{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:11:49Z","timestamp":1778037109052,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T00:00:00Z","timestamp":1741219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck KGaA, Darmstadt, Germany","award":["ARL-010042"],"award-info":[{"award-number":["ARL-010042"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Platinum-based chemotherapy (PBC) followed by avelumab maintenance is a treatment option for patients with advanced urothelial carcinoma (aUC) patients. However, the optimal treatment sequencing in the era of antibody\u2013drug conjugates (ADCs) is yet to be determined. Recent studies suggest that the timing of immune checkpoint inhibitor (ICI) administration may impact patient outcomes, with a potential benefit from morning infusions. Methods: This retrospective study included 105 patients with aUC treated with avelumab in Portugal and intended to assess the safety and clinical outcomes (progression-free survival (PFS), overall survival (OS), and overall response rate (ORR)) and evaluate the impact of treatment timing (morning vs. afternoon) on patient outcomes. Results: The median follow-up from the start of avelumab was 17.7 months, the median PFS (mPFS) was 9.8 months (95% CI 4.9\u201314.7), and the median OS (mOS) was 39.5 months (95% CI 13.2\u201365.7). Immune-related adverse events (irAEs) were reported in 65.8% of patients, with 6.7% experiencing G3 irAEs. Among those who received a subsequent-line ADC upon disease progression (43%), the mOS from the start of avelumab was 23.1 months (95% CI 9.2\u201337.0). Multivariate analysis showed significant improvement in mOS with morning avelumab infusions (HR 0.35, 95% CI: 0.12\u20130.97, p = 0.042) and a trend towards improved mPFS (HR 0.43, 95% CI: 0.179\u20131.02, p = 0.055). Conclusions: This study confirms the clinical efficacy and safety of avelumab, showing improved outcomes over JAVELIN Bladder 100 and suggesting that morning infusions may offer a survival benefit in this context. Further research is needed to optimize treatment sequencing and explore the impact of infusion timing in ICI strategies.<\/jats:p>","DOI":"10.3390\/cancers17050898","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:02:13Z","timestamp":1741240933000},"page":"898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Avelumab Maintenance Therapy in Advanced Urothelial Carcinoma: Implications of Timing and Treatment Sequencing"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-5217","authenticated-orcid":false,"given":"Lisa","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Department of Oncology, Unidade Local de Sa\u00fade Santa Maria Lisboa, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal"}]},{"given":"Helena","family":"Guedes","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Gaia e Espinho, 4434-502 Vila Nova de Gaia, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5368-2410","authenticated-orcid":false,"given":"Ana Raquel","family":"Fortuna","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Algarve, 8000-386 Faro, Portugal"}]},{"given":"T\u00e2nia","family":"Lemos","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}]},{"given":"Jo\u00e3o","family":"Grama\u00e7a","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Arco Ribeirinho, 2834-003 Barreiro, Portugal"}]},{"given":"Natacha","family":"Mour\u00e3o","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Tr\u00e1s os Montes e Alto Douro, 5000-508 Vila Real, Portugal"}]},{"given":"Gon\u00e7alo","family":"Cunha","sequence":"additional","affiliation":[{"name":"IPO Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Rita","family":"Pichel","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Santo Ant\u00f3nio, 4099-001 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-7621","authenticated-orcid":false,"given":"Pedro","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Loures Odivelas, 2674-514 Loures, Portugal"}]},{"given":"Joana Alves","family":"Lu\u00eds","sequence":"additional","affiliation":[{"name":"Hospital dos Lus\u00edadas, 1500-458 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7059-1312","authenticated-orcid":false,"given":"Rita","family":"Freitas","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Amadora\/Sintra, 2720-276 Amadora, Portugal"}]},{"given":"In\u00eas","family":"Dun\u00f5es","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Alentejo Central, 7000-811 \u00c9vora, Portugal"}]},{"given":"Ana Sofia","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Oncology, Unidade Local de Sa\u00fade Santa Maria Lisboa, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3665-4666","authenticated-orcid":false,"given":"Joana","family":"Marinho","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade Gaia e Espinho, 4434-502 Vila Nova de Gaia, Portugal"}]},{"given":"Lu\u00eds","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Oncology, Unidade Local de Sa\u00fade Santa Maria Lisboa, Avenida Professor Egas Moniz, 1649-035 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"04109","DOI":"10.7189\/jogh.13.04109","article-title":"The global landscape of bladder cancer incidence and mortality in 2020 and projections to 2040","volume":"13","author":"Zhang","year":"2023","journal-title":"J. Glob. Health"},{"key":"ref_2","unstructured":"(2024, November 11). Cancer TODAY|IARC. Available online: https:\/\/gco.iarc.who.int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1200\/JCO.2000.18.17.3068","article-title":"Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study","volume":"18","author":"Hansen","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1200\/JCO.2011.34.8433","article-title":"Treatment of patients with metastatic urothelial cancer \u201cunfit\u201d for Cisplatin-based chemotherapy","volume":"29","author":"Galsky","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1200\/JCO.2011.37.3571","article-title":"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","volume":"30","author":"Bellmunt","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102198","DOI":"10.1016\/j.clgc.2024.102198","article-title":"Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor","volume":"22","author":"Bakaloudi","year":"2024","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1056\/NEJMoa2002788","article-title":"Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma","volume":"383","author":"Powles","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1200\/JCO.22.01792","article-title":"Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After \u22652 Years of Follow-Up","volume":"41","author":"Powles","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.annonc.2024.03.001","article-title":"ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma","volume":"35","author":"Powles","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1056\/NEJMoa2312117","article-title":"Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer","volume":"390","author":"Powles","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1056\/NEJMoa2309863","article-title":"Nivolumab plus Gemcitabine\u2013Cisplatin in Advanced Urothelial Carcinoma","volume":"389","author":"Heijden","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1146\/annurev-immunol-090122-050842","article-title":"Circadian Rhythms in Anticancer Immunity: Mechanisms and Treatment Opportunities","volume":"42","author":"Pick","year":"2024","journal-title":"Annu. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ejca.2023.01.007","article-title":"Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer","volume":"182","author":"Rousseau","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s10388-023-01006-y","article-title":"Timing of the infusion of nivolumab for patients with recurrent or metastatic squamous cell carcinoma of the esophagus influences its efficacy","volume":"20","author":"Nomura","year":"2023","journal-title":"Esophagus"},{"key":"ref_15","first-page":"A886","article-title":"848 Impact of immunotherapy time-of-day infusion on overall survival in patients with metastatic renal cell carcinoma","volume":"10","author":"Patel","year":"2022","journal-title":"J. ImmunoTherapy Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102220","DOI":"10.1016\/j.esmoop.2023.102220","article-title":"Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: A study-level meta-analysis","volume":"9","author":"Landre","year":"2024","journal-title":"ESMO Open"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9542","DOI":"10.1200\/JCO.2024.42.16_suppl.9542","article-title":"Retro TIMing: A multicentric retrospective analysis of immunotherapy timing in metastatic melanoma","volume":"42","author":"Goncalves","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41586-022-05605-0","article-title":"Dendritic cells direct circadian anti-tumor immune responses","volume":"614","author":"Wang","year":"2023","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1016\/j.cell.2024.04.015","article-title":"Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy","volume":"187","author":"Wang","year":"2024","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1158\/1541-7786.MCR-21-0786","article-title":"Diurnal Expression of PD-1 on Tumor-Associated Macrophages Underlies the Dosing Time-Dependent Antitumor Effects of the PD-1\/PD-L1 Inhibitor BMS-1 in B16\/BL6 Melanoma-Bearing Mice","volume":"20","author":"Tsuruta","year":"2022","journal-title":"Mol. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wu, Y., Tao, B., Zhang, T., Fan, Y., and Mao, R. (2019). Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates with T Cell Exhaustion. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02451"},{"key":"ref_22","first-page":"90","article-title":"Using the Common Terminology Criteria for Adverse Events (CTCAE\u2014Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies","volume":"112","author":"Santana","year":"2021","journal-title":"Actas Dermo-Sifiliogr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e16541","DOI":"10.1200\/JCO.2022.40.16_suppl.e16541","article-title":"Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?","volume":"40","author":"Ortego","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.clgc.2023.03.011","article-title":"Evaluating Real-World Characteristics of Patients With Advanced Urothelial Carcinoma Eligible for Avelumab Maintenance Therapy: A Multicountry Retrospective Medical Chart Review","volume":"21","author":"Bellmunt","year":"2023","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1200\/JCO.2023.41.6_suppl.471","article-title":"Full analysis from AVENANCE: A real-world study of avelumab first-line (1L) maintenance treatment in patients (pts) with advanced urothelial carcinoma (aUC)","volume":"41","author":"Barthelemy","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4566","DOI":"10.1200\/JCO.2024.42.16_suppl.4566","article-title":"Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in patients (pts) with low tumor burden","volume":"42","author":"Bellmunt","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1056\/NEJMoa2035807","article-title":"Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma","volume":"384","author":"Powles","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_29","unstructured":"Gilead (2024, October 15). Gilead Provides Update on Phase 3 TROPiCS-04 Study. Available online: https:\/\/www.gilead.com\/news\/news-details\/2024\/gilead-provides-update-on-phase-3-tropics-04-study."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1016\/S1470-2045(21)00546-5","article-title":"Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): A propensity score-matched analysis of a single-centre, longitudinal study","volume":"22","author":"Qian","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2217\/imt-2022-0139","article-title":"Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma","volume":"15","author":"Yeung","year":"2023","journal-title":"Immunotherapy"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Karaboue, A., Collon, T., Pavese, I., Bodiguel, V., Cucherousset, J., Zakine, E., Innominato, P.F., Bouchahda, M., Adam, R., and Levi, F. (2022). Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer. Cancers, 14.","DOI":"10.3390\/cancers14040896"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.annonc.2022.07.1851","article-title":"A multicentre study of pembrolizumab time-of-day infusion patterns and clinical outcomes in non-small-cell lung cancer: Too soon to promote morning infusions","volume":"33","author":"Cortellini","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e21126","DOI":"10.1200\/JCO.2022.40.16_suppl.e21126","article-title":"Time-of-day infusion of immunotherapy may impact outcomes in advanced non-small cell lung cancer patients (NSCLC)","volume":"40","author":"Barrios","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1200\/JCO.2023.41.6_suppl.678","article-title":"Association between time-of-day of the immune checkpoint inhibitor (ICI) infusion and disease outcomes among patients with metastatic renal cell carcinoma (mRCC)","volume":"41","author":"Dizman","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1200\/JCO.2023.41.6_suppl.681","article-title":"Does the time-of-day administration of immune checkpoint inhibitors affect efficacy in patients with metastatic renal cell carcinoma? A single-center study","volume":"41","author":"Aguado","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S835","DOI":"10.1016\/j.annonc.2021.08.1352","article-title":"967P The time of anti-PD-1 infusion improves survival outcomes by fasting conditions simulation in non-small cell lung cancer","volume":"32","author":"Vilalta","year":"2021","journal-title":"Ann. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/5\/898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:47:55Z","timestamp":1760028475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/5\/898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,6]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cancers17050898"],"URL":"https:\/\/doi.org\/10.3390\/cancers17050898","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,6]]}}}