ISPOR Europe 2019, Copenhagen, Denmark, 2-6 November, 2019 COST-EFFECTIVENES ANALYSIS OF AVELUMAB AS SECOND-LINE TREATMENT FOR PATIENTS WITH METASTATIC MERKEL CELL CARCINOMA IN RUSSIA Nikolay A. Avxentyev 1 , Maxim Y. Frolov 2 , Alexander S. Makarov 3 , Roberto Palencia 4 , Oxana V. Kudelya 5 , Elena R. Kovaleva 5 1 Research Institute of Finance and Russian Presidential Academy of National Economy and Public Administration, Moscow, Russia 2 Volgograd State Medical University and Volgograd Medical Scientific Center, Volgograd, Russia 3 Interregional Association of Clinical Pharmacologists, Volgograd, Russia 4 Merck Healthcare KGaA, Darmstadt, Germany 5 LLC “Merck”, Moscow, Russia BACKGROUND • Merkel Cell Carcinoma is a rare, aggressive skin cancer commonly affecting areas of sun- exposure skin in patients > 65 years of age 1 . Approximately 37% of patients will develop metastases over the course of their disease 2 • Avelumab is a human IgG1 monoclonal antibody that targets cancer cells through the inhibition of the immune checkpoint protein PD-L1 3 . Until avelumab received regulatory approval, there were no licensed treatment options for patients with metastatic Merkel cell carcinoma (mMCC) and standard of care (SoC) options had no curative intent 4 • Avelumab has been approved for all mMCC patients in US, Europe, Japan, and other major countries. Regulatory approval in Russia would be limited to the second-line setting only. • Previous analyses suggest that avelumab is likely to be a cost-effective treatment option in the UK 5 , however until recently no economic evaluation was available for Russia. OBJECTIVES • To perform a cost-effectiveness analysis (CEA) that compares avelumab versus current standard of care as a second-line treatment in patients with mMCC from the secondary payer perspective in Russia. METHODS • The following mMMC therapy options were considered: 1. Avelumab (10 mg/kg every 2 weeks); 2. Standard of care – SoC (according to survey conducted among Russian oncologists, who have experience in mMCC treatment): – 87,5%: CAV protocol [сyclophosphamide (1000 mg/m 2 on day 1) + doxorubicin (50 mg/m 2 on day 1) + vincristine (1,4 mg/m 2 on day 1)], with a cycle length of 21 days; – 12,5%: etoposide (120 mg/m 2 on days 1–3) + carboplatine (AUC 5 on day 1), with a cycle length of 21 days. • We employed a partitioned-survival model (figure 1) of using avelumab or SoC as a second-line treatment in patients with mMCC that was based on a model, published earlier 5. CONCLUSION • Avelumab is a cost-effective 2 nd line mMCC treatment option compared to SoC in the Russian setting. • After regulatory approval, avelumab should be recommended for inclusion in the Vital and Essential Drug List (VEDL) in Russia. FUNDING: This study was funded by an affiliate of Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer, Inc. REFERENCES 1. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003; 49(5): 832-41. 2. National Institute for Health and Care Excellence (NICE). Avelumab for treating metastatic Merkel cell carcinoma. https:// www.nice.org.uk/guidance/ta517/documents/committee- papers. Accessed 24 July 2018. 3. Avelumab [summary of product characteristics]. Amsterdam, the Netherlands: Merck Serono Europe Limited; 2017. 4. Lebbe C, et al. Diagnosis and treatment of Merkel cell carcinoma. European consensus- based interdisciplinary guideline. Eur J Cancer. 2015; 51(16): 2396-403. 5. Bullement, Ash, et al. “Cost Effectiveness of Avelumab for Metastatic Merkel Cell Carcinoma.” PharmacoEconomics- open (2019): 1-14. 6. Kaufman, Howard L., et al. “Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.” The lancet oncology 17.10 (2016): 1374-1385. 7. Kaufman, Howard L., et al. “Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥ 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.” Journal for immunotherapy of cancer 6.1 (2018): 7. 8. Cowey, C.L., Mahnke, L., Espirito, J., Helwig, C., Oksen, D., & Bharmal, M. (2017). Real- world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future oncology, 13(19), 1699- 1710. 9. Becker, J ü rgen C., et al. “Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe.” Oncotarget 8.45 (2017): 79731. 10. Omelyanovskiy, V., et al. “PCN286-Incremental cost-effectiveness ratio for the antineoplastic drugs approved and rejected for the vital and essential drugs list in 2017 in Russia.” Value in Health 21 (2018): S62-S63. • Patients transition between different health states were based on progression status (eg, pre- or post- progression), which are used to inform estimates of costs, life years, and health-related quality of life. Overall survival and progression-free survival data for avelumab were obtained from the open-label JAVELIN Merkel 200 trial 6,7, and since this is a single-arm study, survival data for SoC were modelled based on the 100070-Obs001 8,9 retrospective observational study conducted in the US and Europe. We approximated trial results with exponential and generalized gamma distributions. • The model was used to calculate direct medical costs associated with considered options that include: 1. Medications in the 2 nd line (avelumab or SoC) and 3 rd line treatment (oral etoposide 50 mg/m 2 on 1–21 days for 4 week cycle or paclitaxel 80 mg/m 2 three times every 4 weeks); 2. Monitoring; 3. Adverse events treatments; 4. Palliative radiotherapy; 5. Pain relief. • Incremental cost-effectiveness ratios (ICERs) for avelumab vs SoC were calculated as cost per life-year gained (LYG), cost per progression-free LYG, and cost per quality-adjusted life-year (QALY) gained. • The Russian healthcare system perspective was used and the time horizon of the model in the base case was 5 years, and we conducted scenario analysis for 10 and 20 years. decrease in cost - e ff ec ti veness Price of avelumab +/-20% Pa ti ent weight, 70 ... 90 kg Distribu ti on used for avelumab OS modelling Distribu ti on used for avelumab PFS modelling Vial sharing (yes/no) Distribu ti on used for SoC OS modelling Distribu ti on used for SoC PFS modelling Price of SOC +/-20% Pa ti ent BSA, 1.5 ... 1.9 sqm increase in cost-e ff ec ti veness 154,470 128,725 102,980 77,235 51,490 Stable disease Progression Death Figure 1. Partitioned-survival model Figure 3. One-way sensitivity analysis of incremental costs per LYG for avelumab vs SoC PCN 383 Table 1. Cost US$* per patient (1US$=65.2287 RUB on 09.05.2019) Costs Option 1 (Avelumab) Option 2 (SOC) Difference Stable disease 162,666.8 218.4 162,448.4 Medication 162,592.1 191.3 162,400.8 AEs 1.5 11.4 –9.9 Pain relief 41.8 9.0 32.8 Monitoring 31.4 6.7 24.6 Progression 455.3 1,344.9 –889.5 Medication 161.7 1,044.1 –882.4 Radiotherapy 201.3 279.5 –78.2 Pain relief 71.4 16.5 54.9 Monitoring 21.0 4.9 16.2 Total 163,122.2 1,563.3 161,558.9 Table 2. Incremental costs of using avelumab vs SoC per LYG per PF LYG per QALY Incremental cost (ICER) – 5 years 102,980.0 172,386.6 137,330.7 Incremental cost (ICER) – 10 years 76,728.1 164,168.9 103,216.8 Incremental cost (ICER) – 20 years 53,346.4 158,791.7 72,403.1 Table 3. ICERs of drugs approved for VEDL in 2017 in Russia 10 , US$ Tumor localization ICER per LYG per Progres- sion-free LYG Breast cancer 68,963 171,709 Rectal and rectosigmoid junction cancer 70,796 75,724 Lung cancer 89,144 109,396 Urogenital cancer 102,009 219,279 Cancer of the lymphatic and hematopoietic tissue 236,543 111,093 Skin cancer – 168,765 Note: ICERs were calculated based on median OS or PFS according to clinical trial data and time on treatment according to clinical trial data or prescribing information. RESULTS: • Assuming a 5-year time horizon, avelumab was associated with 1.97 LYG (1.17 progression-free LYG) and 1.48 QALY, versus 0.4 LYG (0.23 progression-free LYG) and 0.30 QALY obtained by SoC (fig. 2). • Monthly medication costs per patient for avelumab were US$12,450 compared to US$87 for SoC. LYGs 0.8 1.5 Progression QALYs Avelumab 1.17 1,97 Avelumab 0.9 0.58 1,48 SoC 0.23 0.17 0,40 SoC 0.18 0.12 0,30 0 0.5 1 2 2.5 0 0.5 1 1.5 2 Stable disease Stable disease Progression • Five-year total medical costs for avelumab were US$163,122.2 and US$1,563.3 for SoC (table 1). • Incremental costs of using avelumab vs SoC were: • US$102,980.0 per one LYG; • US$172,386.6 per one progression-free LYG; • US$137,330.7 per one QALY gained. • Extending modelling period to 10- and 20-years results in decrease of incremental costs (table 2). • Incremental costs of using avelumab vs SoC are within the actual ICER ranges for antineoplastic drugs, approved for the VEDL in 2017 in Russia 10 (table 3). • Sensitivity analyses showed that results were robust to variations in model assumptions (fig. 3). • Key model limitations include employing na ï ve comparison of considered treatments and difference of SoC in current Russian practice and in the 100070-Obs001 study. Figure 2. Efficacy end-points in the model