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Coming of Age of Immunotherapy of Urothelial Cancer

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Abstract

Following platinum-based regimens becoming the reference standard of care, it has taken almost four decades to find a systemic treatment that improved overall survival in metastatic urothelial tumors. Single-agent immune checkpoint inhibitors have not only improved overall survival but also the quality of life of patients with metastatic urothelial tumors after failure of platinum-based regimens and as a maintenance therapy after four to six cycles of standard first-line chemotherapy. In addition, very promising data are emerging when single-agent immunotherapy is offered as adjuvant or neoadjuvant treatment for patients with muscle-invasive disease and also in the non-muscle-invasive setting. There is an extensive debate about the role of PD-L1 expression as a reliable biomarker to predict the activity of immune-based regimens. Furthermore, the lack of consensus concerning its utility means that there is a need for more and better tools to identify patients who are likely to benefit from these novel approaches. The field of urothelial tumors now additionally exploits novel antibody-drug conjugates and fibroblast growth factor-receptor inhibitors that are being tested in combination with immunotherapy. This added complexity contributes to an enormous increase in the challenges that will be faced shortly.

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References

  1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yagoda A. Chemotherapy of metastatic bladder cancer. Cancer. 1980;45(Suppl 7):1879–88.

    CAS  PubMed  Google Scholar 

  3. Loehrer PJ Sr, 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. J Clin Oncol. 1992;10(7):1066–73.

    PubMed  Google Scholar 

  4. Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci. 2020;8(1):15.

    CAS  Google Scholar 

  5. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011;12(3):211–4.

    PubMed  Google Scholar 

  6. 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. J Clin Oncol. 2011;29(17):2432–8.

    PubMed  Google Scholar 

  7. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.

    PubMed  Google Scholar 

  8. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II–results of EORTC study 30986. J Clin Oncol. 2009;27(33):5634–9.

    PubMed  PubMed Central  Google Scholar 

  9. 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. J Clin Oncol. 2005;23(21):4602–8.

    PubMed  Google Scholar 

  10. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–9.

    PubMed  Google Scholar 

  11. Bamias A, Tzannis K, Harshman LC, Crabb SJ, Wong YN, Kumar Pal S, et al. Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC). Ann Oncol. 2018;29(2):361–9.

    CAS  PubMed  Google Scholar 

  12. Bamias A, Tzannis K, Bamia C, Harshman LC, Crabb S, Plimack ER, et al. The impact of cisplatin- or non-cisplatin-containing chemotherapy on long-term and conditional survival of patients with advanced urinary tract cancer. Oncologist. 2019;24(10):1348–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Necchi A, Pond GR, Raggi D, Giannatempo P, Vogelzang NJ, Grivas P, et al. Efficacy and safety of gemcitabine plus either taxane or carboplatin in the first-line setting of metastatic urothelial carcinoma: a systematic review and meta-analysis. Clin Genitourin Cancer. 2017;15(1):23-30.e2.

    PubMed  Google Scholar 

  14. Pal SK, Lin YI, Yuh B, DeWalt K, Kazarian A, Vogelzang N, Nelson RA. Conditional survival in de novo metastatic urothelial carcinoma. PLoS ONE. 2015;10(8):e0136622.

    PubMed  PubMed Central  Google Scholar 

  15. 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 after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27(27):4454–61.

    CAS  PubMed  Google Scholar 

  16. 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. Ann Oncol. 2013;24(6):1466–72.

    CAS  PubMed  Google Scholar 

  17. Powles T. Immunotherapy: the development of immunotherapy in urothelial bladder cancer. Nat Rev Clin Oncol. 2015;12(4):193–4.

    PubMed  Google Scholar 

  18. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104(10):3967–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Faraj SF, Munari E, Guner G, Taube J, Anders R, Hicks J, et al. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology. 2015;85(3):703.e1-6.

    Google Scholar 

  20. 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(7528):558–62.

    CAS  PubMed  Google Scholar 

  21. 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 chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Necchi A, Joseph RW, Loriot Y, Hoffman-Censits J, Perez-Gracia JL, Petrylak DP, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017;28(12):3044–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Perez-Gracia JL, Loriot Y, Rosenberg JE, Powles T, Necchi A, Hussain SA, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: outcomes by prior number of regimens. Eur Urol. 2018;73(3):462–8.

    CAS  PubMed  Google Scholar 

  24. Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017;18(2):212–20.

    CAS  PubMed  Google Scholar 

  25. Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17(11):1590–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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. Lancet Oncol. 2017;18(3):312–22.

    CAS  PubMed  Google Scholar 

  27. Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, et al. Nivolumab in patients with advanced platinum-resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended follow-up from CheckMate 275. Clin Cancer Res. 2020;26(19):5120–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Powles T, O’Donnell PH, Massard C, Arkenau HT, 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 Oncol. 2017;3(9):e172411.

    PubMed  PubMed Central  Google Scholar 

  30. 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 carcinoma: results from a multicenter. Phase Ib Study J Clin Oncol. 2017;35(19):2117–24.

    CAS  PubMed  Google Scholar 

  31. Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, et al. 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. 2018;19(1):51–64.

    CAS  PubMed  Google Scholar 

  32. Apolo AB, Ellerton JA, Infante JR, Agrawal M, Gordon MS, Aljumaily R, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. J Immunother Cancer. 2020;8(2):e001246.

    PubMed  PubMed Central  Google Scholar 

  33. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of>2 years of follow-up. Ann Oncol. 2019;30(6):970–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, et al. Health-related quality-of-life analysis from KEYNOTE-045: a phase III study of pembrolizumab versus chemotherapy for previously treated advanced urothelial cancer. J Clin Oncol. 2018;36(16):1579–87.

    CAS  PubMed  Google Scholar 

  36. 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(10122):748–57.

    CAS  PubMed  Google Scholar 

  37. 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. Eur Urol. 2019;76(1):73–81.

    CAS  PubMed  Google Scholar 

  38. Barata PC, Gopalakrishnan D, Koshkin VS, Mendiratta P, Karafa M, Allman K, et al. Atezolizumab in metastatic urothelial carcinoma outside clinical trials: focus on efficacy, safety, and response to subsequent therapies. Target Oncol. 2018;13(3):353–61.

    PubMed  Google Scholar 

  39. Haanen J, Ernstoff MS, Wang Y, Menzies AM, Puzanov I, Grivas P, et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann Oncol. 2020;31(6):724–44.

    CAS  PubMed  Google Scholar 

  40. Loriot Y, Sternberg CN, Castellano D, Oosting SF, Dumez H, Huddart R, et al. Safety and efficacy of atezolizumab in patients with autoimmune disease: Subgroup analysis of the SAUL study in locally advanced/metastatic urinary tract carcinoma. Eur J Cancer. 2020;138:202–11.

    CAS  PubMed  Google Scholar 

  41. Necchi A, Madison R, Raggi D, Jacob JM, Bratslavsky G, Shapiro O, et al. Comprehensive assessment of immuno-oncology biomarkers in adenocarcinoma, urothelial carcinoma, and squamous-cell carcinoma of the bladder. Eur Urol. 2020;77(4):548–56.

    CAS  PubMed  Google Scholar 

  42. Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, et al. Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies. Eur Urol. 2020;77(4):439–46.

    CAS  PubMed  Google Scholar 

  43. 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(10064):67–76.

    CAS  PubMed  Google Scholar 

  44. 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. Lancet Oncol. 2017;18(11):1483–92.

    CAS  PubMed  Google Scholar 

  45. Grivas P, Plimack ER, Balar AV, Castellano D, O’Donnell PH, Bellmunt J, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer (KEYNOTE-052): outcomes in older patients by age and performance status. Eur Urol Oncol. 2020;3(3):351–9.

    PubMed  PubMed Central  Google Scholar 

  46. Vuky J, Balar AV, Castellano D, O’Donnell PH, Grivas P, Bellmunt J, et al. Long-Term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol. 2020;38(23):2658–66.

    CAS  PubMed  Google Scholar 

  47. Suzman DL, Agrawal S, Ning YM, Maher VE, Fernandes LL, Karuri S, et al. FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy. Oncologist. 2019;24(4):563–9.

    CAS  PubMed  Google Scholar 

  48. Gevaert T, Cimadamore A, Montironi R, Eckstein M. PD-L1 testing for urothelial carcinoma: interchangeability, reliability and future perspectives. Curr Drug Targets. 2020. https://doi.org/10.2174/1389450121666200510015216.

    Article  PubMed  Google Scholar 

  49. Niglio SA, Jia R, Ji J, Ruder S, Patel VG, Martini A, et al. Programmed death-1 or programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer: a systematic review and meta-analysis. Eur Urol. 2019;76(6):782–9.

    CAS  PubMed  Google Scholar 

  50. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218–30.

    CAS  PubMed  Google Scholar 

  51. Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Horwich A; ESMO Guidelines Working Group. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii40–8. https://www.esmo.org/guidelines/genitourinary-cancers/bladder-cancer/eupdate-bladder-cancer-treatment-recommendations4. Accessed 16 Jul 2020.

  53. Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, et al. Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(3):329–54.

    PubMed  Google Scholar 

  54. Wright KM. FDA approves pembrolizumab for BCG-unresponsive NMIBC. Oncology. 2020;34(2):44.

    PubMed  Google Scholar 

  55. Balar AV, Kulkarni GS, Uchio EM, Boormans J, Mourey L, Krieger LEM, et al. Pembrolizumab for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG): phase II KEYNOTE-057 trial. J Clin Oncol. 2019;37(suppl 7S):350.

    Google Scholar 

  56. Galsky MD, Arija JÁA, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547–57.

    CAS  PubMed  Google Scholar 

  57. Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;S1470–2045(20):30541–6.

    Google Scholar 

  58. Alva A, Csőszi T, Ozguroglu M, Matsubara N, Geczi L, Cheng SY, et al. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol. 2020;31(suppl_4):S1142–215.

    Google Scholar 

  59. Hussain MHA, Powles T, Albers P, Castellano D, Daneshmand S, Gschwend J, et al. IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC). J Clin Oncol. 2020;38(suppl_15):5000.

    Google Scholar 

  60. https://news.bms.com/news/details/2020/Opdivo-nivolumab-Significantly-Improves-Disease-Free-Survival-vs.-Placebo-as-Adjuvant-Therapy-for-Patients-with-High-Risk-Muscle-Invasive-Urothelial-Carcinoma-in-Phase-3-CheckMate--274-Trial/default.aspx. Accessed 24 September 2020.

  61. Apolo AB, Rosenberg JE, Kim WY, Chen RC, Sonpavde G, Srinivas S, et al. Alliance A031501: phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC) (AMBASSADOR) versus observation. J Clin Oncol. 2019;37(suppl 7S):TPS504.

    Google Scholar 

  62. Martini T, Gilfrich C, Mayr R, Burger M, Pycha A, Aziz A, et al. The use of neoadjuvant chemotherapy in patients with urothelial carcinoma of the bladder: current practice among clinicians. Clin Genitourin Cancer. 2017;15(3):356–62.

    PubMed  Google Scholar 

  63. Huo J, Ray-Zack MD, Shan Y, Chamie K, Boorjian SA, Kerr P, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer. Eur Urol Oncol. 2019;2(5):497–504.

    PubMed  Google Scholar 

  64. Sonpavde G, Khan MM, Lerner SP, Svatek RS, Novara G, Karakiewicz PI, et al. Disease-free survival at 2 or 3 years correlates with 5-year overall survival of patients undergoing radical cystectomy for muscle invasive bladder cancer. J Urol. 2011;185(2):456–61.

    PubMed  Google Scholar 

  65. Sonpavde G, Shariat SF. Preoperative chemotherapy for bladder cancer: a standard waits to be optimally deployed. Cancer. 2012;118(1):8–11.

    PubMed  Google Scholar 

  66. Leow JJ, Catto JWF, Efstathiou JA, Gore JL, Hussein AA, Shariat SF, et al. Quality indicators for bladder cancer services: a collaborative review. Eur Urol. 2020;78(1):43–59.

    PubMed  Google Scholar 

  67. Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, Phase II Study. J Clin Oncol. 2018;36(34):3353–60.

    CAS  PubMed  Google Scholar 

  68. Bandini M, Gibb EA, Gallina A, Raggi D, Marandino L, Bianchi M, et al. Does the administration of preoperative pembrolizumab lead to sustained remission post-cystectomy? First survival outcomes from the PURE-01 study. Ann Oncol. 2020;S0923–7534(20):42461–5.

    Google Scholar 

  69. Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706–14.

    CAS  PubMed  Google Scholar 

  70. Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020;26(12):1845–51.

    PubMed  Google Scholar 

  71. van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020;26(12):1839–44.

    PubMed  Google Scholar 

  72. Wei XX, McGregor BA, Lee RJ, Gao X, Kilbridge KL, Preston MA, et al. Durvalumab as neoadjuvant therapy for muscle-invasive bladder cancer: Preliminary results from the Bladder Cancer Signal Seeking Trial (BLASST)-2. J Clin Oncol. 2020;38(6_suppl):507.

    Google Scholar 

  73. Grande E, Guerrero F, Puente J, Galante I, Duran I, Fuentes J, et al. DUTRENEO Trial: A phase II randomized trial of DUrvalumab and TREmelimumab as NEOadjuvant approach in muscle-invasive urothelial bladder cancer (MIBC) patients prospectively selected by immune signature scores. J Clin Oncol. 2020;37(15_suppl):TPS4588.

    Google Scholar 

  74. Gupta S, Sonpavde G, Weight CJ, McGregor BA, Gupta S, Maughan BL, et al. Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy. J Clin Oncol. 2020;38(6_suppl):439.

    Google Scholar 

  75. Hoimes CJ, Abouassaly R, Saltzman JN, Fleming MT, Hoffman-Censits JH, Byrd T, et al. HCRN GU14-188: Neoadjuvant pembrolizumab (P) and gemcitabine (G) with or without cisplatin (C) in muscle invasive urothelial cancer (MIUC). J Clin Oncol. 2020;34(15_suppl):TPS4578.

    Google Scholar 

  76. Kaimakliotis HZ, Adra N, Kelly WK, Trabulsi EJ, Lauer RC, Picus J, et al. Phase II neoadjuvant (N-) gemcitabine (G) and pembrolizumab (P) for locally advanced urothelial cancer (laUC): Interim results from the cisplatin (C)-ineligible cohort of GU14-188. J Clin Oncol. 2020;38(15_suppl):5019.

    Google Scholar 

  77. Woldu SL, Şanli Ö, Lotan Y. Tackling non-muscle invasive bladder cancer in the clinic. Expert Rev Anticancer Ther. 2017;17(5):467–80.

    CAS  PubMed  Google Scholar 

  78. Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163(4):1124–9.

    CAS  PubMed  Google Scholar 

  79. Douglass L, Schoenberg M. The future of intravesical drug delivery for non-muscle invasive bladder cancer. Bladder Cancer. 2016;2(3):285–92.

    PubMed  PubMed Central  Google Scholar 

  80. Peyton CC, Chipollini J, Azizi M, Kamat AM, Gilbert SM, Spiess PE. Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what. World J Urol. 2019;37(10):2017–29.

    PubMed  Google Scholar 

  81. Rosenberg JE, Flaig TW, Friedlander TW, Milowsky MI, Srinivas S, Petrylak DP, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2020;38(suppl 6):441.

    Google Scholar 

  82. van der Heijden GS, Galsky MD, Derleth C, Steinberg J, Kataria R, Powles T. Study EV-302: a 3-arm, open-label, randomized phase III study of enfortumab vedotin plus pembrolizumab and/or chemotherapy, versus chemotherapy alone, in untreated locally advanced or metastatic urothelial cancer. Ann Oncol. 2020;31(suppl_4):S550.

    Google Scholar 

  83. Aggen DH, Drake CG. Biomarkers for immunotherapy in bladder cancer: a moving target. J Immunother Cancer. 2017;5(1):94.

    PubMed  PubMed Central  Google Scholar 

  84. Necchi A, Raggi D, Gallina A, Ross JS, Farè E, Giannatempo P, et al. Impact of molecular subtyping and immune infiltration on pathological response and outcome following neoadjuvant pembrolizumab in muscle-invasive bladder cancer. Eur Urol. 2020;77(6):701–10.

    CAS  PubMed  Google Scholar 

  85. Galsky MD, Banchereau R, Hamidi HR, Leng N, Harris W, O’Donnell PH, et al. Tumor, immune, and stromal characteristics associated with clinical outcomes with atezolizumab (atezo) + platinum-based chemotherapy (PBC) or atezo monotherapy (mono) versus PBC in metastatic urothelial cancer (mUC) from the phase III IMvigor130 study. J Clin Oncol. 2020;38(suppl_15):5011.

    Google Scholar 

  86. Sridhar S, Powles T, Loriot Y, Bellmunt J, Sternberg CN, Petrylak DP, et al. Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers. Ann Oncol. 2020;31(suppl_4):S550.

    Google Scholar 

  87. Ganesh K, Massagué J. TGF-beta inhibition and immunotherapy: checkmate. Immunity. 2018;48(4):626–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Grivas P, Castellano DE, O’Donnell PH, Cristescu R, Frenkl TL, Keefe SM, et al. Association between stromal/TGF-β/EMT gene expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or metastatic urothelial carcinoma. J Clin Oncol. 2019;37(suppl_15):433.

    Google Scholar 

  89. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Furukawa K, Nagano T, Tachihara M, Yamamoto M, Nishimura Y. Interaction between immunotherapy and antiangiogenic therapy for cancer. Molecules. 2020;25(17):3900.

    CAS  PubMed Central  Google Scholar 

  91. van Dijk N, Funt SA, Blank CU, Powles T, Rosenberg JE, van der Heijden MS. The cancer immunogram as a framework for personalized immunotherapy in urothelial cancer. Eur Urol. 2019;75(3):435–44.

    PubMed  Google Scholar 

  92. Zahoor H, Grivas P. The cancer immunogram: a pledge for a comprehensive biomarker approach for personalized immunotherapy in urothelial cancer. Eur Urol. 2019;75(3):445–7.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology Department, MD Anderson Cancer Center Madrid, C/Arturo Soria 270, 28033, Madrid, Spain

    Enrique Grande

  2. Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain

    Javier Molina-Cerrillo

  3. Vita-Salute San Raffaele University, Milan, Italy

    Andrea Necchi

  4. IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy

    Andrea Necchi

  5. Urological Research Institute (URI)-IRCCS San Raffaele Hospital, Milan, Italy

    Andrea Necchi

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  1. Enrique Grande
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  2. Javier Molina-Cerrillo
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  3. Andrea Necchi
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Correspondence to Enrique Grande.

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Conflict of interest

EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific. EG has received research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. JMC declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. AN declares having received honoraria for consulting from Merck, Astra Zeneca, Janssen, Incyte, Roche, Rainier Therapeutics, Clovis Oncology, Bayer, Astellas/Seattle Genetics, Ferring, and Immunomedics. AN has received grant/research support from: Merck, Ipsen, and Astra Zeneca and travel expenses from Roche, Merck, Astra Zeneca, and Janssen.

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Concept, design: EG. Writing, review, and revision: All authors.

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Grande, E., Molina-Cerrillo, J. & Necchi, A. Coming of Age of Immunotherapy of Urothelial Cancer. Targ Oncol 16, 283–294 (2021). https://doi.org/10.1007/s11523-021-00804-7

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  • DOI: https://doi.org/10.1007/s11523-021-00804-7

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