BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

2nd Propaedeutic Department of Internal Medicine ATTIKON University Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece

ASLCN2 Alba Bra Ospedale Michele E Pietro Ferrero Verduno CN Italy

Centro de Pesquisas Oncológicas CEPON Florianópolis SC Brazil

Centro Oncologico Estatal Dr José Luis Barrera Franco del ISSEMYM Toluca de Lerdo Mexico

Chair of Oncology Interdisciplinary Department of Medicine University of Bari Aldo Moro Bari Italy

Clínica AMO Salvador BA Brazil

Clinica de Oncologia Clion Salvador BA Brazil

Clinica Medica Especializada en Oncologia Medica Guatemala City Guatemala

Clinical Oncology Sociedad de Oncología y Hematología del Cesar Valledupar Colombia

Clinicas Medicas Especializadas NUCARE Guatemala City Guatemala

Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Biomedical Sciences Humanitas University Pieve Emanuele Milan Italy

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Genitourinary Medical Oncology and Clinical Pharmacology National Institute of Oncology Budapest Hungary

Department of Health Sciences Section of Clinical Pharmacology and Oncology University of Florence Viale Pieraccini 6 50139 Florence Italy

Department of Medical Oncology Bakirköy Dr SadiKonuk Training and Research Hospital Tevfik Saglam St No 11 Zuhuratbaba District Bakirkoy Istanbul Turkey

Department of Medical Oncology Centre Hospitalier de Jolimont Haine Saint Paul Belgium

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

Department of Medical Oncology Institut d'Investigació Biomèdica Sant Pau Hospital de la Santa Creu i Sant Pau Barcelona Spain

Department of Medical Oncology IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Department of Medical Oncology Maggiore Della Carità University Hospital 28100 Novara Italy

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

Department of Medical Oncology Università Politecnica Delle Marche AOU Ospedali Riuniti Delle Marche Ancona Italy

Department of Oncology and Radiotherapeutics Faculty of Medicine University Hospital in Pilsen Charles University Pilsen Czech Republic

Department of Oncology Hospital Sírio Libanês São Paulo SP Brazil

Department of Oncology IRCCS Humanitas Research Hospital Rozzano Milan Italy

Department of Oncology Radiotherapy Prof Dr Alexandru Trestioreanu Institute of Oncology Carol Davila; University of Medicine and Pharmacy Bucharest Romania

Department of Oncology San Camillo Forlanini Hospital Rome Italy

Department of Precision Medicine in Medical Surgical and Critical Care Section of Medical Oncology University of Palermo Via del Vespro 129 90127 Palermo Italy

Department of Radiological Oncological and Anatomo Pathological Science Sapienza University of Rome Viale Regina Elena 324 00185 Rome Italy

Department of Radiological Oncological and Pathological Sciences Policlinico Umberto 1 University of Rome SapienzaRome Italy

Department of Uro Oncology Maria Sklodowska Curie National Research Institute of Oncology Warsaw Warsaw Poland

Department of Urology Medical University of Innsbruck Anichstrasse 35 6020 Innsbruck Austria

Department of Urology Saitama Medical Center Saitama Medical University Saitama Japan

Department of Urology University Hospital Bonn 53127 Bonn Germany

Dipartimento di Oncologia Medica Fondazione IRCCS Istituto Nazionale Dei Tumori Milan Italy

Dipartimento Oncologico USL Sud Est Toscana Area Senese Località Campostaggia S N C 53036 Poggibonsi Italy

Division of Cancer Prevention and Genetics IEO European Institute of Oncology IRCCS Milan Italy

Division of Medical Oncology A O U Consorziale Policlinico Di Bari Piazza G Cesare 11 70124 Bari Italy

Fundacion Centro Oncologico de Integracion Regional COIR Mendoza Argentina

Hospital AC Camargo São Paulo SP Brazil

Hospital Angel Roffo Buenos Aires CABA Argentina

Hospital Beneficencia Portuguesa de São Paulo São Paulo SP Brazil

Hospital do Câncer Porto Dias Rede Mater Dei de Saúde Belém PA Brazil

Hospital Erasto Gaertner Curitiba PR Brazil

Hospital Israelita Albert Einstein São Paulo SP Brazil

Hospital Santa Casa de Sao Paulo São Paulo SP Brazil

Hospital São Rafael Oncologia D'Or Salvador BA Brazil

Hospital Sao Rafael Salvador BA Brazil

Hospital Sirio Libanês Brasília DF Brazil

Hospital Sirio Libanes Buenos Aires CABA Argentina

Instituto Alexander Fleming Buenos Aires CABA Argentina

Instituto D'Or de Ensino e Pesquisa Rio de Janeiro RJ Brazil

IRCCS Ospedale Policlinico San Martino Genoa Italy

Klinik für Urologie Ratzeburger Allee 160 23538 Lübeck Germany

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Markey Cancer Center University of Kentucky Lexington KY 40536 0293 USA

Medical Oncology 1 IRCCS Regina Elena National Cancer Institute Rome Italy

Medical Oncology 1 Unit Department of Oncology Istituto Oncologico Veneto IOV IRCCS 35128 Padova Italy

Medical Oncology Department La Paz University Hospital Madrid Spain

Medical Oncology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

Medical Oncology Unit Department of Medicine and Surgery University Hospital of Parma University of Parma Parma Italy

Medical Oncology Unit Gemelli Molise Hospital Università Cattolica del Sacro Cuore Campobasso Italy

Medical Oncology Unit Santa Chiara Hospital Trento Italy

Medicine and Pharmacy Faculty National Institute of Oncology Medical Oncology Unit Mohamed 5 University Rabat Morocco

National Cancer Centre Singapore Singapore Singapore

Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda Milan Italy

Oncologia D'Or Fortaleza CE Brazil

Oncologia Medica Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Oncologia Medica Ospedale Maggiore di Cremona Cremona Italy

Oncology Candiolo Cancer Institute IRCCS FPO 10060 Turin Italy

Oncology Institute of Vojvodina Faculty of Medicine University Novi Sad Novi Sad Serbia

Oncology Unit 2 University Hospital of Pisa 56126 Pisa Italy

Oncology Unit A R N A S Civico Palermo Italy

Oncology Unit Macerata Hospital via Santa Lucia 2 62100 Macerata Italy

ONCOR Life Medical Center Saltillo Mexico

Pontificia Universidade Católica do Rio Grande do Sul PUCRS Porto Alegre RS Brazil

Section of Oncology Department of Medicine University of Verona School of Medicine and Verona University Hospital Trust Verona Italy

Southampton Experimental Cancer Medicine Centre University of Southampton Southampton UK

Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico Don Tonino Bello 1 R C C S Istituto Tumori Giovanni Paolo 2 Viale Orazio Flacco 65 70124 Bari Italy

Unità di Oncologia Medica Azienda Ospedaliero Universitaria di Cagliari Cagliari Italy

Universidade Federal de Minas Gerais UFMG Belo Horizonte MG Brazil

University of Colorado Anschutz Medical Campus Aurora CO USA

UO Oncologia Azienda Ospedaliera Universitaria Renato Dulbecco PO Pugliese Ciaccio Catanzaro Catanzaro Italy

UOC di Oncologia Azienda Ospedaliera di Rilievo Nazionale Cardarelli di Napoli Naples Italy

UOC Oncologia Azienda Ospedaliera Ospedali Riuniti Marche Nord Fano Italy

UOC Oncologia Medica Ospedale A Murri Fermo Italy

Urologic Oncology Champalimaud Clinical Center 1400 038 Lisbon Portugal

Zobrazit více v PubMed

https://gco.iarc.fr/ Accessed on October 8th, 2022

Mohanty SK, Lobo A, Cheng L. The 2022 revision of World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges. Hum Pathol. 2022;S0046–8177(22):00224–226. PubMed

Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, et al. Annual report to the Nation on the status of cancer, part I: national cancer statistics. Cancer. 2018;124(13):2785–2800. doi: 10.1002/cncr.31551. PubMed DOI PMC

Mollica V, Rizzo A, Montironi R, Cheng L, Giunchi F, Schiavina R, et al. Current strategies and novel therapeutic approaches for metastatic urothelial carcinoma. Cancers (Basel) 2020;12(6):1449. doi: 10.3390/cancers12061449. PubMed DOI PMC

Powles T, Smith K, Stenzl A, Bedke J. Immune checkpoint inhibition in metastatic urothelial cancer. EurUrol. 2017;72:477–481. PubMed

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–1026. doi: 10.1056/NEJMoa1613683. PubMed DOI PMC

Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019;30(6):970–976. doi: 10.1093/annonc/mdz127. PubMed DOI PMC

Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1-Update and clarification: from the RECIST committee. Eur J Cancer. 2016;62:132–137. doi: 10.1016/j.ejca.2016.03.081. PubMed DOI PMC

van der Heijden MS, Loriot Y, Durán I, Ravaud A, Retz M, Vogelzang NJ, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma: a long-term overall survival and safety update from the phase 3 IMvigor211 clinical trial. Eur Urol. 2021;80(1):7–11. doi: 10.1016/j.eururo.2021.03.024. PubMed DOI

Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218–1230. doi: 10.1056/NEJMoa2002788. PubMed DOI

Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102–2114. doi: 10.1056/NEJMoa2034442. PubMed DOI PMC

Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, 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(34):3353–3360. doi: 10.1200/JCO.18.01148. PubMed DOI

Szabados B, Kockx M, Assaf ZJ, van Dam PJ, Rodriguez-Vida A, Duran I, et al. Final results of neoadjuvant atezolizumab in cisplatin-ineligible patients with muscle-invasive urothelial cancer of the bladder. Eur Urol. 2022;82(2):212–222. doi: 10.1016/j.eururo.2022.04.013. PubMed DOI

Meghani K, Cooley LF, Choy B, Kocherginsky M, Swaminathan S, Munir SS, et al. First-in-human intravesical delivery of pembrolizumab identifies immune activation in bladder cancer unresponsive to bacillus Calmette-Guérin. Eur Urol. 2022;82(6):602–610. doi: 10.1016/j.eururo.2022.08.004. PubMed DOI PMC

Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9–16. doi: 10.1038/bjc.2017.434. PubMed DOI PMC

Bellmunt J, de Wit R, Fradet Y, Climent MA, Petrylak DP, Lee JL, et al. Putative biomarkers of clinical benefit with pembrolizumab in advanced urothelial cancer: results from the KEYNOTE-045 and KEYNOTE-052 landmark trials. Clin Cancer Res. 2022;28(10):2050–2060. doi: 10.1158/1078-0432.CCR-21-3089. PubMed DOI

Lee KWC, Lord SJ, Kasherman L, Marschner I, Stockler M, Gralla R, et al. The impact of smoking on the effectiveness of immune checkpoint inhibitors - a systematic review and meta-analysis. Acta Oncol. 2020;59(1):96–100. doi: 10.1080/0284186X.2019.1670354. PubMed DOI

Hu D, Pang X, Luo J, Zhou J, Wang N, Tang H, et al. The correlation between the influencing factors and efficacy of immune checkpoint inhibitor therapy: an umbrella meta-analysis of randomized controlled trials. Ann Med. 2023;55(1):2215543. doi: 10.1080/07853890.2023.2215543. PubMed DOI PMC

Makrakis D, Talukder R, Lin GI, Diamantopoulos LN, Dawsey S, Gupta S, et al. Association between sites of metastasis and outcomes with immune checkpoint inhibitors in advanced urothelial carcinoma. Clin Genitourin Cancer. 2022;20(5):e440–e452. doi: 10.1016/j.clgc.2022.06.001. PubMed DOI PMC

Powles TB, Perez Valderrama B, Gupta S, Bedke J, Kikuchi E, Hoffman-censits J, et al. Ann Oncol. 2023;34(suppl_2):S1254–S1335.

Real-Life Impact of Enfortumab Vedotin or Chemotherapy in the Sequential Treatment of Advanced Urothelial Carcinoma: The ARON-2 Retrospective Experience

Pembrolizumab in Patients with Advanced Urothelial Carcinoma with ECOG Performance Status 2: A Real-World Study from the ARON-2 Project

Radiotherapy plus pembrolizumab for advanced urothelial carcinoma: results from the ARON-2 real-world study