Article Data

  • Views 252
  • Dowloads 144


Open Access

Changes in the treatment landscape for metastatic urothelial cancer: current therapy and future directions

  • Sang Hoon Yeon1
  • Hyo Jin Lee1,*,

1Department of Internal Medicine, Chungnam National University Hospital, 35015 Daejeon, Republic of Korea

DOI: 10.31083/j.jomh1805107 Vol.18,Issue 5,May 2022 pp.1-11

Submitted: 01 November 2021 Accepted: 20 December 2021

Published: 31 May 2022

*Corresponding Author(s): Hyo Jin Lee E-mail:


Despite the development of several new drugs, cisplatin-containing chemotherapy remains the standard frontline option for advanced urothelial carcinoma (UC). Since the cisplatin-based regimen became the standard therapy for metastatic UC, there have been few advances in chemotherapy, until recently. A better understanding of molecular pathobiology of UC and advances in cancer immunology have led to a sharp increase in clinical trials for metastatic UC with the rapidly changing systemic treatment for this disease. This review summarizes current chemotherapy and immunotherapy for metastatic UC, as well as novel agents and ongoing trials.


urothelial carcinoma; cytotoxic chemotherapy; immunotherapy; targeted agent; antibody-drug conjugate; biomarker

Cite and Share

Sang Hoon Yeon,Hyo Jin Lee. Changes in the treatment landscape for metastatic urothelial cancer: current therapy and future directions. Journal of Men's Health. 2022. 18(5);1-11.


[1] Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, Clark PE, et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2017; 15: 1240–1267.

[2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a Cancer Journal for Clinicians. 2019; 69: 7–34.

[3] Bethesda MD, et al. SEER Cancer Stat Facts: Bladder Cancer. NIH NCI: Surveillance, Epidemiology, and End Results Pro-gram. 2019.

[4] Flaig TW, Spiess PE, Agarwal N, et al. NCCN Guidelines Version 2.2021 Bladder Cancer. 2021. rofessionals/physician_gls/pdf/bladder.pdf (Accessed: 21 April 2021).

[5] Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, et al. Phase III trial of methotrexate, vinblastine, doxoru-bicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004; 100: 1639–1645.

[6] von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and Cisplatin Versus Methotrex-ate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study. Journal of Clinical Oncology. 2000; 18: 3068–3077.

[7] von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver 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. Journal of Clinical Oncology. 2005; 23: 4602–4608.

[8] Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De San-tis M, Daugaard G, et al. Randomized phase III study compar-ing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial can-cer without prior systemic therapy: EORTC Intergroup Study 30987. Journal of Clinical Oncology. 2012; 30: 1107–1113.

[9] Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of Patients with Metastatic Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy. Journal of Clinical Oncology. 2011; 29: 2432–2438.

[10] Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemother-apy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387: 1909–1920.

[11] Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cis-platin (MVAC) chemotherapy and recombinant human granulo-cyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. Journal of Clinical On-cology. 2001; 19: 2638–2646.

[12] Oliver RT, Newlands ES, Wiltshaw E, Malpas JS. A phase 2 study of Cis-platinum in patients with recurrent bladder carci-noma. The London and Oxford Co-operative Urological Cancer Group. British Journal of Urology. 1981; 53: 444–447.

[13] Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Ef-ficacy and patterns of response and relapse. Cancer. 1989; 64: 2448–2458.

[14] Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology. 1992; 10: 1066–1073.

[15] Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tu-mors. Journal of Clinical Oncology. 1990; 8: 1050–1055.

[16] von der Maase H. Gemcitabine in transitional cell carcinoma of the urothelium. Expert Review of Anticancer Therapy. 2003; 3: 11–19.

[17] Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. 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 tu-mours. European Journal of Cancer. 2006; 42: 50–54.

[18] De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemc-itabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. Journal of Clinical Oncology. 2012; 30: 191–199.

[19] Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J, Fong L, et al. Pembrolizumab as second-Line Therapy for Advanced Urothe-lial Carcinoma. The New England Journal of Medicine. 2017; 376: 1015–1026.

[20] Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gur-ney H, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. The New England Journal of Medicine. 2020; 383: 1218–1230.

[21] Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a

randomised, double-blind, phase 3 trial. The Lancet. 2017; 309: 2266–2277.

[22] Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee J, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. New England Journal of Medicine. 2021; 384: 1125–1135.

[23] Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tret-ter C, et al. Neoadjuvant dose-dense methotrexate, vinblas-tine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. Journal of Clinical Oncology. 2014; 32: 1889–1894.

[24] De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized Phase II/III Trial Assessing Gem-citabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients with Advanced Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy: Phase II—Results of EORTC Study 30986. Journal of Clinical Oncology. 2009; 27: 5634–5639.

[25] Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petri-oli R, et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Annals of Oncology. 2012; 23: 406–410.

[26] Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Hor-wich A. Bladder cancer: ESMO Practice Guidelines for diag-nosis, treatment and follow-up. Annals of Oncology. 2014; 25: iii40–iii48.

[27] Witjes J, Compérat E, Cowan N, De Santis M, Gakis G, Lebret T, et al. Guidelines on muscle-invasive and metastatic bladder cancer. In EAU Guidelines, Edition Presented at the 28th EAU Annual Congress, Milan. 2013.

[28] Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, et al. Gemcitabine plus cisplatin versus gemcitabine plus car-boplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. European Urology. 2007; 52: 134–141.

[29] Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III Trial of Vinflunine Plus Best Supportive Care Compared with Best Supportive Care alone af-ter a Platinum-Containing Regimen in Patients with Advanced Transitional Cell Carcinoma of the Urothelial Tract. Journal of Clinical Oncology. 2009; 27: 4454–4461.

[30] Bellmunt J, Kerst JM, Vázquez F, Morales-Barrera R, Grande E, Medina A, et al. A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN). Annals of Oncol-ogy. 2017; 28: 1517–1522.

[31] Lee J, Ahn J, Park SH, Lim HY, Kwon JH, Ahn S, et al. Phase II study of a cremophor-free, polymeric micelle formulation of paclitaxel for patients with advanced urothelial cancer pre-viously treated with gemcitabine and platinum. Investigational New Drugs. 2012; 30: 1984–1990.

[32] Beer TM, Goldman B, Nichols CR, Petrylak DP, Agarwal M, Ryan CW, et al. Southwest Oncology Group phase II study of irinotecan in patients with advanced transitional cell carci-noma of the urothelium that progressed after platinum-based chemotherapy. Clinical Genitourinary Cancer. 2008; 6: 36–39.

[33] Joly F, Houédé N, Noal S, Chevreau C, Priou F, Chinet-Charrot P, et al. Do patients with advanced urothelial carcinoma bene-fit from weekly paclitaxel chemotherapy? A GETUG phase II study. Clinical Genitourinary Cancer. 2009; 7: E28–E33.

[34] Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. British Journal of Cancer. 1997; 75: 606–607.

[35] Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Investigational New Drugs. 2007; 25: 265–270.

[36] Witte RS, Manola J, Burch PA, Kuzel T, Weinshel EL, Loehrer PJ. Topotecan in previously treated advanced urothelial carci-noma: an ECOG phase II trial. Investigational New Drugs. 1998; 16: 191–195.

[37] Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, et al. Eastern Cooperative Oncology Group phase II trial of ifos-famide in the treatment of previously treated advanced urothelial carcinoma. Journal of Clinical Oncology. 1997; 15: 589–593.

[38] Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. Journal of Clinical Oncology. 2006; 24: 3451–3457.

[39] Ko Y, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, et al. Nanoparticle albumin-bound paclitaxel for second-line treat-ment of metastatic urothelial carcinoma: a single group, multi-centre, phase 2 study. The Lancet. Oncology. 2013; 14: 769–776.

[40] Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, et al. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Annals of Oncol-ogy. 2013; 24: 1466–1472.

[41] Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA. Phase II study of single-agent gemcitabine in previously untreated pa-tients with metastatic urothelial cancer. Journal of Clinical On-cology. 1997; 15: 3394–3398.

[42] Sideris S, Aoun F, Zanaty M, Martinez NC, Latifyan S, Awada A, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothe-lial bladder cancer. Molecular and Clinical Oncology. 2016; 4: 1063–1067.

[43] McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. Journal of Clinical Oncology. 1997; 15: 1853–1857.

[44] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair De-ficiency. The New England Journal of Medicine. 2015; 372: 2509–2520.

[45] Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope landscape in breast and colorectal cancer. Cancer Research. 2008; 68: 889–892.

[46] Singh P, Black P. Emerging role of checkpoint inhibition in lo-calized bladder cancer. Urologic Oncology. 2016; 34: 548–555.

[47] Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Develop-ment of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999; 11: 141–151.

[48] Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nature Reviews. Immunology. 2004; 4: 336–347.

[49] Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Mat-sumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291: 319–322.

[50] Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515: 568–571.

[51] Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541: 321–330.

[52] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554: 544–548.

[53] Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. New England Journal of Medicine. 2015; 372: 311–319.

[54] Hamid O, Robert C, Daud A, Hodi FS, Hwu W, Kefford R, et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. New England Journal of Medicine. 2013; 369: 134–144.

[55] Herbst RS, Soria J, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 an-tibody MPDL3280a in cancer patients. Nature. 2015; 515: 563–567.

[56] Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280a (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515: 558–562.

[57] Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. Journal of Clinical Oncology. 2014; 32: 1020–1030.

[58] Brahmer JR, Tykodi SS, Chow LQM, Hwu W, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England Journal of Medicine. 2012; 366: 2455–2465.

[59] Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499: 214–218.

[60] Richard P, et al. FDA Alerts Health Care Professionals and Oncology Clinical Investigators about an Efficacy Issue Identi-fied in Clinical Trials for Some Patients Taking Keytruda (pem-brolizumab) or Tecentriq (atezolizumab) as Monotherapy to Treat Urothelial Cancer with Low Expression of PD-L1. Agust 16. 2018.

[61] Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. 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. The Lancet Oncology. 2017; 18: 1483–1492.

[62] Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017; 389: 67–76.

[63] Kamat AM, Bellmunt J, Galsky MD, Konety BR, Lamm DL, Langham D, et al. Society for Immunotherapy of Cancer con-sensus statement on immunotherapy for the treatment of bladder carcinoma. Journal for Immunotherapy of Cancer. 2018; 5: 68.

[64] Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III KEYNOTE-045 trial of pem-brolizumab versus paclitaxel, docetaxel, or vinflunine in recur-rent advanced urothelial cancer: results of >2 years of follow-up. Annals of Oncology. 2019; 30: 970–976.

[65] Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018; 391: 748–757.

[66] Sternberg CN, Loriot Y, James N, Choy E, Castellano D, Lopez-Rios F, et al. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract. European Urology. 2019; 76: 73–81.

[67] Pal SK, Hoffman-Censits J, Zheng H, Kaiser C, Tayama D, Bell-munt J. Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Clinical Experience from an Expanded Access Study in the United States. European Urology. 2018; 73: 800–806.

[68] Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet. Oncology. 2017; 18: 312–322.

[69] Sharma P, Siefker-Radtke A, de Braud F, Basso U, Calvo E, Bono P, et al. Nivolumab alone and with Ipilimumab in Previ-ously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. Journal of Clinical Oncology. 2019; 37: 1608–1616.

[70] Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, in Patients with Refractory Metastatic Urothelial Car-cinoma: Results from a Multicenter, Phase Ib Study. Journal of Clinical Oncology. 2017; 35: 2117–2124.

[71] Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Alju-maily R, et al. Avelumab in metastatic urothelial carcinoma af-ter platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. The Lancet. Oncology. 2018; 19: 51–64.

[72] Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint In-hibitor, in Patients with Advanced Urothelial Bladder Cancer. Journal of Clinical Oncology. 2016; 34: 3119–3125.

[73] Powles T, O’Donnell PH, Massard C, Arkenau H, Friedlander TW, Hoimes CJ, et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results from a Phase 1/2 Open-label Study. JAMA Oncology. 2017; 3: e172411.

[74] Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. 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. Journal of Clinical Oncology. 2020; 38: LBA1–LBA1.

[75] Grivas P, Agarwal N, Pal S, Kalebasty AR, Sridhar SS, Smith J, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial find-ings to clinical practice. Cancer Treatment Reviews. 2021; 97: 102187.

[76] Szekanecz Z, Koch AE. Mechanisms of Disease: angiogenesis in inflammatory diseases. Nature Clinical Practice. Rheumatol-ogy. 2007; 3: 635–643.

[77] Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tu-mor angiogenesis. Cancer Cell. 2004; 6: 409–421.

[78] Motz GT, Coukos G. The parallel lives of angiogenesis and im-munosuppression: cancer and other tales. Nature Reviews. Im-munology. 2011; 11: 702–711.

[79] Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, et al. Docetaxel as Monotherapy or Combined with Ra-mucirumab or Icrucumab in second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: an Open-Label, Three-Arm, Randomized Controlled Phase II Trial. Journal of Clinical Oncology. 2016; 34: 1500–1509.

[80] Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular Cancer Therapeutics. 2011; 10: 2298–2308.

[81] Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. Journal of Clinical Oncology. 2020; 38: 3672–3684.

[82] Weinstein JN, Akbani R, Broom BM, Wang W, Verhaak RGW, McConkey D, et al. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014; 507: 315–322.

[83] Ross JS, Wang K, Khaira D, Ali SM, Fisher HAG, Mian B, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Can-cer. 2016; 122: 702–711.

[84] Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nature Reviews. Cancer. 2010; 10: 116–129.

[85] Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. The New England Jourmal of Medicine. 2019; 381: 338–348.

[86] Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Stein-berg G, et al. Molecular Drivers of the Non-T-cell-Inflamed Tu-mor Microenvironment in Urothelial Bladder Cancer. Cancer Immunology Research. 2016; 4: 563–568.

[87] Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015; 523: 231–235.

[88] Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunology Research. 2019; 7: 1457–1471.

[89] Siefker-Radtke AO, Currie G, Abella E, Vaena DA, Rezazadeh Kalebasty A, Curigliano G, et al. FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis. Journal of Clinical Oncology. 2019; 37: 4511–4511.

[90] Joerger M, Cassier P, Penel N, Cathomas R, Richly H, Schostak M, et al. Rogaratinib treatment of patients with advanced urothe-lial carcinomas prescreened for tumor FGFR mRNA expression. Journal of Clinical Oncology. 2018; 36: 494–494.

[91] Rosenberg JE, Gajate P, Morales-Barrera R, Lee J, Necchi A, Penel N, et al. Safety and efficacy of rogaratinib in combination with atezolizumab in cisplatin-ineligible patients (pts) with lo-cally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression in the phase Ib/II FORT-2 study. Journal of Clinical Oncology. 2021; 39: 4521–4521.

[92] Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, et al. Enfortumab vedotin antibody-drug conjugate targeting Nectin-4 is a highly potent therapeutic agent in mul-tiple preclinical cancer models. Cancer Research. 2016; 76: 3003–3013.

[93] Mandai K, Rikitake Y, Mori M, Takai Y. Nectins and Nectin-Like Molecules in Development and Disease. Current Topics in Developmental Biology. 2015; 112: 197–231.

[94] Rosenberg JE, O’Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal Trial of Enfortumab Vedotin in Urothe-lial Carcinoma after Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of Clinical On-cology. 2019; 37: 2592–2600.

[95] Rosenberg JE, Flaig TW, Friedlander TW, Milowsky MI, Srini-vas S, Petrylak DP, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Journal of Clinical Oncology. 2020; 38: 441–441.

[96] Avellini C, Licini C, Lazzarini R, Gesuita R, Guerra E, Tossetta G, et al. The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer. Oncotarget. 2017; 8: 58642–58653.

[97] Tagawa ST, Balar A, Petrylak DP, Grivas P, Agarwal N, Stern-berg CN, et al. Initial results from TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients (Pts) with metastatic urothelial cancer (mUC) after failure of platinum-based regimens (PLT) or immunotherapy. Annals of Oncology. 2019; 30: v890–v891.

[98] Kitano S, Nakayama T, Yamashita M. Biomarkers for Immune Checkpoint Inhibitors in Melanoma. Frontiers in Oncology. 2018; 8: 270.

[99] Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune eva-sion by tumors. Advances in Immunology. 2006; 90: 51–81.

[100] Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992; 258: 1795–1798.

[101] Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 480: 480–489.

[102] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England Journal of Medicine. 2012; 366: 2443–2454.

[103] McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. JAMA Oncology. 2016; 2: 46–54.

[104] Hutarew G. PD-L1 testing, fit for routine evaluation? From a pathologist’s point of view. Memo. 2016; 9: 201–206.

[105] Balar AV, Dreicer R, Loriot Y, Perez-Gracia JL, Hoffman-Censits JH, Petrylak DP, et al. Atezolizumab (atezo) in first-line cisplatin-ineligible or platinum-treated locally advanced or metastatic urothelial cancer (mUC): Long-term efficacy from phase 2 study IMvigor210. Journal of Clinical Oncology. 2018; 36: 4523–4523.

[106] Schumacher TN, Schreiber RD. Neoantigens in cancer im-munotherapy. Science. 2015; 348: 69–74.

[107] Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nature Re-views Cancer. 2019; 19: 133–150.

[108] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357: 409–413.

[109] Kim TJ, Cho KS, Koo KC. Current status and future per-spectives of immunotherapy for locally advanced or metastatic urothelial carcinoma: a comprehensive review. Cancers. 2020; 12: 192.

[110] Teo MY, Bambury RM, Zabor EC, Jordan E, Al-Ahmadie H, Boyd ME, et al. DNA Damage Response and Repair Gene Alterations are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma. Clini-cal Cancer Research. 2017; 23: 3610–3618.

[111] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010; 140: 883–899.

[112] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454: 436–444.

[113] Shrotriya S, Walsh D, Bennani-Baiti N, Thomas S, Lorton C. C- reactive protein is an important biomarker for prognosis tu-mor recurrence and treatment response in adult solid tumors: a systematic review. PLoS ONE. 2015; 10: e0143080.

[114] Ishioka J, Saito K, Sakura M, Yokoyama M, Matsuoka Y, Nu-mao N, et al. Development of a nomogram incorporating serum C- reactive protein level to predict overall survival of patients with advanced urothelial carcinoma and its evaluation by deci-sion curve analysis. British Journal of Cancer. 2012; 107: 1031–1036.

[115] Yoshida S, Saito K, Koga F, Yokoyama M, Kageyama Y, Masuda H, et al. C-reactive protein level predicts prognosis in patients with muscle-invasive bladder cancer treated with chemoradiotherapy. BJU International. 2008; 101: 978–981.

[116] Eggers H, Seidel C, Schrader AJ, Lehmann R, Wegener G, Kuczyk MA, et al. Serum C-reactive protein: a prognostic factor in metastatic urothelial cancer of the bladder. Medical Oncology. 2013; 30: 705.

[117] Kim HS, Ku JH. Systemic inflammatory response based on neutrophil-to-lymphocyte ratio as a prognostic marker in blad-der cancer. Disease Markers. 2016; 2016: 8345286.

[118] Moujaess E, Fakhoury M, Assi T, et al. The therapeutic use of human albumin in cancer patients’ management. Critical Re-views in Oncology/Hematology. 2017; 120: 203–209.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Directory of Open Access Journals (DOAJ) DOAJ is a unique and extensive index of diverse open access journals from around the world, driven by a growing community, committed to ensuring quality content is freely available online for everyone.

SCImago The SCImago Journal & Country Rank is a publicly available portal that includes the journals and country scientific indicators developed from the information contained in the Scopus® database (Elsevier B.V.)

Publication Forum - JUFO (Federation of Finnish Learned Societies) Publication Forum is a classification of publication channels created by the Finnish scientific community to support the quality assessment of academic research.

Scopus CiteScore 0.7 (2021) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

Norwegian Register for Scientific Journals, Series and Publishers Search for publication channels (journals, series and publishers) in the Norwegian Register for Scientific Journals, Series and Publishers to see if they are considered as scientific. (

Submission Turnaround Time