In-Center Hemodialysis in the Netherlands.

INTRODUCTION: In the Netherlands, the current standard of care for treating patients with end-stage renal disease is three sessions of in-center hemodialysis (conventional ICHD). However, the literature indicates that high dose hemodialysis (high dose HD) may provide better health outcome such as survival and quality of life. The objective of this study was to determine the cost-effectiveness of high dose HD, both in-center and at home, in comparison to conventional ICHD from a Dutch payer's perspective over a 5 year period. Additionally, the cost-effectiveness of conventional HD at home in comparison to conventional ICHD will be analysed. METHODS: A Markov model was developed assuming 28-day treatment cycles and was populated with data from Dutch and international renal registries, official tariffs and medical literature. Univariable and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: Using publicly available tariffs from the Dutch Healthcare Authority (Nederlandse Zorgautoriteit) of 2015, doing high dose ICHD instead of conventional ICHD shows an incremental cost-effectiveness ratio (ICER) of €275,747 per quality-adjusted life year (QALY) gained. In contrast, the ICER of high dose HD at home in comparison to conventional ICHD is €3248 per gained QALY. The final analysis shows that conventional HD at home is less costly per patient (-€3063) than conventional ICHD and results in health benefit improvement (+0.249 QALYs), and is therefore regarded as cost saving. CONCLUSION: Treating dialysis patients with conventional HD at home shows to be cost saving in comparison to conventional ICHD. However, the magnitude of clinical benefit of high dose HD at home is over two times greater than the clinical benefit of conventional HD at home. According to our analysis, from a payer's perspective, high dose HD should be offered as a home therapy to obtain its clinical benefits in a cost-effective manner. Future research should consider our findings alongside societal factors, such as patient preference, monitoring cost for the home patient, productivity loss and capacity. FUNDING: Baxter BV, The Netherlands.