Aktueller Stand der Immunonkologie bei urologischen Tumoren

Zusammenfassung

Immuncheckpoint-Inhibitoren etablieren sich derzeit als neue systemische Therapieoption (neben der Chemotherapie und der targeted Therapie) bei metastasierten Tumoren. Über eine (Re-)Aktivierung des Immunsystems können diese Antikörper zu eindrucksvollen, teils lang anhaltenden Remissionen führen. Bei den urologischen Tumoren wurden in diesem Jahr der PD-1-Antikörper Nivolumab (Opdivo^®) beim fortgeschrittenen Nierenzellkarzinom nach Vortherapie und in den USA Atezolizumab (Tecentriq^®) beim metastasierten Urothelkarzinom nach platinbasierter Chemotherapie zugelassen. Für Nivolumab wurden nach antiangiogenetischer Vortherapie eine höhere Remissionsrate (25 vs. 5%) und eine Verlängerung des Gesamtüberlebens um 5,4 Monate im Vergleich zu Everolimus nachgewiesen. Für das Urothelkarzinom nach platinbasierter Vortherapie zeigt sich im indirekten Vergleich zur Chemotherapie eine höhere Remissionsrate (15%) und 1-Jahres-Überlebensrate (37%) für Atezolizumab. Darüber hinaus zeichnen sich diese Therapien durch vergleichsweise geringe Nebenwirkungen aus. Bei einem Teil der Patienten kommt es aber zu sogenannten immunvermittelten Nebenwirkungen die rechtzeitig erkannt und behandelt werden müssen. Derzeit werden Immuncheckpoint-Inhibitoren in zahlreichen Phase-3-Studien geprüft und haben das Potenzial, die bisherigen Erstlinien-Standardtherapien bei metastasierten Tumoren, u. a. dem Urothel- und Nierenzellkarzinom abzulösen. Dabei werden auch Kombinationen aus PD-1/PD-L1-Antikörpern und CTLA4-Immuncheckpoint-Inhibitoren bzw. einer antiangiogenetischen Therapie geprüft. Auch die adjuvante Situation ist Gegenstand zulassungsrelevanter Studien.

Abstract

Immune checkpoint inhibitors are establishing itselves as a new systemic treatment option (in addition to chemotherapy and targeted therapy) for metastatic tumours. (Re)activating the immune system, these antibodies may lead to impressive remissions lasting for a long time in some patients. Regarding urological tumours, the anti-PD-1 antibody Nivolumab (Opdivo^®) has been approved this year for advanced, previously treated renal cell carcinoma. In the United States, Atezolizumab (Tecentriq^®) has been approved for metastatic urothelial carcinoma after platinum-based chemotherapy. In patients pre-treated with antiangiogenic drugs, Nivolumab has achieved a higher rate of remission (25 vs. 5%) and a 5.4-month increase in overall survival compared with Everolimus. An indirect comparison with chemotherapy demonstrates an increased remission rate (15%) and an increased 1-year survival rate (37%) for urothelial carcinoma after platinum-based chemotherapy with Atezolizumab. The frequency of side-effects resulting from these treatments is comparatively low. However, some patients experience what is called immune-mediated side-effects, which must be recognised and treated in a timely manner. Immune checkpoint inhibitors are being tested in numerous ongoing phase III clinical trials and have the potential to replace current first-line treatment options for metastatic tumours such as urothelial and renal cell carcinoma. These trials are also investigating anti-PD-1/anti-PD-L1 antibodies in combination with CTLA4 immune checkpoint inhibitors or antiangiogenic treatments. Approval trials are also investigating the role of immune checkpoint inhibitors in the adjuvant setting.

Schlüsselwörter

Immunonkologie - Immuncheckpoint-Inhibitoren - PD-1/PD-L1-Antikörper - CTLA4-Antikörper

Key words

immunooncology - immune checkpoint inhibitors - anti-PD-1/anti-PD-L1 antibody - anti-CTLA4 antibody

• Literatur

• 1 Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348: 56-61
• 2 Ribas A. Releasing the Brakes on Cancer Immunotherapy. N Engl J Med 2015; 373: 1490-1492
• 3 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264
• 4 Grimm MO, Winkler Y, Fetter I et al. Renaissance der Immunonkologie bei urologischen Tumoren. Der Urologe 2016; 55: 621-626
• 5 Oppel-Heuchel H, Grimm MO. Therapiemonitoring und Nebenwirkungsmanagement bei PD-1/PD-L1-Immuncheckpoint-Inhibition. Der Urologe 2016; 55: 677-690
• 6 Kwon ED, Drake CG, Scher HI et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700-712
• 7 Bristol-Myers Squibb. Press Release: Bristol-Myers Squibb Reports Second Quarter Financial Results. Im Internet: http://investor.bms.com/investors/news-and-events/press-releases/press-release-details/2015/Bristol-Myers-Squibb-Reports-Second-Quarter-Financial-Results/default.aspx
• 8 Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma (Checkmate 025). N Engl J Med 2015; 373: 1803-1813
• 9 McDermott DF, Motzer RJ, Atkins MB et al. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. J Clin Oncol 2016; 34 (suppl abstr 4507)
• 10 Apolo AB, Infante JR, Hamid O et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, and PD-L1 expression. J Clin Oncol 2016; 34 (suppl abstr 4514)
• 11 Massard C, Gordon MS, Sharma S et al. Safety and efficacy of durvalumab (MEDI4736), a PD-L1 antibody, in urothelial bladder cancer. J Clin Oncol 2016; 34 (suppl; abstr 4502)
• 12 Bellmunt J, Théodore C, Demkov T 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: 4454-4461
• 13 Dreicer R, Hoffman-Censits JH, Flaig TW et al. Updated efficacy and >1-y follow up from IMvigor210: Atezolizumab (atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma (mUC). J Clin Oncol 2016; 34 (suppl abstr 4515)
• 14 Balar AV, Galsky MD, Loriot Y et al. Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC): Primary analysis of IMvigor210 cohort 1. J Clin Oncol 2016; 34 (suppl abstr LBA4500)
• 15 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
• 16 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 Oncol 2016; 387: 1909-1920
• 17 Choueiri TK, Fishman MN, Escudier B et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC): Association of biomarkers with clinical outcomes. J Clin Oncol 2015; 33 (suppl abstr 4500)