Real-World Outcomes of Second-Line Pembrolizumab in Urothelial Carcinoma: A Multicenter Analysis from the Campania Oncological Network (ROC)

Real-World Outcomes of Second-Line Pembrolizumab in Urothelial Carcinoma: A Multicenter Analysis from the Campania Oncological Network (ROC) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-World Outcomes of Second-Line Pembrolizumab in Urothelial Carcinoma: A Multicenter Analysis from the Campania Oncological Network (ROC) Rosa Tambaro, Gabriele Calvanese, Andrea Muto, Luigi Formisano, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8651439/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background Platinum-based chemotherapy followed by second-line immunotherapy has been traditionally the standard of care for locally advanced or metastatic urothelial cancer (La/mUC). However, checkpoint inhibitors are remarkably reshaping the therapeutic landscape for urothelial cancer. Despite these advances, La/mUC remains a highly lethal disease with poor prognosis and limited therapeutic response. Moreover, discrepancies between clinical trial populations and real-world patients often result in different outcomes and toxicity profiles. In this context, oncology networks have become critical in generating Real-World Data (RWD), which can be translated into Real-World Evidence (RWE) to support clinical decision-making in everyday practice. We retrospectively analysed La/mUC patients treated with second-line pembrolizumab within the Campania Oncological Network (Rete Oncologica Campana, ROC). Patients and methods This multicenter retrospective study included adult patients (≥18 years) with histologically or cytologically confirmed La/mUC, who had previously received chemotherapy and were treated with Pembrolizumab (200 mg every three weeks) across six ROC centres. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results Between January 2021 and November 2023, 132 patients with La/mUC received at least one Pembrolizumab dose. The median age was 67 years (range 30–88), and most were male (73.5%). The majority had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (20.5%) or 1 (62.1%). Histologically, 115 patients (87.1%) had pure urothelial carcinoma, while 17 (12.9%) had rare urothelial carcinoma subtypes, including squamous, sarcomatoid/carcinosarcoma, micropapillary or nested variants. At the time of initial diagnosis, 45 (34.1%) patients presented with metastatic disease (stage IV), and 72 (54.5%) had undergone radical cystectomy. Metastatic sites included lymph nodes 98 (74.2%), lung 51 (38.6%), bones 45 (34.1%), and liver 21 (15.9%). After a median follow-up of 20 months (95% CI 12.7- 32.6), 108 patients (81.8%) experienced disease progression or death. Median PFS was 3.75 months (95% CI: 3.4 to 4.7), while median OS was 7.3 months (95% CI: 6.05–9.33). The ORR was 13.5% (95% CI: 7.4% - 19.7%), DCR was 33.9% (95% CI: 25.6%-42.0%). Among 17 patients with rare subtypes of urothelial carcinoma, the ORR was 23.5% (95% CI: 3.3% to 43.7%). Multivariate analysis revealed that metastatic disease at diagnosis (HR = 2.01, p = 0.02) and liver metastases (HR = 2.11, p = 0.02) were independently associated with increased mortality risk (Tab.3B). Lymph node-only metastases had a significantly lower risk of disease progression (HR = 0.46, p = 0.004) and death (HR = 0.52, p = 0.02). (). Univariate analysis indicated that prior cystectomy was associated with improved PFS (HR = 0.67, p = 0.04) and OS (HR = 0.54, p = 0.003), suggesting its role as a favourable prognostic factor in this cohort 16 (Tab 3A and 3B). A total of 114 treatment-related AEs were reported, with 79.8% being grade 1–2 and 20.2% grade 3–4. No treatment-related deaths occurred. Pembrolizumab was discontinued in 7.6% of patients due to AEs. The most common events were asthenia (20.0%), pruritus (10.0%), and myalgia (7.0%). Conclusions This real-world analysis supports the clinical applicability of second-line Pembrolizumab in La/mUC, demonstrating efficacy and acceptable safety. Prognostic indicators, including metastatic sites and prior cystectomy, significantly impacted outcomes. These findings highlight the value of oncology networks in generating real-world evidence to refine treatment approaches Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Bladder cancer (BC) is the ninth most commonly diagnosed cancer worldwide, with 614,298 new cases and an age-standardised incidence rate (ASR) of 5.6 in 2022 1 . The incidence rises with age, and it is four times higher in men than in women 2 . In Europe, ASRs are 60.5 per 100,000 in men and 14.1 in women, with 165,684 new cases 3 . Italy reports higher rates: 84.8 in men and 18.5 in women (34,850 cases), with Campania showing the highest regional incidence (ASR 88.4 in men, 15.6 in women). Alongside lung and liver cancers, BC is one of the most common cancers in Campania 4 . Globally, BC ranks 13th in cancer mortality, with 220,596 deaths in 2022 and an ASR of 1.81 1 . Europe reported 67,289 deaths (ASR 17.8 in men, 3.7 in women) 3 , while Italy recorded 6,108 deaths (ASR 18.0 in men, 3.4 in women). Campania again exceeded national averages. The five-year survival rate is 79% in Italy and 76.5% in Campania 4 . Smoking remains the most significant modifiable risk factor, contributing to over 50% of cases 5 . Other established risks include poor diet, inactivity, exposure to aromatic amines, schistosomiasis, hair dyes, and water contaminants 6 . Additional factors are adverse drug reactions, geographic differences, and socioeconomic status 7 , 8 . Up to 95% of BCs are urothelial carcinomas (UCs), with subtypes such as conventional UC, micropapillary, and squamous variants, the latter associated with worse prognosis 9 , 10 . Urothelial carcinomas of the upper urinary tract (UTUC) represent 5–10% of cases, with a poorer prognosis than bladder UC. Standard of care for early UTUC includes radical nephroureterectomy (RNU), followed by intravesical or systemic chemotherapy depending on pathological staging 11 . Approximately 70% of BC cases are diagnosed as non-muscle-invasive bladder cancer (NMIBC), limited to the mucosa 7 . NMIBC is stratified into risk categories based on features such as size, grade, multifocality, and presence of carcinoma in situ 12 – 14 . Treatment consists of transurethral resection (TURB) and risk-adapted intravesical therapy. Muscle-invasive bladder cancer (MIBC) accounts for about 25% of UC cases. For cisplatin-eligible patients (based on Galsky’s criteria 15 ), the standard treatment is neoadjuvant chemotherapy with Durvalumab and Cisplatin, followed by radical cystectomy and lymphadenectomy, and maintenance Durvalumab 20 . Adjuvant Nivolumab or cisplatin-based chemotherapy may be considered in non-perioperative treated, high-risk patients (pT3, pT4, or N+) 14 . Recently, the CheckMate-274 trial showed that 1 year of adjuvant Nivolumab improved disease-free and overall survival, especially in PD-L1–positive patients 18 , 19 . While < 5% of BCs are metastatic at diagnosis, up to 50% of patients treated for MIBC relapse within two years 21 The treatment landscape for metastatic UC (mUC) has evolved significantly. First-line standards now include Enfortumab Vedotin (EV) plus Pembrolizumab, platinum-based chemotherapy followed by avelumab maintenance, or the combination of Nivolumab with Cisplatin and Gemcitabine for cisplatin-eligible patients 22 . For years, no global standard existed after platinum failure. Agents such as paclitaxel, docetaxel 23 , 24 , and vinflunine 25 , 26 were commonly used. The KEYNOTE-045 trial established Pembrolizumab as superior to chemotherapy in overall survival (10.3 vs 7.4 months; HR 0.73) and response rate (21% vs 11%), with fewer grade 3–4 toxicities 27 , 28 . A 5-year follow-up confirmed durable benefit 29 . Based on this, the FDA and EMA approved Pembrolizumab as a second-line treatment after platinum failure, independently of PD-L1 status. Despite its efficacy, Pembrolizumab introduces a new spectrum of immune-related toxicities that require proactive management. Furthermore, clinical trials often exclude patients with poor performance status, comorbidities, or prior malignancies 30 , limiting generalizability. This study aims to evaluate real-world outcomes of Pembrolizumab in platinum-refractory UC, with a focus on efficacy and safety. PATIENTS AND METHODS Study population A retrospective study was conducted within the ROC, promoted by the Istituto Nazionale Tumori—IRCCS—Fondazione "G. Pascale" in Naples, Italy, and approved by the local Ethics Committee. The study was performed in accordance with the revised version of the Declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000). Data were collected for patients aged 18 years or older, with a histological diagnosis of metastatic urothelial carcinoma who received Pembrolizumab 200 mg every 3 weeks, up to unacceptable toxicity or disease progression, after first-line platinum-based chemotherapy or recurring within <12 months since adjuvant or neoadjuvant chemotherapy. All patients provided written informed consent. Evaluation of outcomes RECIST 1.1 criteria were used to assess tumour response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The following parameters were collected: causes of treatment discontinuation, comorbidities, progression-free survival (PFS), overall survival (OS), objective response rate (ORR, defined as the sum of CR and PR) and treatment-related toxicities. Adverse events (AEs) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Statistical analysis Demographic and clinical data were analysed using descriptive statistical analysis. Categorical variables were presented in terms of frequencies and proportions,either the means or standard deviation or median and interquartile ranges (IQRs) according to their distribution, as assessed by the Shapiro-Wilk normality test, were used for continuous variables. To assess patient prognosis, we used Progression-Free Survival (PFS) and Overall Survival (OS) as primary outcomes. The inverse Kaplan-Meier method was used to estimate the median follow-up time. PFS was calculated from the start of Pembrolizumab treatment until evidence of PD or death, whichever occurs first. OS was calculated from the start of Pembrolizumab treatment to death or censoring at the last follow-up. Survival times were analysed using the Kaplan–Meier method. ORR and DCR were reported as percentages. A multivariate Cox regression model, based on baseline clinical characteristics of patients (Histology, Gender, Sites of Metastases, and Body Mass Index (BMI)), yielded adjusted Hazard Ratios (HRs). To assess the prognosis according to Response to Pembrolizumab, patients who exhibited CR or PR as best response were considered as Responders, patients who exhibited SD or PD were considered as Non-Responders and PFS and OS were used as outcomes The differences in prognosis between responders and non-responders were tested using the log-rank test, and the results were displayed using Kaplan-Meier curves. The analyses were performed using the software R (version 4.3.3). Ethical Approval This study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Results From January 2021 to November 2023, 132 patients treated with at least one dose of pembrolizumab were enrolled across six centres in the Campania Oncology Network. Baseline characteristics are summarised in Table 1. Median age was 67 years (IQR 30–89), 73.5% were male, and 38.6% had ECOG ≥1. Pure urothelial carcinoma was present in 115 patients (87.1%); the remaining had mixed or variant histologies (e.g., sarcomatoid, micropapillary, nested). At diagnosis, 45 patients (34.1%) had stage IV disease. The most frequent metastatic sites were lymph nodes (74.2%), lung (38.6%), bone (34.1%), and liver (15.9%). Disease progression (PD) was the primary cause of treatment discontinuation (74.2%), followed by adverse events (AEs) in 7.6%. At the time of analysis, 24 patients (18.9%) were still undergoing treatment. Among those who discontinued Pembrolizumab, 23 patients received subsequent anticancer therapies as follows: 10 patients received Paclitaxel, 7 patients started Vinflunine, 2 patients initiated Enfortumab Vedotin, 2 patients began Erdafitinib, 1 patient received Docetaxel, and 1 patient received Carboplatin. Median follow-up, calculated via reverse Kaplan-Meier, was 20 months (95% CI 12.7- 32.6). Overall, 108 patients (81.8%) experienced progression or death. Median PFS was 3.75 months (95% CI: 3.38–4.73), and median OS was 7.29 months (95% CI: 6.05–9.33) (Figures 1A–1B). ORR was 13.5% (95% CI: 7.4–19.7), including 3 complete responses and 13 partial responses. Disease control rate (DCR) was 33.9% (95% CI: 25.6–42.0) (Table 2). Subgroup analysis by histology showed an ORR of 10.8% and DCR of 31.5% in pure urothelial carcinoma (n=115), compared to 23.5% and 29.4% in patients with mixed/variant histologies (n=17), respectively. Univariate analysis identified cystectomy as protective for both PFS (HR 0.67; p=0.04) and OS (HR 0.54; p=0.003), while metastatic disease at diagnosis was associated with worse outcomes (PFS: HR 1.79; p=0.03; OS: HR 2.23; p<0.005) (Tables 3A, 3B, Figure 2, 3). Although not statistically significant, male sex (HR 1.15; p=0.08) and bone metastases (HR 1.40; p=0.09) showed trends toward worse PFS. In multivariate analysis (Tables 3A–3B), metastatic disease at diagnosis was associated with borderline worse PFS (HR 1.69; p=0.053) and significantly reduced OS (HR 2.01; p=0.02). Liver metastases were independently associated with poor OS (HR 2.11; p=0.02), while lymph node metastases were linked to improved outcomes (PFS: HR 0.46; p=0.004; OS: HR 0.52; p=0.02). Overall, 114 any grade adverse events occurred, where 91 (79.8%) were G1-G2, and 23 (20.2%) were G3-G4 AEs. No treatment-related AEs resulted in death. Ten (7.6%) patients discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were asthenia (20.0%), itching (10.0%), and myalgias (7.0%). As shown in Fig. 4, the overall safety profile was characterised by a predominance of grade 1–2 adverse events, with no treatment-related deaths. Discussion Our retrospective, multicenter real-world study in the Campania Oncology Network (ROC) represents a real-world evaluation that adds to the growing body of evidence supporting pembrolizumab as an effective and well-tolerated second-line therapy in patients with advanced or metastatic urothelial carcinoma (UC). This work is essential because real-world clinical cohorts tend to include patients who are more heterogeneous and fragile than those typically enrolled in rigorous registration trials. In this unselected population, our study reported a median overall survival (OS) of 7.29 months and a median progression-free survival (PFS) of 3.75 months. The numerically lower efficacy compared to the data from the Phase III KEYNOTE-045 trial 28, 29 , which led to the drug's approval, reflects the nuanced differences in our regional population characteristics and broader patient eligibility. In comparison, the pivotal phase III KEYNOTE-045 trial 28, 29 reported a median OS of 10.3 months and PFS of 2.1 months and an Objective Response Rate (ORR) of 21% compared to 13.5% in our study. This difference reflects real-world conditions. Our cohort included a significant proportion of patients with a poorer ECOG performance status (≥1 in 38.6% of our patients), an advanced median age of 67 years, a higher proportion of patients with visceral metastases (including liver: 15.9% and bone: 34.1%), and fewer exclusions based on comorbidities or prior therapies. These factors are often excluded or underrepresented in clinical trials but are known predictors of a less favourable prognosis. Our study, therefore, does not negate the drug's efficacy but realistically defines its value in a more fragile and representative population.Yet the study’s disease control rate (DCR) of 33.9% supports pembrolizumab's role in stabilising disease, particularly in a less-selectively recruited population. Our findings also compare consistently with the large-scale global ARON-2 study by Massari et al. 31, which included 836 patients across 23 countries and reported a median OS of 10.5 months and PFS of 6.2 months. Their ORR was notably higher at 31%, possibly reflecting a more heterogeneous global cohort and inclusion of patients relapsing post-adjuvant/neoadjuvant therapy (cohort B), who showed better outcomes than those progressing during first-line treatment (14.6 vs 9.1 months OS, respectively). In our cohort, all patients were treated in a strictly platinum-refractory setting, likely aligning more closely with ARON-2’s cohort A, where the ORR was 29% and OS was 9.1 months. The prognostic factor analysis yielded critical insights for risk stratification and treatment optimisation. Metastatic disease at diagnosis, liver, and bone metastases were associated with worse outcomes, consistent with both Santoni et al. and ARON-2 findings. 32 Liver metastatic involvement emerged as the most powerful independent predictor of negative outcome in the multivariate analysis (OS: HR 2.11; p=0.02), consistent with both Santoni 32 et al. and the ARON-2 findings 31 . This finding supports the biological notion that liver metastases often indicate a disease with higher aggressiveness and a particularly immunosuppressive tumour microenvironment, which hinders the efficacy of checkpoint inhibitors. In contrast, primary lymph node involvement resulted in a significant protective factor for outcomes (PFS: HR 0.46; OS: HR 0.52). This result suggests that disease predominantly limited to the lymph node compartment, compared to visceral disease, has a less aggressive biology, and perhaps it is a more fertile ground for triggering an effective immune response. Lymph nodes, being key sites for immune activation, may facilitate antigen presentation and the success of immunotherapy. This subgroup, therefore, represents the population that derives the greatest and most durable benefit from pembrolizumab therapy. The numerically higher ORR in patients with mixed/variant histologies (23.5%) compared to pure urothelial carcinoma (10.8%), although in a limited cohort, is consistent with the hypothesis that these variants may harbour a higher tumour mutational burden (TMB), making them particularly targetable by immunotherapy. However, given the small sample size and the absence of a significant survival advantage, this observation should be considered hypothesis-generating and requires validation in larger studies." Furthermore, prior radical cystectomy seems to be a significant protective factor (OS: HR 0.54). This likely reflects a patient selection with originally less advanced disease and better general health, allowing for a longer follow-up. Importantly, the ARON-2 study 31 developed a prognostic scoring system based on ECOG ≥2, liver/bone metastases, and line of pembrolizumab therapy. Patients with all adverse factors had a median OS of just 4.1 months, compared to 29.4 months in those without any. While our study did not formally stratify patients using this model, our data showed similar trends, highlighting the urgent need for predictive tools to guide immunotherapy use more precisely in clinical practice. In our study, the observed safety profile was consistent with known data, with the majority of adverse events (AEs) classified as Grade 1-2. The low rate of treatment discontinuation due to AEs (7.6%) confirms that, in an experienced oncology centre, immune-mediated toxicities (irAEs) are manageable. The documentation of subsequent therapies after pembrolizumab failure is also important. The predominance of standard chemotherapies (paclitaxel and vinflunine) still reflects the standard of practice during the enrollment period, particularly in regions such as ours, where third-line agents like EV were limited during data collection. The emergence of innovative-targeted treatments like enfortumab vedotin and erdafitinib indicates that the therapeutic landscape is rapidly evolving. Moreover, the phase III EV-302/KEYNOTE-A39 trial 22 results will likely influence future sequencing strategies. Despite the importance of the real-world data generated, this study has limitations inherent to its retrospective design, potential selection bias, and lack of centralised radiological review. The relatively small sample size, particularly for patients with variant histologies or subsequent therapies, also limits the generalizability of subgroup analyses. However, the multicenter design and representation of a real-world population (often underrepresented in randomised controlled trials) strengthen its relevance. Although the median follow-up duration was calculated using the reverse Kaplan-Meier method ( 20.0 months), the variability across the six centres and the relatively short enrollment period may lead to heterogeneity in the follow-up data. Analyses conducted on specific subgroups, particularly those referred to the variant histology (n=17) or various subsequent treatments, are limited by the small number of patients. Conclusions drawn from these subgroups, such as the higher ORR in variant histologies, must be considered as hypothesis generating and require validation in larger cohort studies. Despite these limitations, the strength of our study lies in its ability to capture the daily clinical reality of a large Italian region, providing essential survival data and identifying valuable prognostic factors for the management of platinum-refractory metastatic urothelial carcinoma. Conclusion This regional real-world study confirms the clinical utility of pembrolizumab as a second-line treatment for platinum-refractory UC, including in patients with poor performance status and variant histologies. Prognostic factors such as liver and bone metastases, ECOG status, and surgical history should guide treatment decisions. In light of evolving standards such as EV + pembrolizumab in first-line therapy, continued generation of real-world data is crucial to contextualise these developments and inform practice, especially in resource-limited settings. Ultimately, this real-world study provides the basis for designing prospective studies focused on tumour biology, predictive biomarkers, and optimal therapeutic sequences to maximise survival across all subgroups of mUC patients. Abbreviations La/mUC: locally advanced or metastatic urothelial carcinoma; ROC: Campania Oncological Network (Rete Oncologica Campana); PFS: progression-free survival; OS: overall survival; ORR: objective response rate; DCR: disease control rate; ECOG: Eastern Cooperative Oncology Group; AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events. Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale” of Naples (registration number 32/22 oss, 19 Oct 2022). Written informed consent to participate in the study was obtained from all individual participants included in the study. CONSENT FOR PUBLICATION Not Applicable. AVAILABILITY OF DATA AND MATERIALS The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. COMPETING INTERESTS The authors declare that they have no competing interests. FUNDING This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ACKNOWLEDGEMENTS Not applicable. AUTHOR CONTRIBUTIONS DECLARATIONS Conceptualization: Rosa Tambaro; Methodology: Rosa Tambaro; Data curation: Elisabetta Coppola, Davide Limongello; Investigation: Rosa Tambaro; Formal analysis: Elisabetta Coppola; Writing – Original Draft: Rosa Tambaro; Writing – Review & Editing: Rosa Tambaro, Gabriele Calvanese, Andrea Muto, Luigi Formisano, Giuseppe Lorenzo, Carlo Buonerba, Davide Bosso, Francesco Sabbatino, Elisabetta Coppola, Marilena Napoli, Sabrina Rossetti, Carmela Pisano, Sabrina Chiara Cecere, Anna Passarelli, Jole Ventriglia, Lorenzo Lobianco, Davide Limongello, Erica Perri, Mariarosaria Lamia, Chiara D’Alessio, Roberto Contieri, Florinda Feroce, Sandro Pignata; Project administration: Rosa Tambaro; Resources: Davide Limongello; Software: Elisabetta Coppola; Visualization: Davide Limongello; Validation: Rosa Tambaro; Supervision: Sandro Pignata. All authors have read and approved the final manuscript. DECLARATION OF INTEREST STATEMENT The authors declare no conflicts of interest related to the content of this manuscript. No financial or personal relationships have influenced the work. The study was conducted without external commercial funding. All authors have reviewed and approved the final manuscript FUNDING SOURCE This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2024;74:229–63. Ploeg M, Aben KKH, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27:289–93. 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Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. ANN ONCOL. 2013;24:1466–72. Bellmunt J, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376:1015–26. Fradet Y, 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;30:970–6. Bellmunt J, et al. Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial. JCO. 2021;39:4532–4532. Franklin JM, Schneeweiss S. When and How Can Real World Data Analyses Substitute for Randomized Controlled Trials? Clin Pharmacol Ther. 2017;102:924–33. Francesco, Massari et al. Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study C ancer Immunol Immunother 2024;73(6):106. doi: 10.1007/s 00262-024-03682-w Matteo Santoni, et al., Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study. Cancer Immunol Immunother2023;72(9):2961–70. doi: 10.1007/s00262-023-03469-5. .Epub 2023 May 29. Tables Table 1. Baseline Characteristics of the Study Population (N = 132) Summary of baseline demographic, clinical and pathological features of the enrolled patients. Characteristic N (%) or Median (Range) Age, years 67.0 (30.0 – 89.0) ≤ 65 years 58 (43.9%) > 65 years 74 (56.1%) Sex Male 97 (73.5%) Female 35 (26.5%) Comorbidities Hypertension 52 (39.4%) Cardiovascular disease 31 (23.5%) Diabetes 18 (13.6%) Metabolic disease 13 (9.8%) Kidney disease 6 (4.5%) Lung disease 5 (3.8%) Previous hepatitis 4 (3.0%) Cystectomy performed 72 (54.5%) Histology Urothelial 115 (87.1%) Minor/mixed variants 17 (12.9%) Metastatic disease 45 (34.1%) Site of metastasis Lymph nodes 98 (74.2%) Lung 51 (38.6%) Liver 21 (15.9%) Bones 45 (34.1%) Peritoneal carcinomatosis 7 (5.3%) Brain 6 (4.5%) Body Mass Index (BMI) ≤ 25 kg/m² 44 (33.3%) > 25 kg/m² 76 (57.6%) Missing 12 (9.1%) ECOG Performance Status ECOG 0 25 (18.9%) ECOG ≥ 1 51 (38.6%) Unknown 56 (42.4%) Table 2. Response Outcomes in the overall population and by Histological Subtype Distribution of best tumour response and disease control following pembrolizumab treatment in the overall cohort and by histological subtype. Outcome Overall (n=132) Urothelial (n=115) Minor or mixed variants (n=17) ORR, % (95% CI) 13.5% (7.4%–19.7%) 10.8% (5.0%–16.6%) 23.5% (3.3%–43.7%) DCR, % (95% CI) 33.9% (25.6%–42.0%) 31.5% (23.0%–40.0%) 29.4% (7.8%–51.0%) CR, n (%) 3 (2.5%) 2 (1.8%) 1 (5.9%) PR, n (%) 13 (11.0%) 10 (9.0%) 3 (17.6%) SD, n (%) 24 (20.3%) 23 (20.7%) 1 (5.9%) PD, n (%) 78 (66.1%) 66 (59.4%) 12 (70.6%) Not evaluable 14 14 0 Table 3A.Univariate and Multivariate Cox Regression Analysis PFS Association between baseline clinical variables and progression-free survival as assessed by univariate and multivariate Cox regression analysis . HR Univ. (95% CI) p Univ. HR Multiv. (95% CI) p Multiv. Age >65 yrs. 1.01 (0.69-1.48) 0.95 - - Gender: Male 1.15 (0.66–2.03) 0.08 - - N. of Comorbidities ≥1 1.01 (0.68-1.51) 0.94 - - Cystectomy performed 0.67 (0.46-0.98) 0.04 0.92 (0.58-1.48) 0.79 Histology: Pure urothelial carcinoma 1.21 (0.67-2.15) 0.52 - - BMI ≤ 25 kg/m² 1.37 (0.91-2.05) 0.13 - - Brain metastases 0.55 (0.22-1.38) 0.20 - - Bone metastases 1.40 (0.94-2.07) 0.09 - - Lung metastases 1.27 (0.86-1.89) 0.22 - - Lymph nodal metastases 0.77 (0.50-1.19) 0.24 0.46 (0.27-0.78) 0.004 Liver metastases 1.14 (0.69-1.90) 0.59 1.63 (0.92-2.90) 0.09 Carcinosis 1.44 (0.58-3.57) 0.79 - - Metastatic disease at diagnosis 1.79 (1.21-2.64) 0.03 1.69 (0.99-2.89) 0.053 Table 3B. Univariate and Multivariate Cox Regression Analysis of OS Association between baseline clinical variables and overall survival as assessed by univariate and multivariate Cox regression analysis. HR Univ. (95% CI) p Univ. HR Multiv. (95% CI) p Multiv. Age >65 yrs. 1.13 (0.75-1.71) 0.54 - - Gender: Male 1.23 (0.79–1.96) 0.39 - - N. of Comorbidities ≥1 0.79 (0.52-1.20) 0.28 - - Cystectomy performed 0.54 (0.36-0.81) 0.003** 0.72 (0.43-1.20) 0.21 Histology: Pure urothelial carcinoma 1.39 (0.72-2.69) 0.32 - - BMI ≤ 25 kg/m² 0.88 (0.56-1.39) 0.60 - - Brain metastases 0.47 (0.17-1.29) 0.14 - - Bone metastases 1.33 (0.84-1.93) 0.18 - - Lung metastases 1.28 (0.86-1.89) 0.24 - - Lymph nodal metastases 0.74 (0.48-1.67) 0.20 0.52 (0.29-0.92) 0.02** Liver metastases 1.48 (0.86-2.54) 0.15 2.11 (1.13-3.92) 0.02** Carcinosis 0.93 (0.29-2.97) 0.91 - - Metastatic disease at diagnosis 2.23 (1.47-3.37) <0.005** 2.01 (1.11-3.66) 0.02** Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Mar, 2026 Reviews received at journal 26 Mar, 2026 Reviewers agreed at journal 23 Mar, 2026 Reviewers agreed at journal 20 Mar, 2026 Reviews received at journal 16 Mar, 2026 Reviews received at journal 27 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers agreed at journal 13 Feb, 2026 Reviewers invited by journal 11 Feb, 2026 Editor assigned by journal 09 Feb, 2026 Editor invited by journal 09 Feb, 2026 Submission checks completed at journal 06 Feb, 2026 First submitted to journal 06 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8651439","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":592380228,"identity":"0e464263-b697-4d9c-b545-e20c833aa184","order_by":0,"name":"Rosa Tambaro","email":"data:image/png;base64,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","orcid":"","institution":"Istituto Nazionale Tumori IRCCS \"Fondazione G. 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The incidence rises with age, and it is four times higher in men than in women \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. In Europe, ASRs are 60.5 per 100,000 in men and 14.1 in women, with 165,684 new cases\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Italy reports higher rates: 84.8 in men and 18.5 in women (34,850 cases), with Campania showing the highest regional incidence (ASR 88.4 in men, 15.6 in women). Alongside lung and liver cancers, BC is one of the most common cancers in Campania\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGlobally, BC ranks 13th in cancer mortality, with 220,596 deaths in 2022 and an ASR of 1.81\u003csup\u003e1\u003c/sup\u003e. Europe reported 67,289 deaths (ASR 17.8 in men, 3.7 in women)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, while Italy recorded 6,108 deaths (ASR 18.0 in men, 3.4 in women). Campania again exceeded national averages. The five-year survival rate is 79% in Italy and 76.5% in Campania\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSmoking remains the most significant modifiable risk factor, contributing to over 50% of cases\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Other established risks include poor diet, inactivity, exposure to aromatic amines, schistosomiasis, hair dyes, and water contaminants\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Additional factors are adverse drug reactions, geographic differences, and socioeconomic status\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUp to 95% of BCs are urothelial carcinomas (UCs), with subtypes such as conventional UC, micropapillary, and squamous variants, the latter associated with worse prognosis\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Urothelial carcinomas of the upper urinary tract (UTUC) represent 5\u0026ndash;10% of cases, with a poorer prognosis than bladder UC. Standard of care for early UTUC includes radical nephroureterectomy (RNU), followed by intravesical or systemic chemotherapy depending on pathological staging \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eApproximately 70% of BC cases are diagnosed as non-muscle-invasive bladder cancer (NMIBC), limited to the mucosa \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. NMIBC is stratified into risk categories based on features such as size, grade, multifocality, and presence of carcinoma in situ \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Treatment consists of transurethral resection (TURB) and risk-adapted intravesical therapy.\u003c/p\u003e \u003cp\u003eMuscle-invasive bladder cancer (MIBC) accounts for about 25% of UC cases.\u003c/p\u003e \u003cp\u003eFor cisplatin-eligible patients (based on Galsky\u0026rsquo;s criteria\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e), the standard treatment is neoadjuvant chemotherapy with Durvalumab and Cisplatin, followed by radical cystectomy and lymphadenectomy, and maintenance Durvalumab\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Adjuvant Nivolumab or cisplatin-based chemotherapy may be considered in non-perioperative treated, high-risk patients (pT3, pT4, or N+)\u003csup\u003e14\u003c/sup\u003e. Recently, the CheckMate-274 trial showed that 1 year of adjuvant Nivolumab improved disease-free and overall survival, especially in PD-L1\u0026ndash;positive patients\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile\u0026thinsp;\u0026lt;\u0026thinsp;5% of BCs are metastatic at diagnosis, up to 50% of patients treated for MIBC relapse within two years\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe treatment landscape for metastatic UC (mUC) has evolved significantly. First-line standards now include Enfortumab Vedotin (EV) plus Pembrolizumab, platinum-based chemotherapy followed by avelumab maintenance, or the combination of Nivolumab with Cisplatin and Gemcitabine for cisplatin-eligible patients\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor years, no global standard existed after platinum failure. Agents such as paclitaxel, docetaxel\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, and vinflunine\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e were commonly used. The KEYNOTE-045 trial established Pembrolizumab as superior to chemotherapy in overall survival (10.3 vs 7.4 months; HR 0.73) and response rate (21% vs 11%), with fewer grade 3\u0026ndash;4 toxicities\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. A 5-year follow-up confirmed durable benefit\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Based on this, the FDA and EMA approved Pembrolizumab as a second-line treatment after platinum failure, independently of PD-L1 status.\u003c/p\u003e \u003cp\u003eDespite its efficacy, Pembrolizumab introduces a new spectrum of immune-related toxicities that require proactive management. Furthermore, clinical trials often exclude patients with poor performance status, comorbidities, or prior malignancies\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, limiting generalizability.\u003c/p\u003e \u003cp\u003eThis study aims to evaluate real-world outcomes of Pembrolizumab in platinum-refractory UC, with a focus on efficacy and safety.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003ch2\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eA retrospective study was conducted within the ROC, promoted by the Istituto Nazionale Tumori—IRCCS—Fondazione \"G. Pascale\" in Naples, Italy, and approved by the local Ethics Committee. The study was performed in accordance with the revised version of the Declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000). Data were collected for patients aged 18 years or older, with a histological diagnosis of metastatic urothelial carcinoma\u0026nbsp;who received Pembrolizumab 200 mg every 3 weeks, up to unacceptable toxicity or disease progression, after first-line platinum-based chemotherapy or recurring within \u0026lt;12 months since adjuvant or neoadjuvant chemotherapy. All patients provided written informed consent.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eEvaluation of outcomes\u0026nbsp;\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eRECIST 1.1 criteria were used to assess tumour response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The following parameters were collected: causes of treatment discontinuation, comorbidities, progression-free survival (PFS), overall survival (OS), objective response rate (ORR, defined as the sum of CR and PR) and treatment-related toxicities. Adverse events (AEs) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eDemographic and clinical data were analysed using descriptive statistical analysis. Categorical variables were presented in terms of frequencies and proportions,either the means or standard deviation or median and interquartile ranges (IQRs) according to their distribution, as assessed by the Shapiro-Wilk normality test, were used for continuous variables.\u003c/p\u003e\n\u003cp\u003eTo assess patient prognosis, we used Progression-Free Survival (PFS) and Overall Survival (OS) as primary outcomes. The inverse Kaplan-Meier method was used to estimate the median follow-up time. PFS was calculated from the start of Pembrolizumab treatment until evidence of PD or death, whichever occurs first. OS was calculated from the start of Pembrolizumab treatment to death or censoring at the last follow-up. Survival times were analysed using the Kaplan–Meier method. ORR and DCR were reported as percentages. A multivariate Cox regression model, based on baseline clinical characteristics of patients (Histology, Gender, Sites of Metastases, and Body Mass Index (BMI)), yielded adjusted Hazard Ratios (HRs).\u003c/p\u003e\n\u003cp\u003eTo assess the prognosis according to Response to Pembrolizumab, patients who exhibited CR or PR as best response were considered as Responders, patients who exhibited SD or PD were considered as Non-Responders and PFS and OS were used as outcomes\u003c/p\u003e\n\u003cp\u003eThe differences in prognosis between responders and non-responders were tested using the log-rank test, and the results were displayed using Kaplan-Meier curves. The analyses were performed using the software R (version 4.3.3).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThis study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom January 2021 to November 2023, 132 patients treated with at least one dose of pembrolizumab were enrolled across six centres in the Campania Oncology Network.\u003c/p\u003e\n\u003cp\u003eBaseline characteristics are summarised in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMedian age was 67 years (IQR 30–89), 73.5% were male, and 38.6% had ECOG ≥1. Pure urothelial carcinoma was present in 115 patients (87.1%); the remaining had mixed or variant histologies (e.g., sarcomatoid, micropapillary, nested).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt diagnosis, 45 patients (34.1%) had stage IV disease. The most frequent metastatic sites were lymph nodes (74.2%), lung (38.6%), bone (34.1%), and liver (15.9%). Disease progression (PD) was the primary cause of treatment discontinuation (74.2%), followed by adverse events (AEs) in 7.6%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the time of analysis, 24 patients (18.9%) were still undergoing treatment. Among those who discontinued Pembrolizumab, 23 patients received subsequent anticancer therapies as follows: 10 patients received Paclitaxel, 7 patients started Vinflunine, 2 patients initiated Enfortumab Vedotin, 2 patients began Erdafitinib, 1 patient received Docetaxel, and 1 patient received Carboplatin.\u003c/p\u003e\n\u003cp\u003eMedian follow-up, calculated via reverse Kaplan-Meier, was 20 months (95% CI 12.7- 32.6). Overall, 108 patients (81.8%) experienced progression or death. Median PFS was 3.75 months (95% CI: 3.38–4.73), and median OS was 7.29 months (95% CI: 6.05–9.33) (Figures 1A–1B). ORR was 13.5% (95% CI: 7.4–19.7), including 3 complete responses and 13 partial responses. Disease control rate (DCR) was 33.9% (95% CI: 25.6–42.0) (Table 2). Subgroup analysis by histology showed an ORR of 10.8% and DCR of 31.5% in pure urothelial carcinoma (n=115), compared to 23.5% and 29.4% in patients with mixed/variant histologies (n=17), respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnivariate analysis identified cystectomy as protective for both PFS (HR 0.67; p=0.04) and OS (HR 0.54; p=0.003), while metastatic disease at diagnosis was associated with worse outcomes (PFS: HR 1.79; p=0.03; OS: HR 2.23; p\u0026lt;0.005) (Tables 3A, 3B, Figure 2, 3).\u003c/p\u003e\n\u003cp\u003eAlthough not statistically significant, male sex (HR 1.15; p=0.08) and bone metastases (HR 1.40; p=0.09) showed trends toward worse PFS. In multivariate analysis (Tables 3A–3B), metastatic disease at diagnosis was associated with borderline worse PFS (HR 1.69; p=0.053) and significantly reduced OS (HR 2.01; p=0.02). Liver metastases were independently associated with poor OS (HR 2.11; p=0.02), while lymph node metastases were linked to improved outcomes (PFS: HR 0.46; p=0.004; OS: HR 0.52; p=0.02).\u003c/p\u003e\n\u003cp\u003eOverall, 114 any grade adverse events occurred, where 91 (79.8%) were G1-G2, and 23 (20.2%) were G3-G4 AEs. No treatment-related AEs resulted in death. Ten (7.6%) patients discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were asthenia (20.0%), itching (10.0%), and myalgias (7.0%). As shown in Fig. 4, the overall safety profile was characterised by a predominance of grade 1–2 adverse events, with no treatment-related deaths.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur retrospective, multicenter real-world study in the Campania Oncology Network (ROC) represents a real-world evaluation that adds to the growing body of evidence supporting pembrolizumab as an effective and well-tolerated second-line therapy in patients with advanced or metastatic urothelial carcinoma (UC).\u003c/p\u003e\n\u003cp\u003eThis work is essential because real-world clinical cohorts tend to include patients who are more heterogeneous and fragile than those typically enrolled in rigorous registration trials.\u003c/p\u003e\n\u003cp\u003eIn this unselected population, our study reported a median overall survival (OS) of 7.29 months and a median progression-free survival (PFS) of 3.75 months.\u003c/p\u003e\n\u003cp\u003eThe numerically lower efficacy compared to the data from the Phase III KEYNOTE-045 trial\u003csup\u003e28, 29\u003c/sup\u003e, which led to the drug's approval, reflects the nuanced differences in our regional population characteristics and broader patient eligibility. In comparison, the pivotal phase III KEYNOTE-045 trial\u003csup\u003e28, 29\u003c/sup\u003e reported a median OS of 10.3 months and PFS of 2.1 months and an Objective\u0026nbsp;Response Rate (ORR) of 21% compared to 13.5% in our study. This difference reflects real-world conditions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur cohort included a significant proportion of patients with a poorer ECOG performance status (≥1 in 38.6% of our patients), an advanced median age of 67 years, a higher proportion of patients with visceral metastases (including liver: 15.9% and bone: 34.1%), and fewer exclusions based on comorbidities or prior therapies. These factors are often excluded or underrepresented in clinical trials but are known predictors of a less favourable prognosis. Our study, therefore, does not negate the drug's efficacy but realistically defines its value in a more fragile and representative population.Yet the study’s disease control rate (DCR) of 33.9% supports pembrolizumab's role in stabilising disease, particularly in a less-selectively recruited population.\u003c/p\u003e\n\u003cp\u003eOur findings also compare consistently with the large-scale global ARON-2 study by Massari et al.\u003csup\u003e31,\u003c/sup\u003e which included 836 patients across 23 countries and reported a median OS of 10.5 months and PFS of 6.2 months. Their ORR was notably higher at 31%, possibly reflecting a more heterogeneous global cohort and inclusion of patients relapsing post-adjuvant/neoadjuvant therapy (cohort B), who showed better outcomes than those progressing during first-line treatment (14.6 vs 9.1 months OS, respectively). In our cohort, all patients were treated in a strictly platinum-refractory setting, likely aligning more closely with ARON-2’s cohort A, where the ORR was 29% and OS was 9.1 months.\u003c/p\u003e\n\u003cp\u003eThe prognostic factor analysis yielded critical insights for risk stratification and treatment optimisation. Metastatic disease at diagnosis, liver, and bone metastases were associated with worse outcomes, consistent with both Santoni et al. and ARON-2 findings.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eLiver metastatic involvement emerged as the most powerful independent predictor of negative outcome in the multivariate analysis (OS: HR 2.11; p=0.02),\u0026nbsp;consistent with both Santoni \u003csup\u003e32\u003c/sup\u003eet al. and the ARON-2 findings\u003csup\u003e31\u003c/sup\u003e.\u0026nbsp;This finding supports the biological notion that liver metastases often indicate a disease with higher aggressiveness and a particularly immunosuppressive tumour microenvironment, which hinders the efficacy of checkpoint inhibitors.\u003c/p\u003e\n\u003cp\u003eIn contrast, primary lymph node involvement resulted in a significant protective factor for outcomes (PFS: HR 0.46; OS: HR 0.52). This result suggests that disease predominantly limited to the lymph node compartment, compared to visceral disease, has a less aggressive biology, and perhaps it is a more fertile ground for triggering an effective immune response. Lymph nodes, being key sites for immune activation, may facilitate antigen presentation and the success of immunotherapy. This subgroup, therefore, represents the population that derives the greatest and most durable benefit from pembrolizumab therapy.\u003c/p\u003e\n\u003cp\u003eThe numerically higher ORR in patients with mixed/variant histologies (23.5%) compared to pure urothelial carcinoma (10.8%), although in a limited cohort, is consistent with the hypothesis that these variants may harbour a higher tumour mutational burden (TMB), making them particularly targetable by immunotherapy.\u0026nbsp;However, given the small sample size and the absence of a significant survival advantage, this observation should be considered hypothesis-generating and requires validation in larger studies.\"\u003c/p\u003e\n\u003cp\u003eFurthermore, prior radical cystectomy seems to be a significant protective factor (OS: HR 0.54). This likely reflects a patient selection with originally less advanced disease and better general health, allowing for a longer follow-up.\u003c/p\u003e\n\u003cp\u003eImportantly, the ARON-2 study\u003csup\u003e31\u003c/sup\u003edeveloped a prognostic scoring system based on ECOG ≥2, liver/bone metastases, and line of pembrolizumab therapy. Patients with all adverse factors had a median OS of just 4.1 months, compared to 29.4 months in those without any. While our study did not formally stratify patients using this model, our data showed similar trends, highlighting the urgent need for predictive tools to guide immunotherapy use more precisely in clinical practice.\u003c/p\u003e\n\u003cp\u003eIn our study, the observed safety profile was consistent with known data, with the majority of adverse events (AEs) classified as Grade 1-2. The low rate of treatment discontinuation due to AEs (7.6%) confirms that, in an experienced oncology centre, immune-mediated toxicities (irAEs) are manageable.\u003c/p\u003e\n\u003cp\u003eThe documentation of subsequent therapies after pembrolizumab failure is also important. The predominance of standard chemotherapies (paclitaxel and vinflunine) still reflects the standard of practice during the enrollment period, particularly in regions such as ours, where third-line agents like EV were limited during data collection.\u003c/p\u003e\n\u003cp\u003eThe emergence of innovative-targeted treatments like enfortumab vedotin and erdafitinib indicates that the therapeutic landscape is rapidly evolving. Moreover, the phase III EV-302/KEYNOTE-A39\u0026nbsp;trial\u003csup\u003e22\u003c/sup\u003e results will likely influence future sequencing strategies.\u003c/p\u003e\n\u003cp\u003eDespite the importance of the real-world data generated, this study has limitations inherent to its retrospective design, potential selection bias, and lack of centralised radiological review.\u003c/p\u003e\n\u003cp\u003eThe relatively small sample size, particularly for patients with variant histologies or subsequent therapies, also limits the generalizability of subgroup analyses. However, the multicenter design and representation of a real-world population (often underrepresented in randomised controlled trials) strengthen its relevance.\u003c/p\u003e\n\u003cp\u003eAlthough the median follow-up duration was calculated using the reverse Kaplan-Meier method\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003e20.0 months), the variability across the six centres and the relatively short enrollment period may lead to heterogeneity in the follow-up data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalyses conducted on specific subgroups, particularly those referred to the variant histology (n=17) or various subsequent treatments, are limited by the small number of patients. Conclusions drawn from these subgroups, such as the higher ORR in variant histologies, must be considered as hypothesis generating and require validation in larger cohort studies.\u003c/p\u003e\n\u003cp\u003eDespite these limitations, the strength of our study lies in its ability to capture the daily clinical reality of a large Italian region, providing essential survival data and identifying valuable prognostic factors for the management of platinum-refractory metastatic urothelial carcinoma.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis regional real-world study confirms the clinical utility of pembrolizumab as a second-line treatment for platinum-refractory UC, including in patients with poor performance status and variant histologies. Prognostic factors such as liver and bone metastases, ECOG status, and surgical history should guide treatment decisions. In light of evolving standards such as EV + pembrolizumab in first-line therapy, continued generation of real-world data is crucial to contextualise these developments and inform practice, especially in resource-limited settings.\u003c/p\u003e\n\u003cp\u003eUltimately, this real-world study provides the basis for designing prospective studies focused on tumour biology, predictive biomarkers, and optimal therapeutic sequences to maximise survival across all subgroups of mUC patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLa/mUC: locally advanced or metastatic urothelial carcinoma;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ROC: Campania Oncological Network (Rete Oncologica Campana);\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PFS: progression-free survival;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;OS: overall survival;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ORR: objective response rate;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DCR: disease control rate;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ECOG: Eastern Cooperative Oncology Group;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AE: adverse event;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CTCAE: Common Terminology Criteria for Adverse Events.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Istituto Nazionale Tumori IRCCS \u0026ldquo;Fondazione G. Pascale\u0026rdquo; of Naples (registration number 32/22 oss, 19 Oct 2022).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten informed consent to participate in the study was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS DECLARATIONS\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;\u003cstrong\u003eConceptualization:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eMethodology:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eData curation:\u003c/strong\u003e Elisabetta Coppola, Davide Limongello;\u003cbr\u003e\u003cstrong\u003eInvestigation:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eFormal analysis:\u003c/strong\u003e Elisabetta Coppola;\u003cbr\u003e\u003cstrong\u003eWriting \u0026ndash; Original Draft:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eWriting \u0026ndash; Review \u0026amp; Editing:\u003c/strong\u003e Rosa Tambaro, Gabriele Calvanese, Andrea Muto, Luigi Formisano, Giuseppe Lorenzo, Carlo Buonerba, Davide Bosso, Francesco Sabbatino, Elisabetta Coppola, Marilena Napoli, Sabrina Rossetti, Carmela Pisano, Sabrina Chiara Cecere, Anna Passarelli, Jole Ventriglia, Lorenzo Lobianco, Davide Limongello, Erica Perri, Mariarosaria Lamia, Chiara D\u0026rsquo;Alessio, Roberto Contieri, Florinda Feroce, Sandro Pignata;\u003cbr\u003e\u003cstrong\u003eProject administration:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eResources:\u003c/strong\u003e Davide Limongello;\u003cbr\u003e\u003cstrong\u003eSoftware:\u003c/strong\u003e Elisabetta Coppola;\u003cbr\u003e\u003cstrong\u003eVisualization:\u003c/strong\u003e Davide Limongello;\u003cbr\u003e\u003cstrong\u003eValidation:\u003c/strong\u003e Rosa Tambaro;\u003cbr\u003e\u003cstrong\u003eSupervision:\u003c/strong\u003e Sandro Pignata.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDECLARATION OF INTEREST STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest related to the content of this manuscript.\u003c/p\u003e\n\u003cp\u003eNo financial or personal relationships have influenced the work. The study was conducted without external commercial funding. All authors have reviewed and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING SOURCE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2024;74:229\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePloeg M, Aben KKH, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27:289\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eECIS - European Cancer Information System | ECIS. - European Cancer Information System. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ecis.jrc.ec.europa.eu/\u003c/span\u003e\u003cspan address=\"https://ecis.jrc.ec.europa.eu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRegistro Tumori Regione Campania-Registro regionale Tumori-Regione Campania. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.regione.campania.it/regione/it/tematiche/registro-regionale-tumori/registro-tumori-regione-campania\u003c/span\u003e\u003cspan address=\"https://www.regione.campania.it/regione/it/tematiche/registro-regionale-tumori/registro-tumori-regione-campania\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFreedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association Between Smoking and Risk of Bladder Cancer Among Men and Women. JAMA. 2011;306:737\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurger M, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63:234\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkali Z, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66:4\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePelucchi C, Bosetti C, Negri E, Malvezzi M. La Vecchia, C. Mechanisms of disease: The epidemiology of bladder cancer. Nat Clin Pract Urol. 2006;3:327\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGill E, Perks CM. Mini-Review: Current Bladder Cancer Treatment\u0026mdash;The Need for Improvement. Int J Mol Sci. 2024;25:1557.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEckstein M, et al. Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes. Eur Urol Oncol. 2024;7:128\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoumigui\u0026eacute; M, et al. French AFU Cancer Committee Guidelines - Update 2024\u0026ndash;2026: Upper urinary tract urothelial cancer (UTUC). Fr J Urol. 2024;34:102722.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGontero P et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ)-A Summary of the 2024 Guidelines Update \u003cem\u003eEur Urol\u003c/em\u003e 2024;86(6):531\u0026ndash;549. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eururo.2024.07\u003c/span\u003e\u003cspan address=\"http://10.1016/j.eururo.2024.07\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003cem\u003e027. Epub 2024 Aug 17.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Ann Oncol. 2022;33:244\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang SS, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196:1021\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalsky MD et al. Treatment of Patients With Metastatic Urothelial Cancer Unfit for Cisplatin-Based Chemotherapy. \u003cem\u003eJCO\u003c/em\u003e 29, 2432\u0026ndash;2438 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVale CL. Neoadjuvant Chemotherapy in Invasive Bladder Cancer: Update of a Systematic Review and Meta-Analysis of Individual Patient Data: Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol. 2005;48:202\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBajorin DF, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384:2102\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalsky MD, et al. Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274. J Clin Oncol. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.24.00340\u003c/span\u003e\u003cspan address=\"10.1200/JCO.24.00340\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, et al. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. N Engl J Med. 2024;391:1773\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHemenway G, et al. Advancements in Urothelial Cancer Care: Optimizing Treatment for Your Patient. Am Soc Clin Oncol Educ Book. 2024;44:e432054.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTBPowles T et al. Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial Ann Oncol 2025Oct;36(10):1212\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2025.05.536\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2025.05.536\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2025 Jun 1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOing C, et al. Second Line Chemotherapy for Advanced and Metastatic Urothelial Carcinoma: Vinflunine and Beyond-A Comprehensive Review of the Current Literature. J Urol. 2016;195:254\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaggi D, et al. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27:49\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, 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\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, et al. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. ANN ONCOL. 2013;24:1466\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376:1015\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFradet Y, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of \u0026gt;\u0026thinsp;2 years of follow-up. Ann Oncol. 2019;30:970\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, et al. Pembrolizumab (pembro) versus investigator\u0026rsquo;s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial. JCO. 2021;39:4532\u0026ndash;4532.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranklin JM, Schneeweiss S. When and How Can Real World Data Analyses Substitute for Randomized Controlled Trials? Clin Pharmacol Ther. 2017;102:924\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancesco, Massari et al. Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study C\u003cem\u003eancer Immunol Immunother\u003c/em\u003e 2024;73(6):106. doi: 10.1007/s\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e00262-024-03682-w\u003c/span\u003e\u003cspan address=\"http://00262-024-03682-w\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatteo Santoni, et al., Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study. Cancer Immunol Immunother2023;72(9):2961\u0026ndash;70. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00262-023-03469-5.\u003c/span\u003e\u003cspan address=\"10.1007/s00262-023-03469-5.\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.Epub 2023 May 29.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Characteristics of the Study Population (N = 132)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSummary of baseline demographic, clinical and pathological features of the enrolled patients.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN (%) or Median (Range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67.0 (30.0 \u0026ndash; 89.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026le; 65 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e58 (43.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026gt; 65 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e74 (56.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e97 (73.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e35 (26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52 (39.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Cardiovascular disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31 (23.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (13.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Metabolic disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13 (9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Kidney disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Previous hepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCystectomy performed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Urothelial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e115 (87.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Minor/mixed variants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17 (12.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMetastatic disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e45 (34.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSite of metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e98 (74.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e51 (38.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21 (15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Bones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e45 (34.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Peritoneal carcinomatosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Brain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBody Mass Index (BMI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026le; 25 kg/m\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e44 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026gt; 25 kg/m\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e76 (57.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Missing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eECOG Performance Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; ECOG 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25 (18.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; ECOG \u0026ge; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e51 (38.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56 (42.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Response Outcomes in the overall population and by Histological Subtype\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDistribution of best tumour response and disease control following pembrolizumab treatment in the overall cohort and by histological subtype.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (n=132)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrothelial (n=115)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMinor or mixed variants (n=17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eORR, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e13.5% (7.4%\u0026ndash;19.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e10.8% (5.0%\u0026ndash;16.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e23.5% (3.3%\u0026ndash;43.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eDCR, % (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e33.9% (25.6%\u0026ndash;42.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e31.5% (23.0%\u0026ndash;40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e29.4% (7.8%\u0026ndash;51.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eCR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e3 (2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e13 (11.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e10 (9.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e3 (17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSD, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e24 (20.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e23 (20.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePD, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e78 (66.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e66 (59.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e12 (70.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eNot evaluable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 158px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3A.Univariate and Multivariate Cox Regression Analysis PFS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssociation between baseline clinical variables and progression-free survival as assessed by univariate and multivariate Cox regression analysis\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHR Univ. (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003ep Univ.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eHR Multiv. (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003ep Multiv.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge \u0026gt;65 yrs.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.01 (0.69-1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender: Male\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.15 (0.66\u0026ndash;2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN. of Comorbidities \u0026ge;1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.01 (0.68-1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCystectomy performed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0.67 (0.46-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.92 (0.58-1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology: Pure urothelial carcinoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.21 (0.67-2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI \u0026le; 25 kg/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.37 (0.91-2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBrain metastases\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0.55 (0.22-1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.40 (0.94-2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.27 (0.86-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph nodal metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0.77 (0.50-1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0.46 (0.27-0.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.14 (0.69-1.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.63 (0.92-2.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCarcinosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.44 (0.58-3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 255px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic disease at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1.79 (1.21-2.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1.69 (0.99-2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3B. Univariate and Multivariate Cox Regression Analysis of OS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssociation between baseline clinical variables and overall survival as assessed by univariate and multivariate Cox regression analysis.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR Univ. (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep Univ.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR Multiv. (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep Multiv.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge \u0026gt;65 yrs.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.13 (0.75-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender: Male\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.23 (0.79\u0026ndash;1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN. of Comorbidities \u0026ge;1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.79 (0.52-1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCystectomy performed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.54 (0.36-0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.72 (0.43-1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology: Pure urothelial carcinoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.39 (0.72-2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI \u0026le; 25 kg/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.88 (0.56-1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBrain metastases\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.47 (0.17-1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.33 (0.84-1.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.28 (0.86-1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph nodal metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.74 (0.48-1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.52 (0.29-0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e1.48 (0.86-2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e2.11 (1.13-3.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCarcinosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e0.93 (0.29-2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 242px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic disease at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e2.23 (1.47-3.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.005**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 124px;\"\u003e\n \u003cp\u003e2.01 (1.11-3.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8651439/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8651439/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlatinum-based chemotherapy followed by second-line immunotherapy has been traditionally the standard of care for locally advanced or metastatic urothelial cancer (La/mUC). However, checkpoint inhibitors are remarkably reshaping the therapeutic landscape for urothelial cancer.\u003c/p\u003e\n\u003cp\u003eDespite these advances, La/mUC remains a highly lethal disease with poor prognosis and limited therapeutic response. Moreover, discrepancies between clinical trial populations and real-world patients often result in different outcomes and toxicity profiles. In this context, oncology networks have become critical in generating Real-World Data (RWD), which can be translated into Real-World Evidence (RWE) to support clinical decision-making in everyday practice. We retrospectively analysed La/mUC patients treated with second-line pembrolizumab within the Campania Oncological Network (Rete Oncologica Campana, ROC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter retrospective study included adult patients (≥18 years) with histologically or cytologically confirmed La/mUC, who had previously received chemotherapy and were treated with Pembrolizumab (200 mg every three weeks) across six ROC centres. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween January 2021 and November 2023, 132 patients with La/mUC received at least one Pembrolizumab dose. The median age was 67 years (range 30–88), and most were male (73.5%). The majority had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (20.5%) or 1 (62.1%). Histologically, 115 patients (87.1%) had pure urothelial carcinoma, while 17 (12.9%) had rare urothelial carcinoma subtypes, including squamous, sarcomatoid/carcinosarcoma, micropapillary or nested variants. At the time of initial diagnosis, 45 (34.1%) patients presented with metastatic disease (stage IV), and 72 (54.5%) had undergone radical cystectomy. Metastatic sites included lymph nodes 98 (74.2%), lung 51 (38.6%), bones 45 (34.1%), and liver 21 (15.9%). After a median follow-up of 20 months (95% CI 12.7- 32.6), 108 patients (81.8%) experienced disease progression or death. Median PFS was 3.75 months (95% CI: 3.4 to 4.7), while median OS was 7.3 months (95% CI: 6.05–9.33). The ORR was 13.5% (95% CI: 7.4% - 19.7%), DCR was 33.9% (95% CI: 25.6%-42.0%). Among 17 patients with rare subtypes of urothelial carcinoma, the ORR was 23.5% (95% CI: 3.3% to 43.7%).\u003c/p\u003e\n\u003cp\u003eMultivariate analysis revealed that metastatic disease at diagnosis (HR = 2.01, p = 0.02) and liver metastases (HR = 2.11, p = 0.02) were independently associated with increased mortality risk (Tab.3B). Lymph node-only metastases had a significantly lower risk of disease progression (HR = 0.46, p = 0.004) and death (HR = 0.52, p = 0.02). (). Univariate analysis indicated that prior cystectomy was associated with improved PFS (HR = 0.67, p = 0.04) and OS (HR = 0.54, p = 0.003), suggesting its role as a favourable prognostic factor in this cohort\u003csup\u003e16\u003c/sup\u003e (Tab 3A and 3B).\u003c/p\u003e\n\u003cp\u003eA total of 114 treatment-related AEs were reported, with 79.8% being grade 1–2 and 20.2% grade 3–4. No treatment-related deaths occurred. Pembrolizumab was discontinued in 7.6% of patients due to AEs. The most common events were asthenia (20.0%), pruritus (10.0%), and myalgia (7.0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis real-world analysis supports the clinical applicability of second-line Pembrolizumab in La/mUC, demonstrating efficacy and acceptable safety. Prognostic indicators, including metastatic sites and prior cystectomy, significantly impacted outcomes. These findings highlight the value of oncology networks in generating real-world evidence to refine treatment approaches\u003c/p\u003e","manuscriptTitle":"Real-World Outcomes of Second-Line Pembrolizumab in Urothelial Carcinoma: A Multicenter Analysis from the Campania Oncological Network (ROC)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 14:49:30","doi":"10.21203/rs.3.rs-8651439/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-27T07:20:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-26T14:22:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335523250472253571332423134319582663194","date":"2026-03-23T04:42:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247529457438915067110527643002970177121","date":"2026-03-21T00:42:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-16T22:41:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-27T14:48:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66737108075187506586523784804219263740","date":"2026-02-19T15:21:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276581922770731695794615908982072086346","date":"2026-02-16T20:40:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220358257684532003631726145967832647754","date":"2026-02-13T20:20:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-11T20:30:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-09T09:38:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-09T07:26:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-06T09:46:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-02-06T09:03:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"58797b3e-4d3d-400c-b899-09fdfdd20eba","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T13:09:33+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 14:49:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8651439","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8651439","identity":"rs-8651439","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}