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Emerging Role of Immunotherapy in Advanced Urothelial Carcinoma

  • Vadim S. Koshkin
  • Petros Grivas
Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Genitourinary Cancers

Abstract

Purpose of Review

Advanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape.

Recent Findings

Since May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting. Clinical outcomes and safety profiles of these agents appear relatively comparable across separate trials; however, only pembrolizumab is supported by level I evidence from a large randomized phase III trial showing overall survival benefit over conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.

Summary

Pembrolizumab has the highest level of evidence in platinum-refractory aUC, whereas pembrolizumab and atezolizumab have comparable level of evidence in the frontline setting in cisplatin-ineligible patients. Ongoing research is evaluating novel agents, various rational combinations, and sequences, as well as predictive and prognostic biomarkers.

Keywords

Metastatic bladder cancer Advanced urothelial carcinoma Immunotherapy Immune checkpoint inhibitors PD-1 PD-L1 Cisplatin-ineligible Platinum-refractory Atezolizumab Pembrolizumab Avelumab Nivolumab Durvalumab Biomarkers clinical trials 

Notes

Compliance with Ethical Standards

Conflict of Interest

Vadim S. Koshkin declares that he has no conflict of interest.

Petros Grivas has received compensation from Genentech, Dendreon, Bayer, Merck, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, and EMD Serono for service as a consultant; participated in educational, unbranded, not product-related speaker’s program (after providing direct input for slides content) for Genentech and Bristol-Myers Squibb; and received support for conduction of clinical trials (to Cleveland Clinic Foundation) from Genentech, Bayer, Merck, Mirati, Oncogenex, Pfizer, Bristol-Myers Squibb, and AstraZeneca.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Cancer of the Urinary Bladder - Cancer Stat Facts. Available at: https://seer.cancer.gov/statfacts/html/urinb.html. Accessed: 15th November 2017.
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol. 2003;44:672–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48:202–5; discussion 205-206.CrossRefGoogle Scholar
  5. 5.
    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 Off J Am Soc Clin Oncol. 2005;23:4602–8.CrossRefGoogle Scholar
  6. 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 Off J Am Soc Clin Oncol. 2011;29:2432–8.CrossRefGoogle Scholar
  7. 7.
    Sternberg CN, Yagoda A, Scher HI, Watson RC, Herr HW, Morse MJ, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol. 1988;139:461–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Loehrer PJ, 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 Off J Am Soc Clin Oncol. 1992;10:1066–73.CrossRefGoogle Scholar
  9. 9.
    Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom A, et al. 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. 2001;19:2638–46.CrossRefGoogle Scholar
  10. 10.
    Sternberg CN, 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 tumours. Eur J Cancer Oxf Engl. 2006;1990(42):50–4.CrossRefGoogle Scholar
  11. 11.
    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 Off J Am Soc Clin Oncol. 2000;18:3068–77.CrossRefGoogle Scholar
  12. 12.
    Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, et al. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013;24:1011–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R, et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol. 2012;23:406–10.CrossRefPubMedGoogle Scholar
  14. 14.
    De Santis M, 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 Off J Am Soc Clin Oncol. 2009;27:5634–9.CrossRefGoogle Scholar
  15. 15.
    De Santis M, 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 Off J Am Soc Clin Oncol. 2012;30:191–9.CrossRefGoogle Scholar
  16. 16.
    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. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:3451–7.CrossRefGoogle Scholar
  17. 17.
    Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20:937–40.CrossRefGoogle Scholar
  18. 18.
    Lorusso V, et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer Oxf Engl. 1998;1990(34):1208–12.CrossRefGoogle Scholar
  19. 19.
    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. J Clin Oncol Off J Am Soc Clin Oncol. 1997;15:1853–7.CrossRefGoogle Scholar
  20. 20.
    Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 1997;15:589–93.CrossRefGoogle Scholar
  21. 21.
    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 Off J Am Soc Clin Oncol. 2009;27:4454–61.CrossRefGoogle Scholar
  22. 22.
    Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375:1767–78.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Brown JA, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol Baltim Md. 2003;1950(170):1257–66.Google Scholar
  24. 24.
    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;515:558–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Petrylak DP, Powles T, Bellmunt J, Braiteh FS, Loriot Y, Morales R, et al. Atezolizumab (atezo) in patients with metastatic urothelial carcinoma (mUC): a 2-year clinical update from a phase Ia study. J Clin Oncol. 2017;35:290.CrossRefGoogle Scholar
  26. 26.
    • Rosenberg JE, 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;387:1909–20. Summarizes the results of Cohort 2 in IMvigor 210, a phase II trial of atezolizumab in platinum-refractory aUC. This trial led to the first approval of an immunotherapy agent (atezolizumab) in platinum-refractory aUC. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Rosenberg JE, et al. PD-L1 expression, cancer genome atlas (TCGA) subtype, and mutational load as independent predictors of response to atezolizumab (atezo) in metastatic urothelial carcinoma (mUC; IMvigor210). J Clin Oncol. 2016;34:104.CrossRefGoogle Scholar
  28. 28.
    Necchi A, et al. Atezolizumab (atezo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): post-progression outcomes from the phase 2 IMvigor210 study. Ann Oncol. 2017;28(suppl_5):v295–329.  https://doi.org/10.1093/annonc/mdx371.Google Scholar
  29. 29.
    Press Announcements - FDA approves new, targeted treatment for bladder cancer. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm. Accessed: 18th November 2017.
  30. 30.
    A study of atezolizumab compared with chemotherapy in participants with locally advanced or metastatic urothelial bladder cancer [IMvigor211]—full text view - ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02302807. Accessed: 17th November 2017.
  31. 31.
    Roche provides update on phase III study of TECENTRIQ® (atezolizumab) in people with previously treated advanced bladder cancer. Available at: http://www.roche.com/media/store/releases/med-cor-2017-05-10.htm. Accessed: 18th November 2017.
  32. 32.
    Powles, 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. 2017.Google Scholar
  33. 33.
    Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQM, 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;18:212–20.CrossRefPubMedGoogle Scholar
  34. 34.
    •• Bellmunt J, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015–26. Summarizes the results of a landmark phase III trial (KEYNOTE-045) showing an overall survival advantage of pembrolizumab compared to chemotherapy in platinum-refractory aUC. This trial established pembrolizumab as the current standard of care in platinum-refractory aUC. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Research, C. for D. E and. approved drugs—pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm559300.htm. Accessed: 18th November 2017.
  36. 36.
    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;17:1590–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    • Sharma P, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312–22. Summarizes results of CheckMate 275, a phase II trial of nivolumab in platinum-refractory aUC. CrossRefPubMedGoogle Scholar
  38. 38.
    Research, C. for D. E. and approved drugs - Nivolumab for Treatment of Urothelial Carcinoma. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm539646.htm. Accessed: 18th November 2017.
  39. 39.
    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 Off J Am Soc Clin Oncol. 2016;34:3119–25.CrossRefGoogle Scholar
  40. 40.
    • Hahn NM, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). J Clin Oncol. 2017;35:4525. Abstract with the most updated results of the trial of durvalumab in platinum-refractory aUC. The Massard et al. reference above describes in manuscript form an earlier analysis of the same trial. Google Scholar
  41. 41.
    Research, C. for D. E. and approved drugs—durvalumab (Imfinzi). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm. Accessed: 18th November 2017.
  42. 42.
    Study of MEDI4736 with or without tremelimumab versus standard of care chemotherapy in urothelial cancer—full text view - ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT02516241. Accessed: 18th November 2017.
  43. 43.
    Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN solid tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–98.CrossRefPubMedGoogle Scholar
  44. 44.
    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 Off J Am Soc Clin Oncol. 2017;35:2117–24.CrossRefGoogle Scholar
  45. 45.
    Patel MR, Ellerton JA, Infante JR, Agrawal M, Gordon MS, Aljumaliy R, et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from two cohorts of the phase 1b JAVELIN solid tumor trial. J Clin Oncol. 2017;35:330.CrossRefGoogle Scholar
  46. 46.
    • Apolo AB, et al. Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. J Clin Oncol. 2017;35:4528. Abstract describing the most updated results of the phase Ib trial of avelumab in platinum-refractory aUC patients. CrossRefGoogle Scholar
  47. 47.
    Research, C. for D. E. and. Approved drugs—FDA grants accelerated approval to avelumab for urothelial carcinoma. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Accessed: 18th November 2017.
  48. 48.
    • Balar AV, 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;  https://doi.org/10.1016/S1470-2045(17)30616-2. Summarizes the results of KEYNOTE-052, a phase II study of pembrolizumab in cisplatin-ineligible aUC.
  49. 49.
    O’Donnell PH, Grivas P, Balar AV, Bellmunt J. Biomarker findings and mature clinical results from KEYNOTE-052: first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). ASCO; 2017.Google Scholar
  50. 50.
    Powles T, et al. Phase 3 KEYNOTE-361 trial: pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. J Clin Oncol. 2017;35:TPS4590.Google Scholar
  51. 51.
    • Balar AV, 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. Summarizes the results of Cohort 1 in IMvigor 210, a phase II trial of atezolizumab in cisplatin-ineligible patients. CrossRefPubMedGoogle Scholar
  52. 52.
    FDA grants Roche’s TECENTRIQ® (atezolizumab) accelerated approval as initial treatment for certain people with advanced bladder cancer. Available at: http://www.roche.com/media/store/releases/med-cor-2017-04-18.htm. Accessed: 19th November 2017.
  53. 53.
    Szabados B, Van Der Heijden MS, Gomez De Liano Lista A, Tang YZ, Powles T. Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy. J Clin Oncol. 2017;35:–e16004.Google Scholar
  54. 54.
    Sharma P, Callahan MK, Calvo E. Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic urothelial carcinoma: first results from the phase I/II CheckMate 032 study. In: 2016 SITC Annual Meeting; 2016.Google Scholar
  55. 55.
    Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35:–4503.Google Scholar
  56. 56.
    Robertson AG, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171:540–556.e25.CrossRefPubMedGoogle Scholar
  57. 57.
    Iyer G, et al. Mismatch repair (MMR) detection in urothelial carcinoma (UC) and correlation with immune checkpoint blockade (ICB) response. J Clin Oncol. 2017;35(15_suppl):4511.Google Scholar
  58. 58.
    Teo M, et al. DNA damage repair and response (DDR) gene alterations (alt) and response to PD1/PDs1 blockade in platinum-treated metastatic urothelial carcinoma (mUC). J Clin Oncol. 2017;35:4509.Google Scholar
  59. 59.
    Le DT, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Barata PC, Koshkin VS, Funchain P, Sohal D, Pritchard A, Klek S, et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann Oncol. 2017;28:2458–63.CrossRefPubMedGoogle Scholar
  61. 61.
    Galsky MD, Wang H, Hahn NM, Twardowski P, Pal SK, Albany C, et al. Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. Eur Urol. 2017.Google Scholar
  62. 62.
    Funt S, et al. Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab. J Clin Oncol. 2016;34(15_suppl):3005.Google Scholar
  63. 63.
    Grivas P, et al. Pembrolizumab (pembro) as first-line therapy in cisplatin-ineligible advanced urothelial cancer (UC): outcomes from KEYNOTE-052 in senior patients (pts) with poor performance status. Ann Oncol. 2017;28(suppl_5):v295–329.CrossRefGoogle Scholar
  64. 64.
    Powles T, et al. Immune checkpoint inhibition in metastatic urothelial cancer. Eur Urol. 2017;72(4):477–81.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cleveland Clinic Taussig Cancer InstituteClevelandUSA
  2. 2.Department of Medicine, Division of Oncology, Seattle Cancer Care AllianceUniversity of Washington and Fred Hutchinson Cancer Research CenterSeattleUSA

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