BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

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

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 Medical Oncology Bakirköy Dr Sadi Konuk Training and Research Hospital Zuhuratbaba District Tevfik Saglam St No 11 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 IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

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

Department of Oncology IRCCS Humanitas Research Hospital Rozzano Milan Italy

Department of Oncology San Camillo Forlanini Hospital Rome Italy

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

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

Division of Medical Oncology National Cancer Centre Singapore Singapore Singapore

Interdisciplinary Department of Medicine University of Bari Aldo Moro Bari 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 Unit Department of Oncology Istituto Oncologico Veneto IOV IRCCS 35128 Padua Italy

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Via Albertoni 15 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 Santa Chiara Hospital Trento Italy

Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda Milan Italy

Oncologia Medica Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Oncology and Hematology Department Hospital Santa Lucia SHLS 716 Cj C Brasília DF 70390 700 Brazil

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 Macerata Hospital Via Santa Lucia 2 62100 Macerata 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 Bari Italy

University of Colorado Cancer Center Anschutz Medical Campus Aurora CO USA

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

Urologic Oncology Champalimaud Clinical Center 1400 038 Lisbon Portugal

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