Advertisement

Der Urologe

, Volume 57, Issue 6, pp 686–692 | Cite as

Fortgeschrittenes Urothelkarzinom

Von der Chemotherapie zur Immuntherapie
  • T. Horn
  • S. Krege
  • M. Retz
Leitthema

Zusammenfassung

Im November 2016 wurden Studiendaten zur Zweitlinientherapie des metastasierten Urothelkarzinoms mit dem PD-1(„programmed cell death protein 1“)-Antikörper Pembrolizumab publiziert, die einen Vorteil im Gesamtüberleben gegenüber einer konventionellen Chemotherapie mit Paclitaxel, Docetaxel oder Vinflunin zeigen. In einer ähnlichen Studie konnte der PD-L1(„programmed cell death ligand 1“)-Antikörper Atezolizumab keinen signifikanten Vorteil gegenüber der Chemotherapie in der Subgruppe PD-L1-positiver Patienten zeigen und verfehlte damit den primären Studienendpunkt. Für andere PD-1/PD-L1-gerichtete Substanzen existieren Daten zu Ansprechen und Gesamtüberleben aus großen Phase-I/II-Studien. Die Substanzklasse der PD-1/PD-L1-Inhibitoren dürfte somit der neue Standard in der Zweitlinientherapie des metastasierten Urothelkarzinoms sein. In randomisierten Phase-III-Studien wird der Einsatz von PD-1/PD-L1-gerichteten Substanzen auch in der Erstlinientherapie des metastasierten Urothelkarzinoms untersucht. Dabei werden verschiedene Therapiestrategien verfolgt: Monotherapien mit PD-1/PD-L1-Inhibitoren sowie deren Kombinationen mit CTLA-4(„cytotoxic t‑lymphocyte-associated protein 4“)-Inhibitoren oder konventioneller Chemotherapie. Es liegen bereits Daten aus einarmigen Phase-II-Studien zur Monotherapie vor. Erste Daten aus randomisierten Studien werden im Laufe des Jahres 2018 erwartet.

Schlüsselwörter

Atezolizumab Antikörper Cisplatin Pembrolizumab Kombinationstherapie 

Advanced bladder cancer

From chemo- to immunotherapy

Abstract

In November 2016, the results of a phase III clinical trial with the protein cell death (PD)-1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published and showed an overall survival benefit in comparison with conventional chemotherapy with vinflunine, docetaxel, or paclitaxel. In a similar trial the PD-L1 antibody atezolizumab showed no significant benefit in comparison to chemotherapy in the subgroup of PD-L1-positive patients and, thus, missed its primary endpoint. For other PD-1/PD-L1 directed substances, large phase I/II trials reported data concerning response rates and overall survival. This substance class will most likely become the new treatment standard in second-line treatment of metastatic urothelial cancer. Currently, PD-1/PD-L1 inhibitors are also being tested within randomized phase III trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or cytotoxic T‑lymphocyte-associated protein (CTLA)-4 inhibitors. Whereas data from single-arm phase II clinical trials have already been published, preliminary phase III data are expected in 2018.

Keywords

Atezolizumab Cisplatin Antibodies Pembrolizumab Combination therapy 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

T. Horn: Vortrags‑/Beratertätigkeit: Roche, MSD, Astellas, BMS, Medac, Ipsen; Reiseunterstützung: Janssen, Bayer. S. Krege gibt an, dass kein Interessenkonflikt besteht. M. Retz: Vortrags‑/Beratertätigkeit: Janssen-Cilag, BMS, Roche, MSD, Astellas, Ipsen, Pfizer, Bayer; Reiseunterstützung: Janssen-Cilag, BMS, Roche, Ipsen.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    von der Maase H, Sengelov L, Roberts JT et al (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 23:4602–4608CrossRefPubMedGoogle Scholar
  2. 2.
    Boussiotis VA (2016) Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med 375:1767–1778CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    LeMaoult J, Carosella ED, Schreiber RD et al (2011) Cancer immunoediting: integrating immunity‚s roles in cancer suppression and promotion. J Immunol Res 331:1565–1570Google Scholar
  4. 4.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352CrossRefPubMedGoogle Scholar
  5. 5.
    Blank C, Gajewski TF, Mackensen A (2005) Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54:307–314CrossRefPubMedGoogle Scholar
  6. 6.
    Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3:611–618CrossRefPubMedGoogle Scholar
  7. 7.
    Hodi FS, O‘Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Galsky MD, Chen GJ, Oh WK et al (2012) Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol 23:406–410CrossRefPubMedGoogle Scholar
  9. 9.
    Galsky MD, Hahn NM, Rosenberg J et al (2011) Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 29:2432–2438CrossRefPubMedGoogle Scholar
  10. 10.
    De Santis M, Bellmunt J, Mead G et al (2012) 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 30:191–199CrossRefPubMedGoogle Scholar
  11. 11.
    Balar AV, Galsky MD, Rosenberg JE et al (2017) Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389:67–76CrossRefPubMedGoogle Scholar
  12. 12.
    Reck M, Rodriguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833CrossRefPubMedGoogle Scholar
  13. 13.
    Bellmunt J, Theodore C, Demkov T et al (2009) 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 27:4454–4461CrossRefPubMedGoogle Scholar
  14. 14.
    Massard C, Gordon MS, Sharma S et al (2016) 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 34:3119–3125CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sharma P, Callahan MK, Bono P et al (2016) Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17:1590–1598CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Powles T, Eder JP, Fine GD et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562CrossRefPubMedGoogle Scholar
  17. 17.
    Plimack ER, Bellmunt J, Gupta S et al (2017) 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 18:212–220CrossRefPubMedGoogle Scholar
  18. 18.
    Rosenberg JE, Hoffman-Censits J, Powles T et al (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 387:1909–1920CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sharma P, Retz M, Siefker-Radtke A et al (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322CrossRefPubMedGoogle Scholar
  20. 20.
    Bellmunt J, de Wit R, Vaughn DJ et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026.  https://doi.org/10.1056/NEJMoa1613683 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Powles T, Duran I, van der Heijden MS et al (2017) 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 391(10122):748–757.  https://doi.org/10.1016/S0140-6736(17)33297-X CrossRefPubMedGoogle Scholar
  22. 22.
    Vaughn DJ, Bellmunt J, Fradet Y et al (2018) 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.  https://doi.org/10.1200/JCO.2017.76.9562 CrossRefPubMedGoogle Scholar
  23. 23.
    Powles T, Duran I, van der Heijden MS et al (2018) 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 391:748–757CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Urologische Klinik und Poliklinik, Klinikum rechts der IsarTechnische Universität MünchenMünchenDeutschland
  2. 2.Abteilung für Urologie, Kinderurologie und Urologische OnkologieKlinikum Essen-MitteEssenDeutschland

Personalised recommendations