Abstract
Immunotherapy has revolutionized the systemic treatment of solid tumors, including advanced urothelial carcinoma (aUC), providing durable responses with a favorable safety profile. Multiple immune checkpoint inhibitor agents have been approved in monotherapy in second-line setting, and for a selected group of chemo-naïve cisplatin-ineligible patients with high PD-L1 expression. Despite the incorporation of immunotherapy to the systemic treatment landscape of aUC, platinum-based chemotherapy remains the standard of care in frontline setting for vast majority of patients. Urothelial carcinoma is a chemosensitive disease with response rates of up to 50% to frontline chemotherapy. However, the response to chemotherapy is short lasting with vast majority of patients experiencing disease progression and death within months. In this context, maintenance therapy constitutes an attractive therapeutic strategy to maximize the time to treatment failure. Different cytotoxic and targeted agents have been investigated as maintenance therapy for aUC but have not shown an impact on survival. Avelumab has become the first and only drug to improve overall survival as maintenance therapy after frontline platinum-based therapy in aUC patients and the first drug to be approved in this setting. This article will review the rational for maintenance therapy, the different drugs investigated as maintenance therapy for aUC, and the impact of avelumab maintenance therapy as a new standard of care in the management of aUC.
Similar content being viewed by others
References
Alanee S, Alvarado-Cabrero I, Murugan P, Kumar R, Nepple KG, Paner GP, Konety BR (2019) Update of the international consultation on urological diseases on bladder cancer 2018: non-urothelial cancers of the urinary bladder. World J Urol 37(1):107–114. https://doi.org/10.1007/s00345-018-2421-5
Alva A, Csőszi T, Ozguroglu M, Matsubara N, Geczi L, Cheng SY-S, Powles TB (2020) LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol 31:S1155. https://doi.org/10.1016/j.annonc.2020.08.2252
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Özgüroğlu M (2017) Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 377(20):1919–1929. https://doi.org/10.1056/NEJMoa1709937
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J (2017a) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet (lond, Engl) 389(10064):67–76. https://doi.org/10.1016/S0140-6736(16)32455-2
Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, Bellmunt J (2017b) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18(11):1483–1492. https://doi.org/10.1016/S1470-2045(17)30616-2
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, KEYNOTE-045 Investigators (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026. https://doi.org/10.1056/NEJMoa1613683
Bellmunt Molins J, García-Donas Jiménez J, Valderrama BP, Virizuela Echaburu JA, Hernando-Polo S, Climent Durán MÁ, Pous AF (2020) Final overall survival analysis of the SOGUG phase 2 MAJA study: maintenance vinflunine versus best supportive care after first-line chemotherapy in advanced urothelial carcinoma. Clin Genitourin Cancer 18(6):452–460. https://doi.org/10.1016/j.clgc.2020.05.004
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492
Brown JS, Sundar R, Lopez J (2018) Combining DNA damaging therapeutics with immunotherapy: more haste, less speed. Br J Cancer 118(3):312–324. https://doi.org/10.1038/bjc.2017.376
Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492):315–322. https://doi.org/10.1038/nature12965
Castellano D, Puente J, de Velasco G, Chirivella I, López-Criado P, Mohedano N, Grande E (2014) Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract after failure of one platinum-based systemic therapy in clinical practice. BMC Cancer 14:779. https://doi.org/10.1186/1471-2407-14-779
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, McConkey DJ (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25(2):152–165. https://doi.org/10.1016/j.ccr.2014.01.009
Clarke G, Johnston S, Corrie P, Kuhn I, Barclay S (2015) Withdrawal of anticancer therapy in advanced disease: a systematic literature review. BMC Cancer. https://doi.org/10.1186/s12885-015-1862-0
De Wit M, De Geeter P, Galli L, Hegele A, Schrader M, Schenck M, Pichler A (2015) 2640 Vinflunine maintenance treatment following first-line therapy of advanced urothelial carcinoma—results from the JASiMA trial. Eur J Cancer 51:S527. https://doi.org/10.1016/S0959-8049(16)31457-5
ESMO (n.d.). EMA Recommends Extension of Indications for Avelumab. 15 Mar 2021 https://www.esmo.org/oncology-news/ema-recommends-extension-of-indications-for-avelumab2
Galsky MD, Powles T, Li S, Hennicken D, Sonpavde G (2018) A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901). J Clin Oncol 36(6_suppl):539. https://doi.org/10.1200/JCO.2018.36.6_suppl.TPS539
Galsky MD, Necchi A, Sridhar SS, Ogawa O, Ruscica D, Angra N, Bellmunt J (2019) A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC). J Clin Oncol 37(7):499. https://doi.org/10.1200/JCO.2019.37.7_suppl.TPS499
Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Pal SK (2020a) Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol 38(16):1797–1806. https://doi.org/10.1200/JCO.19.03091
Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E (2020b) Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet (lond, Engl) 395(10236):1547–1557. https://doi.org/10.1016/S0140-6736(20)30230-0
García-Donas J, Font A, Pérez-Valderrama B, Virizuela JA, Climent MÁ, Hernando-Polo S, Bellmunt J (2017) Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial. Lancet Oncol 18(5):672–681a. https://doi.org/10.1016/S1470-2045(17)30242-5
Goldie JH, Coldman AJ (1979) A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63(11–12):1727–1733
Gourd E (2018) EMA restricts use of anti-PD-1 drugs for bladder cancer. Lancet Oncol 19(7):e341. https://doi.org/10.1016/S1470-2045(18)30433-9
Grivas PD, Daignault S, Tagawa ST, Nanus DM, Stadler WM, Dreicer R, Hussain M (2014) Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer 120(5):692–701. https://doi.org/10.1002/cncr.28477
Grivas P, Monk BJ, Petrylak D, Reck M, Foley G, Guenther S, Moehler M (2019) Immune checkpoint inhibitors as switch or continuation maintenance therapy in solid tumors: rationale and current state. Target Oncol 14(5):505–525. https://doi.org/10.1007/s11523-019-00665-1
Kalogirou C, Svistunov A, Krebs M, Lausenmeyer EM, Vergho D, Riedmiller H, Kocot A (2016) Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: a matched-pair single institution analysis. Mol Clin Oncol 4(4):636–642. https://doi.org/10.3892/mco.2016.749
Kasi PM, Grothey A (2016) Chemotherapy Maintenance. Cancer J 22(3):199–204. https://doi.org/10.1097/PPO.0000000000000195
Koshkin VS, O’Donnell P, Yu EY, Grivas P (2019) Systematic review: targeting HER2 in bladder cancer. Bladder Cancer 5(1):1–12. https://doi.org/10.3233/BLC-180196
Lee JE, Chung C-U (2014) Update on the evidence regarding maintenance therapy. Tuberculosis Respir Dis 76(1):1–7. https://doi.org/10.4046/trd.2014.76.1.1
Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Lowe BA (1992) A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol off J Am Soc Clin Oncol 10(7):1066–1073. https://doi.org/10.1200/JCO.1992.10.7.1066
Mitsuzuka K, Yamashita S, Namiki S, Yamada S, Sato K, Saito H, Arai Y (2014) Low-dose maintenance gemcitabine-carboplatin chemotherapy could be an alternative to continuous standard chemotherapy for patients with metastatic urothelial carcinoma: chemotherapy for metastatic UC. Int J Urol 21(11):1114–1119. https://doi.org/10.1111/iju.12532
Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 27:16–25. https://doi.org/10.1016/j.coi.2014.01.004
Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, DiSilvestro P (2018) Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379(26):2495–2505. https://doi.org/10.1056/NEJMoa1810858
Muto S, Abe H, Noguchi T, Sugiura S, Kitamura K, Isotani S, Horie S (2015) Maintenance monotherapy with gemcitabine after standard platinum-based chemotherapy in patients with advanced urothelial cancer: maintenance GEM monotherapy for UC. Int J Urol 22(5):490–494. https://doi.org/10.1111/iju.12727
Oudard S, Culine S, Vano Y, Goldwasser F, Théodore C, Nguyen T, Beuzeboc P (2015) Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer (oxf, Engl) 51(1):45–54. https://doi.org/10.1016/j.ejca.2014.10.009
Palumbo R, Licata L, Sottotetti F, Tagliaferri B, Pozzi E, Teragni C, Bernardo A (2018) Vinflunine in advanced transitional cell cancer of the urothelial tract: a potential option for maintenance therapy? A case series. Oncol Res Treat 41(1–2):8–13. https://doi.org/10.1159/000481098
Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP (2008) Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev Urol 10(1):31–43
Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Apolo AB (2018) Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19(1):51–64. https://doi.org/10.1016/S1470-2045(17)30900-2
Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol J-L, Bidoli P, Gridelli C (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13(3):247–255. https://doi.org/10.1016/S1470-2045(12)70063-3
Philips GK, Halabi S, Sanford BL, Bajorin D, Small EJ (2009) A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102. Ann Oncol off J Eur Soc Med Oncol 20(6):1074–1079. https://doi.org/10.1093/annonc/mdn749
Powles T, O’Donnell PH, Massard C, Arkenau H-T, Friedlander TW, Hoimes CJ, Hahn NM (2017a) Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 3(9):e172411. https://doi.org/10.1001/jamaoncol.2017.2411
Powles T, Huddart RA, Elliott T, Sarker S-J, Ackerman C, Jones R, Chowdhury S (2017b) Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J Clin Oncol off J Am Soc Clin Oncol 35(1):48–55. https://doi.org/10.1200/JCO.2015.66.3468
Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Grivas P (2020a) Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 383(13):1218–1230. https://doi.org/10.1056/NEJMoa2002788
Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Grivas P (2020b) Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 38(18):1. https://doi.org/10.1200/JCO.2020.38.18_suppl.LBA1
Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Harter P (2019) Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381(25):2416–2428. https://doi.org/10.1056/NEJMoa1911361
Reesink DJ, van de Garde EMW, Peters BJM, van der Nat PB, Los M, Horenblas S, van Melick HHE (2020) Treatment patterns and clinical outcomes of chemotherapy treatment in patients with muscle-invasive or metastatic bladder cancer in the Netherlands. Sci Rep 10(1):15822. https://doi.org/10.1038/s41598-020-72820-y
Research C for D E (2018) FDA alerts health care professionals and oncology clinical investigators about an efficacy issue identified in clinical trials for some patients taking keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to treat urothelial cancer with low expression of PD-L1. FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-and-oncology-clinical-investigators-about-efficacy-issue
Research C for D E (2020). FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (lond, Engl) 387(10031):1909–1920. https://doi.org/10.1016/S0140-6736(16)00561-4
Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, Rosenberg JE (2016) Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17(11):1590–1598. https://doi.org/10.1016/S1470-2045(16)30496-X
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551
Sonbol MB, Mountjoy LJ, Firwana B, Liu AJ, Almader-Douglas D, Mody K, Bekaii-Saab T (2020) The role of maintenance strategies in metastatic colorectal cancer: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol 6(3):e194489. https://doi.org/10.1001/jamaoncol.2019.4489
Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE, Vogelzang NJ (2012) Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer 10(1):1–5. https://doi.org/10.1016/j.clgc.2011.11.005
Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol off J Am Soc Clin Oncol 19(10):2638–2646. https://doi.org/10.1200/JCO.2001.19.10.2638
Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT (2006) Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer (oxf, Engl 1990) 42(1):50–54. https://doi.org/10.1016/j.ejca.2005.08.032
Swami U, Grivas P, Pal SK, Agarwal N (2021) Utilization of systemic therapy for treatment of advanced urothelial carcinoma: Lessons from real world experience. Cancer Treat Res Commun 27:100325. https://doi.org/10.1016/j.ctarc.2021.100325
University Hospital, Bordeaux (2020) Gemcitabine-cisplatin plus avelumab or gemcitabine-cisplatin as first-line treatment of patients with locally advanced or metastatic urothelial bladder carcinoma (GCISAVE) (Clinical trial registration No. NCT03324282). Clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT03324282
Update on Phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, Stage IV bladder cancer. (n.d.). Retrieved 17 Sept 2020.https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271. https://doi.org/10.1146/annurev-immunol-031210-101324
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Arning M (2005) 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 off J Am Soc Clin Oncol 23(21):4602–4608. https://doi.org/10.1200/JCO.2005.07.757
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no financial or no-financial competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Carril-Ajuria, L., Martin-Soberón, M.C., de Velasco, G. et al. Immunotherapy maintenance therapy for advanced urothelial carcinoma (aUC): a comprehensive review. J Cancer Res Clin Oncol 148, 1097–1105 (2022). https://doi.org/10.1007/s00432-021-03882-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-021-03882-2