61st ASH Annual Meeting & Exposition, 7–10 December 2019, Orlando, Florida, USA P-4741 Cost-effectiveness of a 12-month fixed duration of venetoclax in combination with in first-line chronic lymphocytic in the United States Matthew S Davids,1 Anuja Chatterjee,2 Arliene Ravelo,3 Sheila Shapouri,3 Beenish S Manzoor,4 Kavita Sail,4 Gijs van de Wetering,2 Michael Hallek5 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2Pharmerit International, York, United Kingdom; 3Genentech, Inc. South San Francisco, CA, USA; 4 AbbVie Inc, Chicago, IL, USA; 5Department I of Internal Medicine, Center for Integrated Oncology Aachen–Bonn–Cologne–Duesseldorf; and German CLL Study Group, University Hospital Cologne, Cologne, Germany

 The substantially higher cost ($1,319,019) for a slight incremental QALY INTRODUCTION Figure 2. Modeled survival curves. RESULTS gain with IG vs VenG is far above the willingness to pay threshold of OS PFS $150,000/QALY.  Historically, chemoimmunotherapy has been the standard of care in  Compared with all other regimens, VenG is projected to be less costly 100% 100%  One-way deterministic sensitivity analyses were performed for all first-line (1L) chronic lymphocytic leukemia (CLL).1 (incremental costs between: -$1,319,019 to -$545,083; Table 2). comparisons; this showed that PPS utility value is the overall driver of the 80% 80%  VenG is estimated to accrue higher QALYs than ClbG, BR, I, and IR (Table  -free regimens based on oral targeted agents such as incremental cost per QALY for VenG versus ClbG (Figure 3); more ClbG 1 2), with incremental benefits of 0.344 vs ClbG, 0.395 vs BR, 0.195 vs I, and have more recently provided effective treatment options; 60% 60% than VenG patients remained in the PPS period. 0.228 vs IR. In contrast, IG is estimated to accrue higher QALYs than however, these require continuous treatment until disease VenG, with a difference of 0.097.  The probabilistic sensitivity analysis results (Figure 4) were in line with the 2 40% 40% progression (PD).  VenG is dominant (more efficacious and cost saving) compared with I- deterministic results. At a willingness to pay of ~$150,000, VenG has >90% probability of being the most cost-effective treatment.  In May 2019, the United States Food and Drug Administration (US 20% 20% based treat-to-progression regimens (I, IR), ClbG, and BR (Table 2). FDA) approved venetoclax plus obinutuzumab (VenG), a highly 0% 0% Table 2. Model results for VenG versus comparator regimens. effective chemotherapy-free combination that is used over a 12- 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Time (years) Time (years) month fixed treatment duration.3 Difference Modeled curves Actual curves (CLL14)  The objective of this study is to estimate the cost-effectiveness of VenG CIbG BR I IG IR VenG KM CIbG KM Background mortality OUTCOME VenG ClbG BR I IG IR VenG vs ClbG VenG vs BR VenG vs I VenG vs IG VenG vs IR VenG in 1L CLL from a US-payer perspective. Model OS and PFS fit using Weibull distribution; KM, Kaplan–Meier. Mean total cost, $ 285,110 830,193 874,026 1,014,357 1,604,128 1,013,318 -545,083 -588,916 -729,247 -1,319,019 -728,208 Drug-related costs,* $ 144,329 61,190 104,936 980,776 1,571,156 976,120 83,204 48,299 -838,255 -1,426,491 -821,381 METHODS Table 1. Model parameters. Disease management costs,† $ 5871 16,157 17,673 10,962 4636 11,748 -10,286 -11,802 -5091 1235 -5877 Subsequent treatment costs,‡ $ 103,675 724,397 724,397 8155 6982 8299 -620,722 -620,722 95,520 96,693 95,376

§ 31 Other costs, $ 31,234 28,448 27,020 14,463 21,356 17,151 1047 -3169 9420 2441 6739  A three-state partitioned-survival model (Figure 1) was used to GENERAL SETTINGS Value END OF LIFE COSTS Value, $ Mean QALYs gained 6.447 6.103 6.052 6.252 6.543 6.219 0.344 0.395 0.195 -0.097 0.228 extrapolate progression-free survival (PFS) and overall survival (OS) Time horizon 20 Terminal care 19,153.36 Discount rate: costs 3.5% Cost per QALY gained, $ Dominant Dominant Dominant ¶ Dominant over a lifetime horizon (20 years). PD COSTS Value, $ Discount rate: efficacy 3.5% Data displayed are rounded: costs to nearest whole dollar; QALYs to the nearest thousandths. *Includes: drug acquisition, wastage, drug administration, treatment-specific monitoring; †Includes: progression-free and post-progression management; ‡Includes: drug acquisition, drug administration, drug monitoring; PD treatment (per cycle) 171 §Includes: one-time costs, terminal care, adverse events. ¶Since the incremental cost-effectiveness ratio (ICER) is in the south-west quadrant where VenG is cost saving and results in slightly fewer QALYs than IG, the resulting ICER ($13,647,900) should be interpreted as being IG vs VenG. Starting age3 71.1 years Figure 1. Survival model. DRUG COSTS17 Cost, $ PFS MODELING Hazard ratio vs VenG (95% CI) Venetoclax (120 × 100mg pills) 11,150.54 NA/Independent model ClbG (CLL14 survival analysis) Figure 3. One-way deterministic sensitivity analysis. (Log-logistic distribution) REFERENCES Obinutuzumab (25mg/mL [40mL]) 6454.19 VenG vs ClbG: ICUR BR 5.35 (2.21–10.79) 1. Liu D and Zhao J. Exp Hematol Oncol 2019;8:15; 2. IMBRUVICA (ibrutinib) US Prescribing Information; 3. Fischer K, et al. N Engl J Med (25 x 2mg pills) 608.19 Utility: PPS -$572,431 $2,502,138 2019;380(23):2225–36; 4. Barr PM, et al. Haematologica 2018;103(9):1502–10; 5. Woyach JA, et al. N Engl J Med 2018;379(26):2517–28; 6. I 1.95 (0.92–3.63) Utility: PFS -$584,049 $1,648,272 Moreno C, et al. Lancet Oncol 2019;20(1):43–56; 7. Eichhorst B, et al. Lancet Oncol 2016;17(7):928–42; 8. AbbVie. Data on file; 9. NICE Ibrutinib (28 x 420mg pills) 12,072.72 Age -$1,620,711 -$1,557,038 PFS PD Death Ven + R mean number of cycles -$1,598,128 -$1,578,124 TA343 2015 (https://www.nice.org.uk/guidance/ta343); 10. NICE TA306 2014 (https://www.nice.org.uk/guidance/ta306); 11. Lloyd A, et al. Br J IG 0.75 (0.38–1.33) Female (%) -$1,591,735 -$1,581,558 Cancer 2006;95(6):683–90; 12. NICE TA216 2011 (https://www.nice.org.uk/guidance/ta216); 13. Buesterien KM, et al. Health Qual Life IV (10mg/mL [10mL]) 939.52 Monitoring: one-time costs VenG -$1,590,659 -$1,582,245 PPS: inpatient non-surgical/medical visit -$1,590,901 -$1,582,801 Outcomes 2010;8(1):50; 14. NICE TA359 2015 (https://www.nice.org.uk/guidance/ta359); 15. Nafees B, et al. Health Qual Life Outcomes IR 2.16 (0.85–4.55) Cost: inpatient non-surgical/medical visit -$1,582,801 -$1,590,901 2008;6:84; 16. Tolley K, et al. Eur J Health Econ 2013;14(5):749–59; 17. https://www.analysource.com/; 18. CMS Clinical Diagnostic Laboratory (25mg/mL [4mL]) 2473.80 Monitoring: one-time costs ClbG -$1,583,595 -$1,590,026 Lower VenG AE incidence: -$1,588,960 -$1,584,200 Upper Fee Schedule 2018; 19. CMS Physician Fee Schedule 2018; 20. Wang S, et al. Curr Med Res Opin 2018;34(6):1135–42; 21. 2018 NPRM Cost OS MODELING Hazard ratio vs VenG (95% CI) Value, % ClbG AE incidence: neutropenia -$1,589,107 -$1,584,366 Statistics Files: 2016; 22. CMS Physician Fee Schedule 2016; 23. CLL14 trial protocol PPS: CT scan -$1,587,922 -$1,585,506 AE PROBABILITIES3–7 (VenG/ClbG/BR/I/IG/IR) NA/Dependent model Cost: CT scan -$1,587,922 -$1,585,506 (https://www.nejm.org/doi/full/10.1056/NEJMoa1815281); 24. Byrd JC, et al. Blood 2019;133(19):2031–42; 25. Kater AP, et al. J Clin Oncol ClbG (CLL14 survival analysis) VenG AE incidence: febrile neutropenia -$1,587,486 -$1,585,549 (Exponential distribution) PPS: hematologist visit -$1,587,646 -$1,585,756 2019;37(4):269–77; 26. Seymour JF, et al. ASH 2018 (Abstract 184); 27. O’Brien S, et al. Blood 2018;131(17):1910–9; 28. Davids MS, et al.  Cost-effectiveness was estimated by comparing long-term survival Asthenia 2.4/0.5/0/0/0/0 Clin Cancer Res 2018;24(18):4371–9; 29. Jones JA, et al. Lancet Oncol 2018;19(1):65–75; 30. Coutre S, et al. Blood 2018;131(15):1704–11; BR 1.00 (0.35–2.25) CT, computed tomography; -$3,000,000 -$2,000,000 -$1,000,000 0 $1,000,000 $2,000,000 $3,000,000 $4,000,000 31. Lafeuille M-H, et al. Leuk 2012;53(6);1146–54 (Inflated with: https://data.bls.gov/pdq/SurveyOutputServlet); 32. Borker R. J Med 4.2/0.5/7.0/4.0/3.0/0 ICUR, incremental cost-utility ratio. Econ 2014;17(11):792–7; 33. HCUP 2015 Hospital Inpatient National Sample (https://hcupnet.ahrq.gov/). for a 12-month fixed duration of VenG versus chlorambucil-G (ClbG) I 1.02 (0.35–2.29) Dyspnea 2.4/0.5/0/0/2.0/0 modeled using PFS and OS estimates from the CLL14 IG 0.85 (0.31–1.91) Febrile neutropenia 5.2/3.7/0/1.0/5.0/1.0 Figure 4. Probabilistic sensitivity analysis. 3 ACKNOWLEDGMENTS (NCT02242942; Figure 2). IR 1.02 (0.33–2.48) Infusion-related reaction 9.0/9.8/0/0/2.0/0 Incremental costs and QALYs of VenG vs. comparators UTILITIES9 Value Venetoclax is being developed in a collaboration between and AbbVie. Genentech and AbbVie provided  Other comparators included treat-to-PD therapies such as ibrutinib Leukopenia 2.4/4.7/48.0/0/1.0/0 $1,000,000 Willingness to pay of ~$150,000/QALY financial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as PFS 0.670 VenG the writing, review, and approval of the poster. Third party medical writing assistance, under the direction of the authors, (I), I + rituximab (IR), and I + G (IG), and a 6-month course of Neutropenia 52.8/48.1/59.0/12.0/37.0/21.0 $500,000 ClbG was provided by Kate Rijnen of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. 4–7 PPS 0.6 bendamustine + rituximab (BR). Pneumonia 4.2/4.2/9.0/0/7.0/0 $0 BR -2 -1 0 1 2 3 4 ROUTINE MONITORING COSTS18–23 Value, $ I 8 Sepsis 3.3/0.9/1.0/0/0/5.0 -$500,000  Using a network meta-analysis, the relative efficacy of external IG 7380.04 (VenG) DISCLOSURES prophylaxis 13.7/15.0/14.0/0/19.0/5.0 IR comparators versus VenG was estimated. 5641.49 (ClbG) -$1,000,000 9–16 17,32,33 MSD: consultancy (AbbVie, AstraZeneca, Genentech, Janssen, MEI Pharma, Pharmacyclics, Syros, Verastem), research Full blood count 9.59 DISUTILITIES COSTS  Health state utilities and adverse event (AE) disutilities were derived ADVERSE EVENT Value Value, $ -$1,500,000 funding (Acerta, Ascentage Pharma, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Lactate dehydrogenase 7.45 costs discounted Incremental Verastem), board of directors or advisory committee (AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, Genentech, 9–16 Asthenia 0.115 4677.90 -$2,000,000 from the literature and applied to the relative efficacy data to Chest X-ray 22.32 Incremental discounted QALYs Gilead, Janssen, Pharmacyclics, TG Therapeutics); AC: consultancy (AbbVie); AR: employment and ownership interests Diarrhea 0.080 6.01 (Genentech); SS: employed by Genentech; BSM: employment and ownership interests (AbbVie); KS: employment and Bone marrow exam 72.72 generate total quality-adjusted life years (QALYs). ownership interests (AbbVie); GW: consultancy (AbbVie); MH: research funding, honoraria, and speaker's bureau  Drug costs for CLL treatment were based on the dosing regimen Hematologist visit 52.20 Dyspnea 0.103 3170.19 (F. Hoffmann-La Roche, AbbVie). Inpatient non-surgical/medical visit 671.12 Febrile neutropenia 0.150 13,494.00 CONCLUSIONS from prescribing information and current acquisition costs.17 Costs of Full blood transfusion 198.54 Infusion-related reaction 0.200 4558.00 18–23 ADDITIONAL INFORMATION Lymphocyte count (if not already routine monitoring were based on published data. 3.13 included in full blood count) Leukopenia 0.090 7828.00  12-month fixed-duration treatment with VenG is projected to be  PD treatment costs were estimated from data for the second-line Computed tomography scan 200.16 Neutropenia 0.090 13,540.00 cost-effective versus ClbG, BR, and I-based treat-to-progression In order to use the QR code, please use or download an app called 24–30 Biochemistry test: renal - urea and ‘QR code reader’ from the Apple Appstore or the Android Playstore treatment of CLL. A US-based clinician was consulted to inform 13.04 Pneumonia 0.195 9008.00 electrolytes test regimens (I, IR) within accepted US cost-effectiveness the resource use inputs for PFS and PD and the subsequent-line Biochemistry test: liver function test 10.09 Sepsis 0.195 17,714.00 thresholds. Receive an instant copy of this poster treatment mix. Model parameters are displayed in Table 1. Immunoglobulins blood test 15.38 Thrombocytopenia 0.108 11,531.00  Taken together, VenG appears to be a cost-effective treatment Request additional presentations of trials  Uncertainty in the model was tested through deterministic, option for 1L CLL patients. sponsored/supported by Roche at this congress probabilistic, and scenario analyses. CI, confidence interval; IV, intravenous; NA, not applicable; PPS, post-progression survival.