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a coST-uTiliTy aNalySiS of NaB-PacliTaXel (aBraXaNe) PluS GeMciTaBiNe iN MeTaSTaTic PaNcreaTic caNcer iN SlovaK rePuBlic radovan Stetka1, Maria Psenkova1, Martina ondrusova1, Tomas Pastorek2, Tomas Salek3 1 Pharm-In ltd., Karadzicova 16, Bratislava, Slovakia, 2Celgene Ltd., Bratislava, Slovakia, 3Narodny onkologicky ustav, Bratislava, Slovakia ISPOR 18th ANNUAL EUROPEAN CONGRESS, 7-11 NOVEMBER 2015, MILAN PCN193 In the clinical trial, Nab-paclitaxel + gemcitabine patients were on treatment longer than patients treated with gemcitabine. The same approach was undertaken and the stratified gamma model was selected, Figure 4. Pancreatic cancer has the worst survival rate amongst all cancers. The average survival rate is between 3 and 6 months from diagnosis with a 1 year survival rate of between 10% and 23% (1). The poor prognosis of pancreatic cancer is partly attributed to the disease being extremely difficult to treat as well as patients being diagnosed at a late stage with over 55% of patients presenting with stage IV at the time of diagnosis (2). The severity of pancreatic cancer, in combination with the limited number of effective treatments, results in a high level of unmet need. ePiDeMioloGy The annual incidence of pancreatic cancer in the United States (US) (2013) and Europe (2012) is estimated at 45,220 and 78,654, respectively (3), (4). Estimated incidence in Slovakia for 2015 was calculated using Join-point regression analysis and represents 942 new cases (crude rates of incidence 17.3/100,000; age-standardized incidence to the World standard population 9.1/100,000) (5). Slovakia is according to the IARC WHO the leading European country in estimated incidence of pancreatic cancer for 2012 (6). Although pancreatic cancer has a lower incidence than other common cancers, it is increasing steadily, and is the fourth-leading cause of cancer death in Slovakia. Figure 4. Percentage On Treatment overview Comparative Survival: Nab-paclitaxel + Gemcitabine vs. Gemcitabine Alone including the ToT modelled in the patient flow Nab -paclitaxel + gemcitabine 100% KM Nab -pac + gem Gemcitabine 3 4 KM Gem 80% 60% 40% 20% 0% 0 1 2 Years 5 ProGNoSiS aND TreaTMeNT Gemcitabine monotherapy is the current standard of care for the first-line treatment of unresectable metastatic pancreatic cancer in the Slovakia. Alternatives include a range of treatments used in combination with gemcitabine (“gem doublets”) (7). FOLFIRINOX is used as the first-line treatment in less than 5% of patients eligible for chemotherapy, and its use is typically only for very fit patients due to tolerability concerns (8). Nab-paclitaxel is a solvent-free paclitaxel formulation approved for first-line treatment of patients with metastatic pancreatic cancer (MPC) in combination with gemcitabine. Treatment with Nab-paclitaxel and gemcitabine has been shown to be clinically effective in this area of high unmet need. Patients treated with Nab-paclitaxel and gemcitabine had an increase in median overall and progression free survival of 1.8 months and 3.3 months in patient subgroup with Karnofsky Performance Score 70-80, compared to those treated with gemcitabine alone (9). coST-uTiliTy aNalySiS This poster presentation outlines a cost-utility analysis of Nab-paclitaxel + gemcitabine regimen for the first-line treatment of metastatic pancreatic cancer in specific patient population with a KPS 70-80 in whom the clinical- and cost-effectiveness of Nab-paclitaxel can be demonstrated to be particularly favorable in Slovak settings. coST-effecTiveNeSS MoDel Figure 1. Model schema Pre p progression: rogression: O On n fi first-line rst-line Trea Treatment tment Pre progression: progression: rst-line Off first-line O ff fi Trea tment Treatment There are four main model states Figure 1.: • pre-progression: on treatment, • pre-progression: off treatment • post-progression or • death. weeks 4w eeks tto o death death Post P ost progressio p rogressio coMParaTor Table 1. The first-line treatments under consideration are: • Nab-paclitaxel + gemcitabine • Gemcitabine monotherapy 4w weeks eeks death to to d eath OS parameters Gemcitabine monotherapy Observed OS 11.82% 0.70% NA Figure 2. Modelled PFS 9.24% 0.64% 0.03% Gemcitabine monotherapy Observed PFS 2.54% NA Nab-paclitaxel + gemcitabine (Total = 38%) 1% 17% 4% 7% 4% 1% 0% 8% 7% 13% 3% 4% 3% 1% 0% 6% Romanus et al. (2012) Local Quality of life data are not published in Slovakia. Therefore, in the base case, Romanus et (11) al utility values were used. This was the only study reporting Mean SE separate utility values by disease stage for advanced pancreatic cancer patients. Pre-progression: Stable Disease 0,80 0,01 Utilities were valued using EQ-5D with TTO values from the general population. The Progressive disease 0,75 0,02 study reported utility values for the pre-progression and post-progression health states at baseline and eight weeks. In order to calculate the utility value for each of the respective states an average of the baseline and eight week value for the pre-progression (0.79,0.81) and post-progression (0.77,0.73) health states were used. Modelled PFS 2.05% 0.15% 0.00 % KM Gem Costs LY € 9,912.13 0.808 € 3,969.52 0.534 € 5,942.61 0.274 € 27,769 Nab-paclitaxel + gemcitabine Gemcitabín Increment ICER Table 8. Table 7. Base case results 0.231 0.147 0.252 0.629 0.193 0.049 0.173 0.415 One way sensitivity analysis (OWSA) was conducted to determine the key input parameters in the model. This analysis was conducted by varying each input to their upper and lower 95% sequentially and recording the results at each stage. The ten most influential parameters are shown in Table 9. coNcluSioN Breakdown of base case cost results (discounted) Nab-paclitaxel + gemcitabine Gemcitabine € 6,376.83 € 615.04 € 147.40 € 134.99 Pre Progression: Drug Cost Pre Progression: Administration Costs Pre Progression: Monitoring Costs Nab-paclitaxel Gemci+ gemcitabine tabine Difference SeNSiTiviTy aNalySiS The stratified gamma survival extrapolation were used in the model, Figure 2, Figure 3 QALY 0.629 0.415 0.214 Breakdown of base case QALY results (discounted) Pre-progression: First-line treatment Pre-progression: Off treatment Post progression Total Data from MPACT study were used to estimate the efficacy of treatment with Nab-paclitaxel + gemcitabine and gemcitabine monotherapy (10). Parametric survival models were estimated for the three endpoints of overall survival (OS), progression free survival (PFS) and time on treatment (ToT), Table 2 and 3. The survival models enable the cost-effectiveness model to incorporate outcomes which occur after the trial period. Gem Table 6. Heath state/treatment Comparative Overall Survival: Nab-pac + Gemcitabine vs. Gemcitabine Alone Nab -pac + gem Percentage Survival Modelled OS 13.11% 0.70% 0.02% PFS parameters Observed PFS 8.97% NA NA Gemcitabine (Total= 42%) cliNical efficacy Nab-pac + gemcitabine 1 year 3 years 5 years Patients moving onto second-line therapies (%) Fluorouracil (5-FU) Fluorouracil (5-FU) + Oxaliplatin Capecitabine + gemcitabine Capecitabine Erlotinib + gemcitabine Erlotinib Nab-paclitaxel + gemcitabine FOLFIRINOX Nab-pac + gemcitabine Table 3. Utilities for Each Health State Official ICER threshold for regular access of medicines to the Reimbursement List in Slovakia for 2015 is € 19,776 and € 28,840 for conditional access. Results for the base case against gemcitabine show an ICER of € 27 769 (discounted), Table 6. Treatment with Nab-paclitaxel + gemcitabine results in an incremental increase of 0.214 QALYs and incremental total cost € 5,942.61. A breakdown of costs and QALYs is given in Table 7 and Table 8. Death Death Second-line treatment Second-line treatment The eight most prevalent second-line treatments reported in the MPACT study have been included in the model and have been adjusted to reflect the difference in the overall percentage of patients moving on to second-line therapy in each arm (i.e. adjusted such that the sum of eight selected therapies is equal to total percentage moving on to second-line treatment in each arm). Patients who do not move on to active second-line therapy move on to palliative care. 1 year 3 years 5 years Table 4. reSulTS The model takes a Slovak health insurance perspective. The only costs accrued in the model are therefore direct costs of the health insurance. The model takes a life-time time horizon. Due to the severity of the condition a 10-year time horizon is long enough to model the cohort of patients until the to death. Costs and health gains are discounted at 5 % per annum in line with the Slovak methodological guideline. Modelled OS 27.84% 2.28% 0.15% QualiTy of life (Qol) Routine care costs as well as treatment costs are applied to each health state and discounted with 5% discount rate defined in the methodological guideline of Slovak Ministry of Health. Costs associated with MPC were derived from a local cost study (12). The cost study was designed to measure the resource utilization and the direct costs associated with health-care management of patients with MPC in Slovakia and to provide a basis for cost-effectiveness evaluations. Dosing information for each of the first-line therapies was taken from studies on each of the relevant interventions. Dosing for most of the interventions is based on body surface area (BSA) as mg/m2 and as such the weekly dose was adjusted to account for the average BSA, which was assumed to be 1.7 m2 for Slovak pancreatic cancer population. The dosing used for each of the treatments in second-line treatment was assumed to be the same as those identified in first line. PerSPecTive aND DiScouNT raTe Observed OS 31.78% 3.97% NA The type, severity and rate of adverse events can vary between chemotherapy treatments leading to differences in overall HRQL, resource use and costs. In order to capture these differences, treatment emergent adverse events of grade three and above that occur in over 5% of patients, on either arm, were included in the model. coSTS The cost-effectiveness analysis evaluates Nab-paclitaxel + gemcitabine in the first-line treatment of metastatic pancreatic cancer. The model uses an “area under the curve” modelling approach to estimate patients transitions between defined health states from beginning of the treatment to death. Patients enter the model in the “Pre progression: on first line treatment” state. All patients remain there for the duration of the first cycle which is one week. Table 2. aDverSe eveNTS 0.038 0.098 0.079 0.214 Table 9. € 1,076.25 € 977.95 Pre Progression: Adverse Event Costs € 232.31 € 308.56 Off Treatment: Monitoring Costs € 128.55 € 42.63 Post Progression: Drug Cost € 416.52 € 424.09 € 67.15 € 64.91 Post Progression: Monitoring Costs € 755.23 € 699.56 Post Progression: Terminal Care € 540.30 € 545.92 Post Progression: Adverse Events € 171.60 € 155.86 € 9,912.13 € 3,969.52 Post Progression: Administration Costs Total OWSA Analysis: ten most influential parameters in CUA Parameter OS Gamma-Treat PFS Stratified Gamma-Ln (sigma) treat PFS Stratified Gamma-Kappa treat OS Gamma-Kappa OS Gamma-Ln(sigma) Administration costs chemotherapy per treatment (simple) OS Gamma-Cons PFS Stratified Gamma-Treat Utility in pre-progression health state Cycle Probability Abraxane armFebrile Neutropenia Lower bound Upper bound Difference € 45,390 € 26,181 € 29,180 € 28,755 € 28,525 € 21,097 € 29,558 € 26,313 € 26,546 € 26,473 € 24,293 € 3,377 € 2,867 € 2,209 € 2,052 € 27,639 € 28,403 € 764 € 28,218 € 28,152 € 27,541 € 27,479 € 27,540 € 30,322 € 739 € 612 € 581 Nab-paclitaxel + gemcitabine fulfils an unmet clinical need in MPC patients offering the high-level efficacy € 27,438 € 28,954 € 516 combined with acceptable tolerability. The extension of life shown in the MPACT study translates to an increase of 0.214 QALYs. An increase of total costs of € 5,942.61 results in an ICER of € 27,769; which is below the threshold set in Slovakia. Nabpaclitaxel + gemcitabine met very strict criteria for approving the conditional access to the Reimbursement List in Slovakia. SourceS KM Nab -pac + gem 1. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2013. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2013; 24(3):792-800. 100% 80% 2. Seufferlein T, Bachet JB, et al. Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 2012; 23 Suppl 7:vii33-40. 60% 3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 2010 http://globocan.iarc.fr. 40% 20% 4. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur.J Cancer. 2013;49(6):1374-1403. 0% 0 1 2 Years 3 4 5 5. Safaei-Diba, Ch., Pleško, I. (eds.): Cancer incidence in the SR in 2008. NCZI, Bratislava 2014, 175 s. ISBN 978-80-89292-37-0. 6. Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F.: GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. [Online] 30. 10 2015. Figure 3. Comparative Progression Free Survival: Nab-pac + Gemcitabine vs. Gemcitabine Alone Nab -pac + gem gamma curve fit Percentage PFS 100% KM Nab -pac + gem KM Gem 7. Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: evaluation of benefi t from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82. gem gamma curve fit 8. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Eng J Med. 2011;364:1817–1825. 9. Hidalgo M, et al. SPARC Analysis in the Phase III MPACT Trial of nab-Paclitaxel Plus Gemcitabine vs Gem Alone for Patients With Metastatic Pancreatic Cancer. ESMO 16th World Congress on Gastrointestinal Cancer 2014; June 25-28; Barcelona, Spain. 80% 60% 10. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. The New England journal of medicine. 2013; 369(18):1691-703. 40% 11. Romanus D, et al. Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial CALGB 80303. Journal of pain and symptom management. 2012; 43(2):205-17. 20% 0% 0 1 2 Years 3 4 5 12. Ondrušová M, Pšenková M. Vybrané ukazovatele deskriptívnej epidemiológie pri karcinóme pankreasu. Pharm-In, spol. s r. o., Bratislava. http://pharmin.sk/sk/epidemiologicke-studie/ Address for correspondence: Maria Psenkova, Pharm-In, spol. s r.o., Karadzicova 16, City Business Center V, 821 08 Bratislava, e-mail: [email protected]