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

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