Cost-Effectiveness and Budget Impact Analyses of Selective Internal Radiation Therapy versus Atezolizumab Plus Bevacizumab from a German Statutory Health Insurance Perspective

Figures & data

Table 1 Comparison of Eligibility Criteria from Participation in the Pivotal Trials

Dosisphere-01

Imbrave 150

Histologically demonstrated Hepatocellular Carcinoma (HCC), not a candidate for surgery or local ablative treatment (radiofrequency etc.) Barcelona Clinic Liver Cancer (BCLC) classification A, B or C At least one lesion ≥7 cm Hepatic reserve (hepatic parenchyma not treated) after the first SIRT ≥ 30% Unilateral involvement, minimal bilateral involvement allowed only with a hepatic reserve ≥30% after SIRT Child-Pugh (CP) class A, or B but with bilirubinemia <35 µmol/L Extra-hepatic metastases, other than adenopathies of the hilum, smaller than 2 cm

Locally advanced or metastatic and/or unresectable Hepatocellular Carcinoma (HCC) No prior systemic therapy for HCC. Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization. At least one measurable untreated lesion ECOG Performance Status of 0 or 1 Adequate hematologic and end-organ function Child-Pugh class A

Table 2 Comparison of the Study Populations of the Respective Trials

Parameter	Dosisphere-01	Imbrave 150
BCLC A/B/C	0%/19%/81%	2%/15%/82%
CP A5 / A6	81%/19%*	72%/28%
Portal vein invasion	65%	38%
Extrahepatic spread	Not applicable	63%
Tumor mean diameter	10 cm	Not available

Note: *and some B7 included in A6 class.

Figure 1 Progression-Free Survival (a) and Overall Survival Estimates (b) Used in the CEA Model.

Abbreviations: CEA, Cost-Effectiveness Analysis; A+B, Atezolizumab plus Bevacizumab; SIRT, yttrium-90 (90Y)-loaded Glass microspheres; PFS, Progression-Free Survival; OS, Overall Survival.

Figure 2 Serious Adverse Events Rates Used in the CEA Model.

Abbreviations: SAE, Serious Adverse Event; A+B, Atezolizumab plus Bevacizumab; SIRT, yttrium-90 (90Y)-loaded Glass microspheres.

Table 3 Overview of Input Values to the CEA and BIA Models

Input Parameter	Value (SD) [PSA Distribution]	Source
Total Population in Germany	84,400,000	Destatis Statistisches Bundesamt^Citation10
SHI Population	73,594,629	German Ministry of Health^Citation11
HCC Incidence per 100,000	7.18	Clouth et al 2018^Citation12
BCLC Stage B / C	28.7% / 34.5%	Weinmann et al 2015^Citation13
Eligibility for SIRT	Stage B 100% / Stage C 25%	Weber et al 2022^Citation4 and expert opinion, here it was estimated by the experts that 25% of BCLC stage C are eligible for SIRT
HCC Patients eligible for SIRT therapy	1972	Calculated using the SHI population, the HCC incidence, the BCLC stage information and expert opinion on eligibility for SIRT
HCC Patients Currently Treated with SIRT	489	InEK DatenBrowser (SIRT in HCC)^Citation14
Current Treatment Mix (SIRT)	24.8%	Calculation based on current SIRT therapy and on total eligible patients (“HCC Patients Currently Treated with SIRT” / “HCC Patients eligible for SIRT therapy”)
Current Treatment Mix (A+B)	75.2%	Assumption: all other patients are treated with A+B
Annual Therapy Costs - A+B	€ 71,557 - € 75,138 (SD €7156-€7514) [gamma]	Lauer-Taxe (15.06.2023)^Citation15
Median PFS in Months - A+B	6.8	Finn et al 2020^Citation5
Therapy Costs – SIRT	€ 26,514 - € 30,385 (SD €2651- €3039) [gamma]	G-DRG Fallpauschalenkatalog 2023^Citation16
SIRT Workup Procedures (%)	100% require workup, 8.3% repeat workup	Pollock et al 2020^Citation17
SIRT Therapy Procedures (%)	100% require n=1, 13.8% n=2 and 3.6% n=3 procedures	Marqueen et al 2021^Citation18
SAE Grade 3: Hospital Stay without ICU	€ 4512 (SD €451) [gamma]	Destatis Statistisches Bundesamt^Citation19
SAE Grade 4: Hospital Stay with ICU	€ 9690 (SD 969) [gamma]	Kaier et al 2020^Citation20
SAE Grade 5: Hospital Stay with ICU (patient dies due to SAE)	€ 7268 (€ 727) [gamma]	Assumption: If patient dies in hospital, this incurs 75% of SAE Grade 4 costs
Utility Value Remission, Mean (SD)	0.8933 (SD 0.1321) [beta]	Gaugain et al 2023^Citation9
Utility Value Progression, Mean (SD)	0.8634 (SD 0.1433) [beta]	Gaugain et al 2023^Citation9
Base Case - Utility Reduction SAE Grade 3/4 (min), Mean (SD)	0.1101 (SD 0.1101) [beta]	Amdahl et al 2016^Citation21 (used in the base case)
Base Case - Utility Reduction SAE Grade 3/4 (max), Mean (SD)	0.2044 (SD 0.2044) [beta]	Amdahl et al 2016^Citation21 (used in the base case)
Sensitivity Analysis - Utility Reduction SAE Grade 3/4 (min), Mean (SD)	0.1800 (SD 0.2200) [beta]	Howell et al 2022^Citation22 (investigated in sensitivity analysis)
Sensitivity Analysis - U. Red.SAE Grade 3/4 (max), Mean (SD)	0.2300 (SD 0.2400) [beta]	Howell et al 2022^Citation22 (investigated in sensitivity analysis)

Notes: Gamma distribution parameter calculation: alpha = (mean/sd)^2 / beta = (sd^2/mean); Beta distribution parameter calculation: alpha = −1*((mean*(sd^2+mean^2-mean))/(sd^2)); beta = ((sd^2+mean^2-mean)*(mean-1))/sd^2.

Abbreviations: CEA, Cost-Effectiveness Analysis; BIA, Budget Impact Analysis; SHI, Statutory Health Insurance; HCC, Hepato-Cellular Carcinoma, BCLC, Barcelona Clinic Liver Cancer; InEK, Institut für das Entgeltsystem im Krankenhaus; G-DRG, German Diagnosis Related Group; ICU, Intensive Care Unit, SAE, Serious Adverse Event, A+B, Atezolizumab plus Bevacizumab; SIRT, yttrium-90 (90Y)-loaded Glass microspheres; min, minimum; max, maximum; SD, Standard Deviation;

Table 4 Overview of Deterministic CEA Model Results

Costs	A+B	SIRT	Incremental (Δ)
Therapy Costs	€ 73,348	€ 28,450	€ −44,898
Total Adverse Event Costs	€ 2377 €	€ 1534	€ −843
Total Costs	€ 75,725	€ 29,984	€ −45,741
Efficacy	A+B	SIRT	Incremental (Δ)
SAEs (SAEs avoided in the Δ)	0.410	0.200	0.210
QALYs	0.694	0.717	0.023
Cost-Effectiveness	A+B	SIRT	Incremental (Δ)
Cost per SAE Avoided	€ 184,694	€ 149,920	€ −217,812
Cost per QALY Gained	€ 109,113	€ 41,819	€ −1,988,717

Notes: Negative cost incremental denote savings.

Abbreviations: CEA, Cost-Effectiveness Analysis; A+B, Atezolizumab plus Bevacizumab; SIRT, yttrium-90 (90Y)-loaded Glass microspheres; SAE, Serious Adverse Event; QALY, Quality-Adjusted Life Year.

Figure 3 Incremental Cost-Effectiveness Planes Comparing A+B vs SIRT from the SHI Perspective.

Abbreviations: SAE, Serious Adverse Event; A+B, Atezolizumab plus Bevacizumab; SIRT, yttrium-90 (90Y)-loaded Glass microspheres; SHI, Statutory Health Insurance; QALY, Quality-Adjusted Life Year.

Figure 4 BIA Analysis Results – Total Cost Savings per Year from the SHI Perspective.

Abbreviations: SAE, Serious Adverse Event; SHI, Statutory Health Insurance; QALY, Quality-Adjusted Life Year.

Destatis Statistisches Bundesamt. Bevölkerungsstand: amtliche Einwohnerzahl Deutschlands; 2022. Available from: https://www.destatis.de/DE/Themen/Gesellschaft-Umwelt/Bevoelkerung/Bevoelkerungsstand/_inhalt.html. Accessed August 19, 2023.

 Google Scholar

Bundesgesundheitsministerium. Gesetzliche Krankenversicherung; Mitglieder, mitversicherte Angehörige und Krankenstand; 2023. Available from: https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/Statistiken/GKV/Mitglieder_Versicherte/KM1_Januar_bis_Mai_2023_bf.pdf. Accessed August 19, 2023.

 Google Scholar

Clouth J, Liepa AM, Moeser G, et al. Hepatocellular carcinoma after prior sorafenib treatment: incidence, healthcare utilisation and costs from German statutory health insurance claims data. Health Econ Rev. 2018;8(1):18. doi:10.1186/s13561-018-0199-1

 PubMedGoogle Scholar

Weinmann A, Koch S, Sprinzl M, et al. Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients. Liver Int. 2015;35(2):591–600. doi:10.1111/liv.12696

 PubMed Web of Science ®Google Scholar

Weber M, Lam M, Chiesa C, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging. 2022;49(5):1682–1699. doi:10.1007/s00259-021-05600-z

 PubMed Web of Science ®Google Scholar

Institut für das Entgeltsystem im Krankenhaus. InEK DatenBrowser; 2019. Available from: https://datenbrowser.inek.org/. Accessed August 19, 2023.

 Google Scholar

Lauer-Taxe - Standardwerk der Arzneimittelinformationen. Arzneimittelkosten Atezolizumab und Bevacizumab; 2023. Available from: https://portal.cgmlauer.cgm.com/LF/Seiten/Verwaltung/Kundencenter/1.aspx. Accessed June 15, 2023.

 Google Scholar

Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745

 PubMed Web of Science ®Google Scholar

Institut für das Entgeltsystem im Krankenhaus. Fallpauschalen-Katalog; 2023. Available from: https://www.g-drg.de/ag-drg-system-2023/fallpauschalen-katalog/fallpauschalen-katalog-20232. Accessed August 19, 2023.

 Google Scholar

Pollock RF, Colaone F, Guardiola L, Shergill S, Brennan VK. A cost analysis of SIR-Spheres yttrium-90 resin microspheres versus tyrosine kinase inhibitors in the treatment of unresectable hepatocellular carcinoma in France, Italy, Spain and the UK. J Med Econ. 2020;23(6):593–602. doi:10.1080/13696998.2020.1731213

 PubMed Web of Science ®Google Scholar

Marqueen KE, Kim E, Ang C, Mazumdar M, Buckstein M, Ferket BS. Cost-effectiveness analysis of selective internal radiotherapy with yttrium-90 versus sorafenib in locally advanced hepatocellular carcinoma. JCO Oncol Pract. 2021;17(2):e266–e277. doi:10.1200/OP.20.00443

 PubMedGoogle Scholar

Destatis Statistisches Bundesamt. Kosten der stationären Krankenhausversorgung; 2023. Available from: https://www.destatis.de/DE/Presse/Pressemitteilungen/2021/04/PD21_194_231.html. Accessed August 19, 2023.

 Google Scholar

Kaier K, Heister T, Wolff J, Wolkewitz M. Mechanical ventilation and the daily cost of ICU care. BMC Health Serv Res. 2020;20(1):267. doi:10.1186/s12913-020-05133-5

 PubMed Web of Science ®Google Scholar

Gaugain L, Cawston H, Dubois de Gennes C, et al. Cost-utility analysis of atezolizumab with bevacizumab in untreated unresectable or advanced hepatocellular carcinoma in France. PLoS One. 2023;18(1):e0280442. doi:10.1371/journal.pone.0280442

 PubMed Web of Science ®Google Scholar

Amdahl J, Diaz J, Park J, Nakhaipour HR, Delea TE. Cost-effectiveness of pazopanib compared with sunitinib in metastatic renal cell carcinoma in Canada. Curr Oncol. 2016;23(4):e340–354. doi:10.3747/co.23.2244

 PubMed Web of Science ®Google Scholar

Howell TA, Matza LS, Jun MP, Garcia J, Powers A, Maloney DG. Health State utilities for adverse events associated with chimeric antigen receptor T-cell therapy in large B-cell lymphoma. Pharmacoecon Open. 2022;6(3):367–376. doi:10.1007/s41669-021-00316-0

 PubMed Web of Science ®Google Scholar