Update Systemtherapie des Urothelkarzinoms – Therapie im Wandel

Zusammenfassung

Die systemische Behandlung des lokal fortgeschrittenen und metastasierten Urothelkarzinoms verändert sich seit wenigen Jahren in einem atemberaubenden Tempo. Zentraler Bestandteil der perioperativen Therapien und der Erstlinienbehandlung im metastasierten Stadium ist aber weiterhin die Platin-basierte Chemotherapie. Immuntherapien mit Immuncheckpoint-Inhibitoren sind inzwischen fester Bestandteil der Therapiealgorithmen. Neue, zielgerichtete Formen der Chemotherapie stehen kurz vor der Zulassung. Fortschritte beim Verständnis der molekulargenetischen Analyse von Tumorgewebe werden in Kürze personalisierte Therapieoptionen ermöglichen.

Der vorliegende Artikel soll einen Überblick über die aktuellen systemischen Therapieoptionen und die zugrunde liegende Datenbasis geben. Neue Entwicklungen sollen aufgezeigt werden, indem laufende Phase-III-Studien vorgestellt werden. Nach lesen des Artikels soll der Leser sich über den aktuellen Stand der systemischen Therapie des Urothelkarzinoms informiert fühlen.

Abstract

The systemic treatment of locally advanced and metastatic urothelial carcinoma has been changing at a breathtaking pace for a few years. However, platinum-based chemotherapy continues to be the central component of perioperative therapies and first-line treatment in the metastatic stage. Immunotherapies with immune checkpoint inhibitors are now an integral part of therapy algorithms. New targeted forms of chemotherapy are about to be approved. Advances in understanding the molecular genetic analysis of tumour tissue will soon enable personalised therapy options.

This article is intended to provide an overview of current systemic therapy options and the underlying database. New developments are identified by presenting ongoing phase III trials. After reading this article, the reader should feel informed about the current status of systemic therapy for urothelial carcinoma.

Schlüsselwörter

Urothelkarzinom - Blasenkarzinom - Tumore des oberen Harntrakts - Chemotherapie - Immuntherapie

Keywords

bladder cancer - upper tract urinary cancer - immunotherapy - urothelial cancer - perioperative therapy

Publikationsverlauf

Eingereicht: 20. September 2021

Angenommen nach Revision: 14. Februar 2022

Artikel online veröffentlicht:
28. März 2022

• Literatur

• 1 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms, Langversion 2.0, 2020, AWMF-Registrierungsnummer 032/038OL. https://www.leitlinienprogramm-onkologie.de/leitlinien/harnblasenkarzinom
• 2 EAU Guidelines. Edn. presented at the EAU Annual Congress Milan, 2021. ISBN 978–94–92671–13–4.
• 3 Necchi A, Anichini A, Raggi D. 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: 3353-3360 DOI: 10.1200/JCO.18.01148. (PMID: 30343614)
• 4 Necchi A, Raggi D, Gallina A. 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: 439-446 DOI: 10.1016/j.eururo.2019.10.026. (PMID: 31708296)
• 5 Powles T, Kockx M, Rodriguez-Vida A. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25: 1706-1714 DOI: 10.1038/s41591-019-0628-7. (PMID: 31686036)
• 6 van Dijk N, Gil-Jimenez A, Silina K. et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med 2020; 26: 1839-1844 DOI: 10.1038/s41591-020-1085-z. (PMID: 33046870)
• 7 Van Dorp J, Suelmann BBM, Mehra N. et al. LBA31 – High- vs low-dose pre-operative ipilimumab and nivolumab in locoregionally advanced urothelial cancer (NABUCCO cohort 2). Annals of Oncology 2021; 32 (Suppl. 05) S1283-S1346 DOI: 10.1016/annonc/annonc741.
• 8 Schmid S, Beckert F, Koll F. et al. 797TiP RACE IT: A prospective, single arm, multicenter, phase II-trial to assess safety and efficacy of preoperative radiation therapy before radical cystectomy combined with immunotherapy in locally advanced urothelial carcinoma of the bladder (AB 65/18). Annals of Oncology 2020; 31: S605 DOI: 10.1016/j.annonc.2020.08.2068.
• 9 Birtle A, Johnson M, Chester J. et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 2020; 395: 1268-1277 DOI: 10.1016/S0140-6736(20)30415-3. (PMID: 32145825)
• 10 Bellmunt J, Hussain M, Gschwend JE. et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021; 22: 525-537 DOI: 10.1016/S1470-2045(21)00004-8. (PMID: 33721560)
• 11 Vandekerkhove G, Lavoie JM, Annala M. et al. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer. Nat Commu 2021; 12: 184 DOI: 10.1038/s41467-020-20493-6. (PMID: 33420073)
• 12 Powles T, Assaf ZJ, Davarpanah N. et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021; 595: 432-437 DOI: 10.1038/s41586-021-03642-9. (PMID: 34135506)
• 13 Bajorin DF, Witjes JA, Gschwend JE. et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021; 384: 2102-2114 DOI: 10.1056/NEJMoa2034442. (PMID: 34077643)
• 14 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. (PMID: 16034041)
• 15 Galsky MD, Chen GJ, Oh WK. et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol 2012; 23: 406-410 DOI: 10.1093/annonc/mdr156. (PMID: 21543626)
• 16 Galsky MD, Hahn NM, Rosenberg J. et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol 2011; 29: 2432-2438 DOI: 10.1200/JCO.2011.34.8433. (PMID: 21555688)
• 17 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. J Clin Oncol 2012; 30: 191-199 DOI: 10.1200/JCO.2011.37.3571. (PMID: 22162575)
• 18 Powles T, Park SH, Voog E. et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020; 383: 1218-1230 DOI: 10.1056/NEJMoa2002788. (PMID: 32945632)
• 19 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. (PMID: 27939400)
• 20 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.
• 21 O'Donnell PH. 2021 ASCO Annual Meeting, Abstract 4508.
• 22 Galsky MD, Arija JÁA, Bamias A. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2020; 395: 1547-1557 DOI: 10.1016/S0140-6736(20)30230-0). (PMID: 32416780)
• 23 De Santis M, Grande E, Mencinger M. et al. IMvigor130 clinical trial in patients (pts) with metastatic urothelial carcinoma (mUC): Analysis of upper tract (UT) and lower tract (LT) subgroups. J Clin Oncol 2020; 38 (Suppl. 06) 551 DOI: 10.1200/JCO.2020.38.6_suppl.551.
• 24 Bamias A, De Santis M, Arranz JÁ. et al. 698O Patient-reported outcomes (PROs) from IMvigor130: A global, randomised, partially blinded phase III study of atezolizumab (atezo) + platinum-based chemotherapy (PBC) vs placebo (PBO) + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). Annals of Oncology 2020; 31 (Suppl. 04) S551-S552
• 25 Powles T, Csőszi T, Özgüroğlu M. et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22: 931-945 DOI: 10.1016/S1470-2045(21)00152-2. (PMID: 34051178)
• 26 Powles T, van der Heijden MS, Castellano D. 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; 21: 1574-1588 DOI: 10.1016/S1470-2045(20)30541-6. (PMID: 32971005)
• 27 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. (PMID: 31340094)
• 28 Siefker-Radtke AO, Necchi A, Park SH. et al. ERDAFITINIB in locally advanced or metastatic urothelial carcinoma (mUC): Long-term outcomes in BLC2001J Clin Oncol. 2020; 38 (Suppl. 15) 5015 DOI: 10.1016/S1470-2045(21)00660-4. (PMID: 35030333)
• 29 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. (PMID: 31356140)
• 30 Powles T, Rosenberg JE, Sonpavde GP. et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021; 384: 1125-1135 DOI: 10.1056/NEJMoa2035807.. (PMID: 33577729)
• 31 Tagawa ST, Balar AV, Petrylak DP. et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol 2021; 39: 2474-2485 DOI: 10.1200/JCO.20.03489.. (PMID: 33929895)