ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicInteraction of cell subtypes in tumor microenvironment, and implications for immunotherapy - Volume IIView all 5 articles
Liver Metastases in Advanced Urothelial Carcinoma (ARON-2): Do Pembrolizumab and Avelumab Make a Difference in a poor-prognosis scenario?
Provisionally accepted
Linda Cerbone1
Giandomenico Roviello2
Fabio Calabrò1Tarek Taha3
Enrique Grande4
Kirstin Binz5
Ravindran Kanesvaran6Alina Pirstuk7Ondřej Fiala8
Javier Molina-Cerrillo9Teresa Alonso-Gordoa9
Alessandro Rizzo10
Renate Pichler11
Zin W Myint12Alexandr Poprach13
Gaetano Facchini14
Bohuslav Melichar15
Hana Studentova15Franco Morelli16
Tomas Buchler17
Alessia Mennitto18
Deniz Tural19
Luigi Formisano20Inmaculada Orejana4
Martina Catalano2*
Sebastiano Buti21
Fernando Monteiro22Andrey Soares23
Shilpa Gupta24
Francesco Massari25Matteo Santoni26- 1IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy
- 2University of Florence, Florence, Italy
- 3The Royal Marsden NHS Foundation Trust, London, United Kingdom
- 4MD Anderson Cancer Center Madrid, Madrid, Spain
- 5The University of Kansas Cancer Center Kansas City, Kansas City, United States
- 6National University of Singapore, Singapore, Singapore
- 7Fakultni nemocnice v Motole, Prague, Czechia
- 8Univerzita Karlova Lekarska fakulta v Plzni, Pilsen, Czechia
- 9Hospital Universitario Ramon y Cajal, Madrid, Spain
- 10Istituto Tumori Bari Giovanni Paolo II IRCCS, Bari, Italy
- 11Medizinische Universitat Innsbruck, Innsbruck, Austria
- 12University of Kentucky School of Information Science, Lexington, United States
- 13Masarykuv onkologicky ustav, Brno, Czechia
- 14Ospedale Santa Maria delle Grazie, Pozzuoli, Italy
- 15Univerzita Palackeho v Olomouci Knihovna, Olomouc, Czechia
- 16Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- 17Ceska zemedelska univerzita v Praze, Prague, Czechia
- 18Azienda Ospedaliero Universitaria Maggiore della Carita, Novara, Italy
- 19Istanbul Universitesi Ilahiyat Fakultesi, Istanbul, Türkiye
- 20Universita degli Studi di Napoli Federico II Scuola di Medicina e Chirurgia, Naples, Italy
- 21Universita degli Studi di Parma, Parma, Italy
- 22Hospital Sirio-Libanes, São Paulo, Brazil
- 23Latin American Cooperative Oncology Group, Porto Alegre, Brazil
- 24Cleveland Clinic Taussig Cancer Center, Cleveland, United States
- 25IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico di Sant'Orsola, Bologna, Italy
- 26Ospedale di Macerata, Macerata, Italy
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Background: Over the past decade, the treatment landscape for metastatic urothelial carcinoma (mUC) has improved significantly with the introduction of immunotherapy, targeted agents, and antibody-drug conjugates. Median overall survival (mOS) has reached 36.7 months in cisplatin-eligible and 25.6 months in cisplatin-ineligible patients in the first-line setting, and over 10 months post-platinum failure. Liver metastases, however, remain a known poor prognostic factor. Methods: We conducted a retrospective analysis of mUC patients treated across 79 global institutions. Two cohorts were defined: Cohort 1 included patients who progressed after platinum-based therapy and received pembrolizumab; Cohort 2 included patients who received avelumab as maintenance. Treatments were administered between January 1, 2016, and October 31, 2024. Results: Cohort 1 (n=1341) had a mOS of 17.5 months. Patients without liver metastases had significantly longer OS than those with liver involvement (20.1 vs 9.4 months, p<0.001). Among liver metastases patients, OS was 11.8 months in males vs 5.8 months in females (p=0.066). OS was longer in those with BMI ≥25 kg/m² (14.1 vs 8.1 months, p=0.028) and better ECOG-PS (ECOG 0: 17.0 months; ECOG 1: 9.8; ECOG ≥2: 3.1; p<0.001). Cohort 2 (n=291) had a mOS of 25.8 months. Again, OS was longer in patients without liver metastases (27.0 vs 16.4 months, p<0.001). Among those with liver involvement, OS was 14.7 months in males and 20.0 in females (p=0.310). Patients with BMI ≥25 had non-reached OS versus 17.1 months in those with lower BMI (p<0.001). ECOG-PS remained a strong prognostic factor (NR for ECOG 0; 14.7 months for ECOG 1; 4.6 months for ECOG ≥2, p<0.001). Conclusion: Liver metastases are associated with significantly reduced survival in mUC patients receiving immunotherapy. However, both pembrolizumab and avelumab demonstrated improved
Keywords: avelumab, Immunothearpy, Liver metastasases, NCT05290038, Pembrolizumab, urothelial carcinoma
Received: 16 Jul 2025; Accepted: 02 Feb 2026.
Copyright: © 2026 Cerbone, Roviello, Calabrò, Taha, Grande, Binz, Kanesvaran, Pirstuk, Fiala, Molina-Cerrillo, Alonso-Gordoa, Rizzo, Pichler, Myint, Poprach, Facchini, Melichar, Studentova, Morelli, Buchler, Mennitto, Tural, Formisano, Orejana, Catalano, Buti, Monteiro, Soares, Gupta, Massari and Santoni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Martina Catalano
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