Cost Effectiveness Analysis Ofadjuvant Therapy With Trastuzumab for Her2+Ve Breast Cancer in Italyutilizing Follow Up Data
2
Cost-effectiveness analysis of adjuvant therapy with trastuzumab for HER2-positive breast cancer in Italy utilising follow-up data G Giuliani, 1 JA Ray, 2 A Urspruch 2 1 Roche S.p.A, Monza, Italy; 2 F Hoffmann-La Roche, Basel, Switzerland Introduction • Trast uzumab (Herceptin®), a recombinant humanised monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2), 1 is well established as an effective treatment for both HER2-positive metastatic and adjuvant breast cancer; 2-6 the latter was demonstrated by a clinical trial programme ofϾ12,000 patients which provided evidence of the efficacy and safety of trastuzuma b as an adjuvant treatment. 5,7,8 • Based on results from the HERceptin Adjuvant (HERA) trial, with a median follow-up time of 1 year, trastuzumab has been licensed and reimbursed in Italy for the treatment of HER2-positive early breast cancer (EBC) since 2006. As the risk of recurrence of breast cancer reduces over time, hazard ratios in breast cancer trials usually increase as more follow-up data become available. Recently , longer-term follow-up data of the HERA trial were reported for 2 and 4 years. 9,10 However, the 4-year follow-up data have been confounded by extensive crossover of the HERA comparator arm and are therefore unsuitable for use in further analyses. Objective • The objective of this analysis was to determine the cost-effectivenes s of 1-year treatment with adjuvant trastuzumab following standard chemotherapy versus observati on, utilising the results from the 2-year follow-up of the HERA trial. Methods • To assess the cost-effectiveness of adjuvant trastuzumab therapy, a previously published Markov model based on the initial HERA results was revised and updated to incorporate the hazard ratios from the 2-year follow-up data and to reflect the impact of trastuzuma b on disease progression. 11 The treatment effect reported was applied for the first 4 years of the model; this allowed the estimation of cost consequences and health benefits associated with the use of adjuvant trastuzumab for 1 year following the completion of adjuvant chemotherapy. Health benefits are expressed in terms of quality-adjusted life-years (QALYs). The primary end point of the evaluation was the incremental cost-effectiveness ratio (ICER), expressed as cost per QALY. • The comparator for this economic evaluation was observation following standard adjuva nt chemotherapy . The costs and consequences of the treatment of HER2-positive metastatic breast cancer are also included. The evaluation is considered from the perspective of an Italian Regional Healthcare Service (IHCS ) and only direct costs are included. Drug acquisition costs were taken from published sources, 12 whereas other medical direct costs associated with health states and events were derived from a costing study conducted in Tuscany. 13 • All costs and benefits were discounted at 3% per annum in line with recommendations for the Italian healthcare setting. 14 Study population • The patients used in the model were aligned with the protocol of the HERA study, defined as women with primary invasive breast cancer that overexpresses HER2, who have completed (neo)adjuvant systemic chemotherapy and radiotherapy, if applicable. • The average age of patients in the HERA study is 50 years and therefore this was the age of patients entering the model at the start of treatment. Model description • Long-term health outcomes were estimated using a lifetime Markov model with annual transition cycles. • Disease progression was divided into four key health states: disease-free state (DFS), metastatic, DFS/his tory of cardiac event, and death (Figure 1). • All patients begin the first cycle in the DFS state and may move to other health states in subsequent cycles according to specified probabilities. The transition probability from metastatic to death was taken from the Munich Cancer Registry, 13 whereas all other transition probabilities were taken from the HERA trial database with a median 1-year follow-up (Table 1). • Patient life expectancy, quality of life and total health service costs for each cohort are estimated to evaluate the cost-effectiveness (cost per QALY) oftrastuzumab. • The baseline risk of disease progression is taken from the HERA trial. The impact of trastuzumab on disease progression is estimated by applying the relative risk (RR) observed in the HERA trial. For the purpose of this analysis, the 2-year median follow-up data were utilised to derive the RR for the probability of developing metastases when in the DFS. The RR is assumed to remain constant between 5 and 10 years and after year 11 (Table 2). • In the base-case model, 80% of the patients who had adjuvant trastuzuma b are assumed to receive tras tuzumab in the metastatic state. In the comparator arm, all patients are assumed to receive trastuzuma b in the metastatic setting. These assumptions were base d on consultation with Italian oncologists. • A lifetime horizon was used for the evaluation. Patient quality of life • Population-ba sed utilities used for the main health states in the model were derived from published literatu re. These included utilities for the disease-free and metastatic states, 15 and disutilities associated with cardiac and chronic cardiac adverse events (Table 3). 11 • The application of utility scores allowed calculation of total QALYs for each patient cohort. Healthcare resource costs Costs applied to the model (Table 4) were collected from the perspective ofan Italian Regional Healthcare Service (Tuscany region): • Drug acquisition costs for trastuzumab in the adjuvant and metastatic settings were derived from published sources. 12 The dosages and number of administrations were taken from the HERA trial. • Drug administrati on costs were derived from published sources; a cost of €40 per administration of trastuzumab was used. 16 • Resource consumption related to the health states was estimated from a survey of 11 oncologists from the Tuscany region. The estimated consumptions were then valued on the basis of regional tariffs, prices and diagnosis-related groups. 13 • Severe and moderate cardiac event costs were derived from published sources. 16 • Cardiac-monitor ing costs were derived from the regional tariff list and it was assumed that each patient had four clinician visits per year, with each visit including an ECG and a cardiac scan. Sensitivity analysis • One- and two-way sensitivity analyses were carried out to identify the key drivers and general sensitiv ity of the model. Treatment effects, retreatment rates and discounting rates were varied and the impact of these parameters on the cost-effectiveness ratio evaluate d. • Probabilistic sensitivity analysis (PSA) was carried out on the base- case model in order to assess the uncertainty around the base-case cost-effectivenes s estimates. In total, 5000 iterations were applied in the PSA with  Pert and  distributions applied to the ranges ofeach parameter. Results Costs • The total lifetime costs of healthcare resources used from the IHCS perspective for a patient with EBC receiving adjuvant trastuzumab were estimated to be €83,253, in comparison to the patient not receiving adjuvant tras tuzumab at a total direct cost of €65,230. This results in an incremental cost for trastuzumab treatment of €18,023. • The difference in cost was primarily attributed to the acquisition costs of trastuzumab; however, these costs were partially offset by a reduction in the time spent in the metastatic state. QALYs • The total (discounted) QALYs generated for treatment with trastuzumab compared to treatment without trastuzumab were estimated to be 11.68 and 10.06, respectively. This results in an increment al discounted QALY of1.62 years for patients treated with trastuzumab. The total mean life years gained for treatment with trastuzumab compared to treatment without trastuzumab were estimated to be 14.41 and 12.60, respectively . This results in 1.81 life years gained for patients treated with trastuzumab. Cost-effectiveness • The base-case cost per QALY for the addition of trastuzumab to standard adjuvant chemotherap y compared to no trastuzumab was estimated to be €11,131, which is in line with previous published analyses 16 and considered cost-effective in the Italian setting. Sensitivity analysis • Sensitivity analyses indicated that the cost-effectiveness of trastuzumab was dependent on some key assumptions within the model, the most significant of which are the assumed length of treatment effect and the proportion of patients who are retreated with trastuzumab in the metastatic setti ng. In addition, the impact of not applying discount rates was explored. • Table 5 presents the various ICERs when these assumptions are changed. The results demonstrate the sensitivity of the model to these assumptions , but that trastuzumab remains cost-effective even with the most conservative assumptions. • The impact of retreatment was explored using three different retreatment rate assumptions in the metastatic setting. In Scenario 1 80% of patients are retreated with trastuzuma b when they develop metastases (base-case assumption). In Scenario 2 it is assumed that all patients who have received adjuvant therapy with trastuzumab will be retreated with trastuzuma b when they develop metastases. In contrast, in Scenario 3 it is assumed that no patients who received adjuvant therapy with trastuzuma b will be retreated with trastuzumab when they enter the metastatic stage. • Each scenario was modelled using differing treatment effects with and without discount rates. Treatment effect is assumed to persist for 5 years, 10 years or over a lifetime. In the scenarios where treatment bene fit persists beyond year 5, the effect is assumed to decrease in a stepwise function at years 5 and 10. • In all scenarios relating to the retreatment rate, duration of treatment and discount rate, the cost per QALY does not exceed €25,000. • PSA has been performed, with 100% of all simulations cost-effectiv e at the chosen willingness-to-pay threshold of €50,000 per QALY gained (Figure 2). This is in line with quoted willingness -to-pay thresholds in the literature and is considered appropriate for the Italian setting. 17 Conclusions • Earlier cost-effectiveness analyses of trastuzumab therapy in HER2-positive EBC demonstrated that the therapy improves life expectancy and the number of QALYs compared to observation alone. 11,16,18 These analyses were based on data from the HERA trial with a median follow-up of 1 year. • By utilising more recent data from the HERA trial, trastuzumab was shown to remain a cost-effective treatment option for HER2-positive EBC in the Italian setting. This finding was confirmed in dete rministic and probabilistic sensitivity analyses. References 1. Carter P et al. Proc Na tl Acad Sci USA 1992; 89: 4285-4289. 2. Slamon DJ et al. N Engl J Med 2001; 344: 783-792. 3. Vogel CL et al. J C lin Oncol 2002; 20: 71 9-726. 4. Cobleigh MA et al. J Clin Oncol 1999; 17: 2639-2648. 5. Piccart-Gebhart MJ et al. N Engl J Med 2005; 353: 1659-1672. 6. Extra JM et al. EJC Suppl 2004; 2: 1 25, abs 239. 7. Romond EH et al. N Engl J Med 2005; 353: 1673-1684. 8. Crown J et al. EJC Suppl 2006; 4: 108, abs 208. 9. Smith I et al. Lancet 2007; 369: 29-36. 10. Gianni L et al. Abstract presented at the St Gallen Oncology Conferences: Primary Therapy of Early Breast Cancer 11th International Conference, St Gallen, Switzerland, 11-14 March 2009. 11. Wardley AM et al. Poster 248PD presented at the 31st ESMO Congress, Istanbul, Turkey, 29 September-3 October 2006. 12. Agenzia Italiana del Farmaco. Available at: http://www.agenziafarmaco.it. 13. Roche. Data on file. 14. Capri S et al. Drug Inf J 2001; 35: 189-201. 15. Van Hanswijck de Jonge P. Poster presented at the 31st ESMO Congress, Istanbul, Turkey, 29 September-3 October 2006. 16. Liberato NL et al. J Clin Oncol 2007; 25: 625-633. 17. Eichler H-G et al. Value Health 2004; 7: 518-528. 18. Polanco C et al. Poster presented at the ISPOR 11th Annual European Congress, Athens, Greece, 8-11 November 2008. Acknowledgements The authors would like to thank Dr Ravasio, Dr Di Leo and the Tuscany Group for the availability of data collected in their study. DFS/history of a cardiac event Death Metastatic DFS Figure 1. Model transitions betw een health states Transition probabilities Value FromDFS to metastatic event 0.07847 FromDFS to cardiac event 0.00531 From cardiac event to metastatic event 0.07847 F ro m c ar di ac e vent to chron ic car di ac eve nt (r e maining in cardiac event ) 0 .0 3500 From metastatic event to death (metastatic death) 0.31480 Table 1. Transiti on probabilities applied in the model 5,13 QALY -1 0 1 2 3 C o s t ( € ) -10,000 0 10,000 20,000 30,000 40,000 Figure 2. Cost/ QALY results from probabilistic sensitivity analysis Range cycle RR for DFS to metastatic Mean Lower Upper Year 1 0.46 0.37 0.55 Year 2 0.59 0.47 0.71 Year 3 0.63 0.5 0.76 Year 4 0.63 0.5 1 Years 5-10 0.75 0.6 1 Year 11-end 0.9 0.72 1 When RR=1, this corresponds to no treatment effect Lower and upper boundaries are used for the probabilistic sensitivity analysis Table 2. RRs applied in the model (HERA trial years 1-4 [follow-up data] from year 5 assumptions) Health state or event Utility/disutility value DFS 15 0.847 Metastatic event and state 15 0.484 Disutility of cardiac event 11 -0.300 Disutility of chronic cardiac event 11 -0.300 Table 3. Util ities and disutilities applied in the model Costs Value, € Trastuzumab-related costs Trastuzumab for 1 year in the adjuvant setting 23,808.75 Tra st uz umab ad mi ni stra ti on fo r 1 ye ar i n t he a dj uvan t se tt in g 589. 60 Trastuzumab for 1 year in the metastatic setting 24,416.72 Tra st uz umab ad mi ni stra ti on fo r 1 y e ar i n the m eta sta ti c se tt in g 16 80 Comparator-related costs Trastuzumab for 1 year in the metastatic setting 24,416.72 Tra st uz umab ad mi ni st ra ti on fo r 1 y ea r i n the me tas tat ic se tt in g 16 80 Health state/event costs (direct) 1 year in DFS 1760 Metastatic event (state cost) 18,349 Cardiac-related costs Severe cardiac adverse event (per event) 1500 Other cardiac adverse event (per event) 752 Chronic cardiac adverse event (per event) 752 Heart monitoring (per year) 291 Table 4. Costs applied in the model Scenario Retreatment Duration of Discount rate, % Cost/QALY, € rate in treatment effect metastatic setting 1a Lifetime, decreasing 3 11,131.58 over time 1b Decreasing over time; 3 12,531.77 no effect after 10 years 1c No effect after 5 years 3 19,261.89 1d Lifetime, decreasing 0 7454.98 over time 2a Lifetime, decreasing 3 12,683.79 over time 2b Decreasing over time; 3 14,262.91 no effect after 10 years 2c No effect after 5 years 3 21,922.04 2d Lifetime, decreasing 0 8728.77 over time 3a Lifetime, decreasing 3 14,286.02 over time 3b Decreasing over time; 3 15,773.97 no effect after 10 years 3c No effect after 5 years 3 23,382.80 3d Lifetime, decreasing 0 9562.35 over time Table 5. Cost-effectivene ss estimates when assumptions are changed 80% for H, arm, 100% for comparator arm 100% in both arms 0% in both arms
