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Cost-Effectiveness of Nadofaragene Firadenovec and Pembrolizumab in Bacillus Calmette-Guérin Immunotherapy Unresponsive Non–Muscle Invasive Bladder Cancer

Published:December 15, 2022DOI:https://doi.org/10.1016/j.jval.2022.12.005

      Highlights

      • There are few therapeutic alternatives for the treatment of bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer. Although cystectomy is potentially curative, many patients are ineligible for or unwilling to undergo cystectomy. Nadofaragene firadenovec and pembrolizumab are new bladder-sparing treatments.
      • This study evaluated the lifetime cost-effectiveness of nadofaragene firadenovec and pembrolizumab from the US health sector perspective.
      • Using a placeholder price, nadofaragene firadenovec was cost-effective in the non–carcinoma in situ (CIS) population but not in the CIS population. Pembrolizumab, at its current price, was not cost-effective in the CIS population. Cost per quality-adjusted life-year gained and threshold price estimates can aid drug pricing negotiations between payers and drug manufacturers.

      Objectives

      Nadofaragene firadenovec is a gene therapy for bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) undergoing Food and Drug Administration review. Pembrolizumab is approved for treating patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS). We evaluated the cost-effectiveness of these treatments compared with a hypothetical therapeutic alternative, at a willingness-to-pay threshold of $150 000 per quality-adjusted life-year (QALY) gained, in CIS and non-CIS BCG-unresponsive NMIBC populations.

      Methods

      We developed a Markov cohort simulation model with a 3-month cycle length and lifetime horizon to estimate the total costs, QALYs, and cost per additional QALY from the health sector perspective. Clinical inputs were informed by results of single-arm clinical trials evaluating the treatments, and systematic literature reviews were conducted to obtain other model inputs. Sensitivity analyses were conducted to assess uncertainty in model results.

      Results

      Nadofaragene firadenovec, at a placeholder price 10% higher than the price of pembrolizumab, had an incremental cost-effectiveness ratio of $263 000 and $145 000 per QALY gained in CIS and non-CIS populations, respectively. Pembrolizumab had an incremental cost-effectiveness ratio of $168 000 per QALY gained for CIS. A 5.4% reduction in pembrolizumab’s price would make it cost-effective. The model was sensitive to many inputs, especially to the probabilities of disease progression, initial treatment response and durability, and drug price.

      Conclusions

      The cost-effectiveness of nadofaragene firadenovec will depend upon its price. Pembrolizumab, although not cost-effective in our base-case analysis, is an important alternative in this population with an unmet medical need. Comparative trials of these treatments are warranted to better estimate cost-effectiveness.

      Keywords

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      References

      1. Cancer Stat Facts: Bladder Cancer. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed February 20, 2022.

        • Lee L.J.
        • Kwon C.S.
        • Forsythe A.
        • Mamolo C.M.
        • Masters E.T.
        • Jacobs I.A.
        Humanistic and economic burden of non-muscle invasive bladder cancer: results of two systematic literature reviews.
        Clinicoecon Outcomes Res. 2020; 12: 693-709
        • Yeung C.
        • Dinh T.
        • Lee J.
        The health economics of bladder cancer: an updated review of the published literature.
        Pharmacoeconomics. 2014; 32: 1093-1104
        • Mossanen M.
        • Gore J.L.
        The burden of bladder cancer care: direct and indirect costs.
        Curr Opin Urol. 2014; 24: 487-491
      2. Bladder cancer: stages and grades. American Society of Clinical Oncology, Cancer.Net.
        • Kirkali Z.
        • Chan T.
        • Manoharan M.
        • et al.
        Bladder cancer: epidemiology, staging and grading, and diagnosis.
        Urology. 2005; 66: 4-34
        • Zlotta A.R.
        • Fleshner N.E.
        • Jewett M.A.
        The management of BCG failure in non-muscle-invasive bladder cancer: an update.
        Can Urol Assoc J. 2009; 3: S199-S205
        • Li R.
        • Sundi D.
        • Zhang J.
        • et al.
        Systematic review of the therapeutic efficacy of bladder-preserving treatments for non-muscle-invasive bladder cancer following intravesical bacillus Calmette-Guérin.
        Eur Urol. 2020; 78: 387-399
        • Williams S.B.
        • Howard L.E.
        • Foster M.L.
        • et al.
        Estimated costs and long-term outcomes of patients with high-risk non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin in the Veterans Affairs health system.
        JAMA Netw Open. 2021; 4e213800
        • Chang S.S.
        • Boorjian S.A.
        • Chou R.
        • et al.
        Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline.
        J Urol. 2016; 196: 1021-1029
        • Flaig T.W.
        • Spiess P.E.
        • Agarwal N.
        • et al.
        Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.
        J Natl Compr Canc Netw. 2020; 18: 329-354
        • Tan W.S.
        • Lamb B.W.
        • Kelly J.D.
        Complications of radical cystectomy and orthotopic reconstruction.
        Adv Urol. 2015; 2015323157
        • Winters B.R.
        • Wright J.L.
        • Holt S.K.
        • Dash A.
        • Gore J.L.
        • Schade G.R.
        Health related quality of life following radical cystectomy: comparative analysis from the Medicare health outcomes survey.
        J Urol. 2018; 199: 669-675
        • Dalbagni G.
        • Russo P.
        • Sheinfeld J.
        • et al.
        Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder.
        J Clin Oncol. 2002; 20: 3193-3198
        • Bartoletti R.
        • Cai T.
        • Gacci M.
        • et al.
        Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a phase II prospective multicenter study.
        Urology. 2005; 66: 726-731
        • Dalbagni G.
        • Russo P.
        • Bochner B.
        • et al.
        Phase II trial of intravesical gemcitabine in bacille Calmette-Guérin-refractory transitional cell carcinoma of the bladder.
        J Clin Oncol. 2006; 24: 2729-2734
        • Gunelli R.
        • Bercovich E.
        • Nanni O.
        • et al.
        Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study.
        Br J Cancer. 2007; 97: 1499-1504
        • Perdonà S.
        • Di Lorenzo G.
        • Cantiello F.
        • et al.
        Is gemcitabine an option in BCG-refractory nonmuscle-invasive bladder cancer? A single-arm prospective trial.
        Anticancer Drugs. 2010; 21: 101-106
        • Addeo R.
        • Caraglia M.
        • Bellini S.
        • et al.
        Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance.
        J Clin Oncol. 2010; 28: 543-548
        • Di Lorenzo G.
        • Perdonà S.
        • Damiano R.
        • et al.
        Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial.
        Cancer. 2010; 116: 1893-1900
        • Skinner E.C.
        • Goldman B.
        • Sakr W.A.
        • et al.
        SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin.
        J Urol. 2013; 190: 1200-1204
        • Sternberg I.A.
        • Dalbagni G.
        • Chen L.Y.
        • Donat S.M.
        • Bochner B.H.
        • Herr H.W.
        Intravesical gemcitabine for high risk, nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment failure.
        J Urol. 2013; 190: 1686-1691
        • Allchorne P.
        • Lamb B.W.
        • Kinsella J.
        • Shamash J.
        • Green J.S.
        Initial experience of intravesical gemcitabine for patients with high-risk superficial transitional cell carcinoma of the bladder following BCG failure.
        Urol Nurs. 2014; 34: 95-99
        • Steinberg R.L.
        • Thomas L.J.
        • O’Donnell M.A.
        • Nepple K.G.
        Sequential intravesical gemcitabine and docetaxel for the salvage treatment of non-muscle invasive bladder cancer.
        Bladder Cancer. 2015; 1: 65-72
        • Milbar N.
        • Kates M.
        • Chappidi M.R.
        • et al.
        Oncological outcomes of sequential intravesical gemcitabine and docetaxel in patients with non-muscle invasive bladder cancer.
        Bladder Cancer. 2017; 3: 293-303
        • Daniels M.J.
        • Barry E.
        • Milbar N.
        • et al.
        An evaluation of monthly maintenance therapy among patients receiving intravesical combination gemcitabine/docetaxel for nonmuscle-invasive bladder cancer.
        Urol Oncol. 2020; 38: 40.e17-40.e24
        • Steinberg R.L.
        • Thomas L.J.
        • Brooks N.
        • et al.
        Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer.
        J Urol. 2020; 203: 902-909
        • Steinberg G.
        • Bahnson R.
        • Brosman S.
        • Middleton R.
        • Wajsman Z.
        • Wehle M.
        Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The valrubicin study group [published correction appears in J Urol. 2008;179(1):386].
        J Urol. 2000; 163: 761-767
        • Dinney C.P.
        • Greenberg R.E.
        • Steinberg G.D.
        Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin.
        Urol Oncol. 2013; 31: 1635-1642
        • Balar A.V.
        • Kamat A.M.
        • Kulkarni G.S.
        • et al.
        Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study [published correction appears in Lancet Oncol. 2021;22(8):e347].
        Lancet Oncol. 2021; 22: 919-930
        • Boorjian S.A.
        • Alemozaffar M.
        • Konety B.R.
        • et al.
        Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
        Lancet Oncol. 2021; 22: 107-117
      3. Atlas S, Touchette D, Beinfeld M, et al. Nadofaragene firadenovec and oportuzumab monatox for BCG-unresponsive, non-muscle invasive bladder cancer: effectiveness and value. Institute for Clinical and Economic Review. https://icer.org/wp-content/uploads/2020/08/ICER_Bladder-Cancer_Final-Report_053122.pdf. Accessed March 20, 2022.

        • Beinfeld M.
        • Atlas S.J.
        • Touchette D.
        • McKenna A.
        • Rind D.
        • Pearson S.D.
        The effectiveness and value of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive non-muscle-invasive bladder cancer.
        J Manag Care Spec Pharm. 2021; 27: 797-804
      4. Value assessment framework 2020-2023. Institute for Clinical and Economic Review.
        • Ryen L.
        • Svensson M.
        The willingness to pay for a quality adjusted life year: a review of the empirical literature.
        Health Econ. 2015; 24: 1289-1301
        • Cameron D.
        • Ubels J.
        • Norström F.
        On what basis are medical cost-effectiveness thresholds set? Clashing opinions and an absence of data: a systematic review.
        Glob Health Action. 2018; 111447828
        • Howard D.H.
        • Bach P.B.
        • Berndt E.R.
        • Conti R.M.
        Pricing in the market for anticancer drugs.
        J Econ Perspect. 2015; 29: 139-162
        • Tan W.S.
        • Panchal A.
        • Buckley L.
        • et al.
        Radiofrequency-induced thermo-chemotherapy effect versus a second course of bacillus Calmette-Guérin or institutional standard in patients with recurrence of non–muscle-invasive bladder cancer following induction or maintenance bacillus Calmette-Guérin therapy (HYMN): A Phase III, open-label, randomised controlled trial.
        Eur Urol. 2019; 75: 63-71
        • Wymer K.M.
        • Sharma V.
        • Saigal C.S.
        • et al.
        Cost-effectiveness analysis of pembrolizumab for bacillus Calmette-Guérin-unresponsive carcinoma in situ of the bladder.
        J Urol. 2021; 205: 1326-1335
        • Nseyo U.O.
        • Shumaker B.
        • Klein E.A.
        • Sutherland K.
        Photodynamic therapy using porfimer sodium as an alternative to cystectomy in patients with refractory transitional cell carcinoma in situ of the bladder. Bladder Photofrin Study Group.
        J Urol. 1998; 160: 39-44
        • Li R.
        • Amrhein J.
        • Cohen Z.
        • Champagne M.
        • Kamat A.M.
        Efficacy of Mycobacterium phlei cell wall-nucleic acid complex (MCNA) in BCG-unresponsive patients.
        Bladder Cancer. 2017; 3: 65-71
        • Ignatoff J.M.
        • Chen Y.H.
        • Greenberg R.E.
        • Pow-Sang J.M.
        • Messing E.M.
        • Wilding G.
        Phase II study of intravesical therapy with AD32 in patients with papillary urothelial carcinoma or carcinoma in situ (CIS) refractory to prior therapy with bacillus Calmette-Guerin (E3897): A trial of the Eastern Cooperative Oncology Group.
        Urol Oncol. 2009; 27: 496-501
        • McKiernan J.M.
        • Holder D.D.
        • Ghandour R.A.
        • et al.
        Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.
        J Urol. 2014; 192: 1633-1638
        • Racioppi M.
        • Di Gianfrancesco L.
        • Ragonese M.
        • Palermo G.
        • Sacco E.
        • Bassi P.F.
        ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk “BCG failure” non muscle invasive bladder cancer: 3 years follow-up outcomes.
        BMC Cancer. 2018; 18: 1224
      5. Human Mortality Database. U.S.A. Total population. https://www.mortality.org/Country/Country?cntr=USA. Accessed March 20, 2022.

        • International Collaboration of Trialists; Medical Research Council
        Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial.
        J Clin Oncol. 2011; 29: 2171-2177
        • Gore J.L.
        • Litwin M.S.
        • Lai J.
        • et al.
        Use of radical cystectomy for patients with invasive bladder cancer.
        J Natl Cancer Inst. 2010; 102: 802-811
        • von der Maase H.
        • Sengelov L.
        • Roberts J.T.
        • et al.
        Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
        J Clin Oncol. 2005; 23: 4602-4608
        • Tully K.H.
        • Cole A.P.
        • Krimphove M.J.
        • et al.
        Contemporary treatment patterns for non-muscle-invasive bladder cancer: has the use of radical cystectomy changed in the BCG shortage era?.
        Urology. 2021; 147: 199-204
        • Shariat S.F.
        • Karakiewicz P.I.
        • Palapattu G.S.
        • et al.
        Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium.
        J Urol. 2006; 176: 2414-2422
        • Kulkarni G.S.
        • Finelli A.
        • Fleshner N.E.
        • Jewett M.A.
        • Lopushinsky S.R.
        • Alibhai S.M.
        Optimal management of high-risk T1G3 bladder cancer: a decision analysis.
        PLoS Med. 2007; 4: e284
        • Mossanen M.
        • Wang Y.
        • Szymaniak J.
        • et al.
        Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories.
        World J Urol. 2019; 37: 2059-2065
        • Seal B.
        • Shermock K.M.
        • Asche C.V.
        • et al.
        Evaluating the cost of treating bladder cancer with and without metastases.
        Value Health. 2015; 18: A201
        • Leow J.J.
        • Reese S.W.
        • Jiang W.
        • et al.
        Propensity-matched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the United States.
        Eur Urol. 2014; 66: 569-576
        • Malangone-Monaco E.
        • Wilson K.
        • Diakun D.
        • Tayama D.
        • Satram S.
        • Ogale S.
        Cost of cystectomy-related complications in patients with bladder cancer in the United States.
        Curr Med Res Opin. 2020; 36: 1177-1185
      6. Pharmaceutical prices. U.S. Department of Veterans Affairs Office of Procurement, Acquisition and Logistics (OPAL). https://www.va.gov/opal/nac/fss/pharmprices.asp. Accessed March 20, 2022.

      7. Valrubicin. Red book. IBM Merative Micromedex. IBM.
        https://www.micromedexsolutions.com
        Date accessed: March 20, 2022
      8. Search the physician fee schedule. Centers for Medicare & Medicaid Services, CMS.gov.
        • Cox E.
        • Saramago P.
        • Kelly J.
        • et al.
        Effects of bladder cancer on UK healthcare costs and patient health-related quality of life: evidence from the BOXIT trial.
        Clin Genitourin Cancer. 2020; 18: e418-e442
        • Slater R.L.
        • Lai Y.
        • Zhong Y.
        • et al.
        The cost effectiveness of pembrolizumab versus chemotherapy or atezolizumab as second-line therapy for advanced urothelial carcinoma in the United States.
        J Med Econ. 2020; 23: 967-977
      9. National data, National income and product accounts. Table 2.3.4. Price indexes for personal consumption expenditures by major type of product. Bureau of Economic Analysis, US Department of Commerce.
        • Husereau D.
        • Drummond M.
        • Augustovski F.
        • et al.
        Consolidated health economic evaluation reporting standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations.
        Value Health. 2022; 25: 3-9
      10. See WA. Commentary on “outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective?” Wong KA, Zisengwe G, Athanasiou T, O’Brien T, Thomas K, The Urology Centre, Guys and St. Thomas’ NHS Foundation Trust. BJU Int. 2013;112(5):561-567.

        • de Bekker-Grob E.W.
        • van der Aa M.N.
        • Zwarthoff E.C.
        • et al.
        Non-muscle-invasive bladder cancer surveillance for which cystoscopy is partly replaced by microsatellite analysis of urine: a cost-effective alternative?.
        BJU Int. 2009; 104: 41-47
        • Heijnsdijk E.A.M.
        • Nieboer D.
        • Garg T.
        • Lansdorp-Vogelaar I.
        • de Koning H.J.
        • Nielsen M.E.
        Cost-effectiveness of surveillance schedules in older adults with non-muscle-invasive bladder cancer.
        BJU Int. 2019; 123: 307-312
        • Wang Z.
        • Xiao H.
        • Wei G.
        • et al.
        Low-dose bacillus Calmette-Guerin versus full-dose for intermediate and high-risk of non-muscle invasive bladder cancer: a Markov model.
        BMC Cancer. 2018; 18: 1108
        • Sutton A.J.
        • Lamont J.V.
        • Evans R.M.
        • et al.
        An early analysis of the cost-effectiveness of a diagnostic classifier for risk stratification of haematuria patients (DCRSHP) compared to flexible cystoscopy in the diagnosis of bladder cancer.
        PLoS One. 2018; 13e0202796
        • Al Hussein Al Awamlh B.
        • Lee R.
        • Chughtai B.
        • Donat S.M.
        • Sandhu J.S.
        • Herr H.W.
        A cost-effectiveness analysis of management of low-risk non-muscle-invasive bladder cancer using office-based fulguration.
        Urology. 2015; 85: 381-386
        • Criss S.D.
        • Weaver D.T.
        • Sheehan D.F.
        • Lee R.J.
        • Pandharipande P.V.
        • Kong C.Y.
        Effect of PD-L1 testing on the cost-effectiveness and budget impact of pembrolizumab for advanced urothelial carcinoma of the bladder in the United States.
        Urol Oncol. 2019; 37: 180.e11-180.e18
        • Sarfaty M.
        • Hall P.S.
        • Chan K.K.W.
        • et al.
        Cost-effectiveness of pembrolizumab in second-line advanced bladder cancer.
        Eur Urol. 2018; 74: 57-62
        • Patel S.
        • Dinh T.
        • Noah-Vanhoucke J.
        • et al.
        Novel simulation model of non-muscle invasive bladder cancer: a platform for a virtual randomized trial of conservative therapy vs. cystectomy in BCG refractory patients.
        Bladder Cancer. 2015; 1: 143-150
        • Jiang R.
        • Janssen M.F.B.
        • Pickard A.S.
        US population norms for the EQ-5D-5L and comparison of norms from face-to-face and online samples.
        Qual Life Res. 2021; 30: 803-816