Download PDF
Aktuelle Urol 2020; 51(04): 371-376
DOI: 10.1055/a-1136-9850
Übersicht

Systemtherapie beim metastasierten Urothelkarzinom − Aktueller Stand und was kommt nach den Checkpointinhibitoren?

Systemic therapy for metastatic urothelial carcinoma – Current status and what comes after checkpoint inhibitors?
Camilla Marisa Grunewald
Heinrich-Heine-Universität Düsseldorf, Medizinische Fakultät, Klinik für Urologie
,
Andreas Hiester
Heinrich-Heine-Universität Düsseldorf, Medizinische Fakultät, Klinik für Urologie
,
Günter Niegisch
Heinrich-Heine-Universität Düsseldorf, Medizinische Fakultät, Klinik für Urologie
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Das zunehmende Wissen um den Einfluss des Immunsystems auf Tumorentstehung und -progression haben unser Verständnis von Tumorbiologie in den letzten Jahren grundlegend verändert. Während sich die zur Verfügung stehenden Therapieoptionen für Patienten mit metastasiertem Urothelkarzinom der Harnblase über Jahrzehnte hinweg kaum verbessert haben, hat der Einzug von Immuncheckpoint-Inhibitoren in kurzer Zeit zu einer starken Wandlung der Behandlungslandschaft geführt.

Zwar bildet die Cisplatin-basierte Kombinationstherapie auch weiterhin die Hauptsäule, darüber hinaus bestehen aber nun zusätzliche wirkungsvolle Behandlungsoptionen mit den in Europa zugelassenen PD-(L)-1-Inhibitoren Atezolizumab, Pembrolizumab und Nivolumab. Einem bemerkenswerten Langzeitansprechen stehen hier das Auftreten teils schwerster immun-vermittelter Nebenwirkungen sowie eine insgesamt nur geringe Ansprechrate von etwa 25 % gegenüber. Eine Vielzahl aktueller klinischer Studien beschäftigt sich daher besonders mit möglichen Kombinationsansätzen und sinnvollen Therapiesequenzen, um mögliche Synergismen sowie additive Effekte der bisher zur Verfügung stehenden Substanzen unter Berücksichtigung eines vertretbaren Nebenwirkungsprofils optimal auszunutzen. Darüber hinaus werden viele neue Therapieansätze in klinischen Studien erprobt. In diesem Zusammenhang sind besonders die Entwicklungen auf dem Gebiet der Antikörper-Wirkstoff-Konjugate und FGFR-Inhibitoren vor dem Hintergrund der erst kürzlich erfolgten FDA-Zulassung hervorzuheben.

Der hier vorliegende Review gibt einen Überblick über die aktuell zur Verfügung stehenden Therapieoptionen im metastasierten Urothelkarzinom der Harnblase und behandelt darüber hinaus schwerpunktmäßig zukünftige Therapieansätze anhand gegenwärtiger Studien.

Abstract

The increasing knowledge of the influence of the immune system on tumour development and progression has fundamentally changed our understanding of tumour biology in recent years. While the available treatment options for patients with metastatic urothelial carcinoma of the urinary bladder have hardly improved over decades, the advent of immune checkpoint inhibitors has caused major changes in the corresponding treatment landscape.

Although cisplatin-based combination therapies remain the main element, additional effective treatment options now exist with the PD-(L)-1 inhibitors atezolizumab, pembrolizumab and nivolumab, which have been approved in Europe. A remarkable long-term response is balanced by the occurrence of occasionally severe immune-mediated side effects and an overall low response rate of approximately 25 %. A large number of current clinical trials therefore address possible combinatory approaches in order to make optimal use of possible synergisms and additive effects of the substances available to date, taking into account an acceptable side effect profile. In addition, many new therapeutic approaches are also being tested in clinical trials. In this context, developments in the field of antibody-drug conjugates and FGFR inhibitors with regards to the very recent FDA approvals are particularly noteworthy.

The present review provides an overview of currently available treatment options in metastatic urothelial carcinoma of the bladder and especially focuses on future therapeutic approaches based on current clinical trials.

Schlüsselwörter

Urothelkarzinom - Chemotherapie - Krebsimmuntherapie

Keywords

urothelial carcinoma - chemotherapy - cancer immunotherapy


Publication History

Article published online:
07 April 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • Literatur

  • 1 Sternberg CN, Yagoda A, Scher HI. et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 1989; 64: 2448-2458
    CrossrefPubMedGoogle Scholar
  • 2 von der Maase H, Sengelov L, Roberts JT. 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: 4602-4608 DOI: 10.1200/JCO.2005.07.757.
    CrossrefPubMedGoogle Scholar
  • 3 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft DK, AWMF). S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms, Langversion 1.1. 2016; AWMF-Registrierungsnummer 032/038OL. (Stand:11/2016) http://leitlinienprogramm-onkologie.de/Harnblasenkarzinom.92.0.html
    PubMedGoogle Scholar
  • 4 Galsky MD, Hahn NM, Rosenberg J. et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011; 29: 2432-2438 DOI: 10.1200/JCO.2011.34.8433.
    CrossrefPubMedGoogle Scholar
  • 5 De Santis M, Bellmunt J, Mead G. 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. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2012; 30: 191-199. doi DOI: 10.1200/JCO.2011.37.3571.
    CrossrefPubMedGoogle Scholar
  • 6 Balar AV, Castellano D, O'Donnell PH. 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: 1483-1492 DOI: 10.1016/S1470-2045(17)30616-2.
    CrossrefPubMedGoogle Scholar
  • 7 Balar AV, Galsky MD, Rosenberg JE. 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 DOI: 10.1016/S0140-6736(16)32455-2.
    CrossrefPubMedGoogle Scholar
  • 8 Rosenberg JE, Hoffman-Censits J, Powles T. 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: 1909-1920 DOI: 10.1016/S0140-6736(16)00561-4.
    CrossrefPubMedGoogle Scholar
  • 9 Powles T, Duran I, van der Heijden MS. 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 DOI: 10.1016/S0140-6736(17)33297-X.
    CrossrefPubMedGoogle Scholar
  • 10 Bellmunt J, de Wit R, Vaughn DJ. et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015-1026 DOI: 10.1056/NEJMoa1613683.
    CrossrefPubMedGoogle Scholar
  • 11 Sharma P, Retz M, Siefker-Radtke A. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18: 312-322 DOI: 10.1016/S1470-2045(17)30065-7.
    CrossrefPubMedGoogle Scholar
  • 12 Szabados B, van Dijk N, Tang YZ. et al. Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer. European urology 2018; 73: 149-152 DOI: 10.1016/j.eururo.2017.08.022.
    CrossrefPubMedGoogle Scholar
  • 13 Gomez de Liano Lista A, van Dijk N, de Velasco Oria de Rueda G. et al. Clinical outcome after progressing to frontline and second-line Anti-PD-1/PD-L1 in advanced urothelial cancer. European urology 2020; 77: 269-276 DOI: 10.1016/j.eururo.2019.10.004.
    CrossrefPubMedGoogle Scholar
  • 14 Galsky MD, Grande E, Davis ID. et al. IMvigor130: A randomized, phase III study evaluating first-line (1L) atezolizumab (atezo) as monotherapy and in combination with platinum-based chemotherapy (chemo) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). Journal of Clinical Oncology 2018; 36 DOI: 10.1200/JCO.2018.36.15_suppl.TPS4589 .
    CrossrefPubMedGoogle Scholar
  • 15 Powles T, Gschwend JE, Loriot Y. et al. Phase 3 KEYNOTE-361 trial: Pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. Journal of Clinical Oncology 2017; 35 DOI: 10.1200/JCO.2017.35.15_suppl.TPS4590.
    CrossrefPubMedGoogle Scholar
  • 16 Grande E, Galsky MD, Arranz Arija JA. et al. IMvigor130: Efficacy and safety from a Phase 3 study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). Annals of Oncology 2019; 30 (Suppl. 05) v851-v934 DOI: 10.1093/annonc/mdz394.
    CrossrefPubMedGoogle Scholar
  • 17 Galsky MD, Pal SK, Mortazavi A. et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182. Journal of Clinical Oncology 2019; 37 DOI: 10.1200/JCO.2019.37.15_suppl.4504.
    CrossrefPubMedGoogle Scholar
  • 18 Sharma P, Siefker-Radtke A, de Braud F. et al. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol 2019; 37: 1608-1616 DOI: 10.1200/JCO.19.00538.
    CrossrefPubMedGoogle Scholar
  • 19 Smith DC, Gajewski T, Hamid O. et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. Journal of Clinical Oncology 2017; 35 DOI: 10.1200/JCO.2017.35.15_suppl.4503.
    CrossrefPubMedGoogle Scholar
  • 20 Long GV, Dummer R, Hamid O. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol 2019; 20: 1083-1097 DOI: 10.1016/S1470-2045(19)30274-8.
    CrossrefPubMedGoogle Scholar
  • 21 Sherif A, Hasan MN, Radecka E. et al. Pilot study of adoptive immunotherapy with sentinel node-derived T cells in muscle-invasive urinary bladder cancer. Scand J Urol 2015; 49: 453-462 DOI: 10.3109/21681805.2015.1059880.
    CrossrefPubMedGoogle Scholar
  • 22 Rosenberg JE, O'Donnell PH, Balar AV. et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2019; 37: 2592-2600 DOI: 10.1200/JCO.19.01140.
    CrossrefPubMedGoogle Scholar
  • 23 Tagawa S, Faltas BM, Lam ET. et al. Sacituzumab govitecan (IMMU-132) in patients with previously treated urothelial cancer: results from a phase I/II study. Journal of Clinical Oncology 2019; 37 DOI: 10.1200/JCO.2019.37.7_suppl.354.
    CrossrefPubMedGoogle Scholar
  • 24 Loriot Y, Necchi A, Park SH. et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2019; 381: 338-348 DOI: 10.1056/NEJMoa1817323.
    CrossrefPubMedGoogle Scholar
  • 25 Grivas P, Mortazavi A, Picus J. et al. Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes. Cancer 2019; 125: 533-540 DOI: 10.1002/cncr.31817.
    CrossrefPubMedGoogle Scholar
  • 26 Juergens RA, Wrangle J, Vendetti FP. et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 2011; 1: 598-607 DOI: 10.1158/2159-8290.CD-11-0214.
    CrossrefPubMedGoogle Scholar
  • 27 Wrangle J, Wang W, Koch A. et al. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget 2013; 4: 2067-2079 DOI: 10.18632/oncotarget.1542.
    CrossrefPubMedGoogle Scholar
  • 28 Rose TL, Chism DD, Alva AS. et al. Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy. Br J Cancer 2018; 119: 801-807 DOI: 10.1038/s41416-018-0229-0.
    CrossrefPubMedGoogle Scholar