Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.

• Keywords
• Chemotherapy, Enfortumab vedotin, Immune checkpoint inhibitors, Metastasis, Urothelial carcinoma,
• MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   administration & dosage   adverse effects   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   MeSH
• Carcinoma, Transitional Cell drug therapy   mortality   pathology   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Antibodies, Monoclonal MeSH
• Urinary Bladder Neoplasms drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Randomized Controlled Trials as Topic MeSH
• Urologic Neoplasms drug therapy   mortality   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Network Meta-Analysis MeSH
• Systematic Review MeSH
• Names of Substances
• enfortumab vedotin MeSH Browser
• Antibodies, Monoclonal, Humanized MeSH
• Immune Checkpoint Inhibitors * MeSH
• Antibodies, Monoclonal MeSH
• pembrolizumab MeSH Browser

CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

• MeSH
• Chemotherapy, Adjuvant methods   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Carcinoma, Transitional Cell * drug therapy   pathology   MeSH
• Humans MeSH
• Urinary Bladder Neoplasms * drug therapy   pathology   MeSH
• Network Meta-Analysis as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH
• Names of Substances
• Immune Checkpoint Inhibitors * MeSH

PURPOSE: To analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex. METHODS: Three databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting. RESULTS: Overall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55-0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68-0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females. CONCLUSIONS: OS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

• Keywords
• Adjuvant, Advanced, Gender, Immune checkpoint inhibitors, Metastatic, Renal cell carcinoma, Sex, Urothelial carcinoma,
• MeSH
• Adjuvants, Immunologic MeSH
• Immune Checkpoint Inhibitors therapeutic use   MeSH
• Carcinoma, Transitional Cell * drug therapy   MeSH
• Carcinoma, Renal Cell * drug therapy   MeSH
• Kidney MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Kidney Neoplasms * drug therapy   MeSH
• Urinary Bladder Neoplasms * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Systematic Review MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• Immune Checkpoint Inhibitors MeSH

Pembrolizumab is the standard for the first and second lines in treating metastatic urothelial carcinoma (UC). This systematic review and meta-analysis aimed to assess the value of pretreatment clinical characteristics and hematologic biomarkers for prognosticating response to pembrolizumab in patients with metastatic UC. PUBMED®, Web of Science™, and Scopus® databases were searched for articles published before May 2021 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they evaluated overall survival (OS) in patients with metastatic urothelial carcinoma treated with pembrolizumab and pretreatment clinical characteristics or laboratory examination. Overall, 13 studies comprising 1311 patients were eligible for the meta-analysis. Several pretreatment patients' demographics and hematologic biomarkers were significantly associated with worse OS as follows: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≥ 2 (Pooled hazard ratio [HR]: 3.24, 95% confidence interval [CI] 2.57-4.09), presence of visceral metastasis (Pooled HR: 1.84, 95% CI 1.42-2.38), presence of liver metastasis (Pooled HR: 4.23, 95% CI 2.18-8.20), higher neutrophil-lymphocyte ratio (NLR) (Pooled HR: 1.29, 95% CI 1.07-1.55) and, higher c-reactive protein (CRP) (Pooled HR: 2.49, 95% CI 1.52-4.07). Metastatic UC patients with poor PS, liver metastasis, higher pretreatment NLR and/or CRP have a worse survival despite pembrolizumab treatment. These findings might help to guide the prognostic tools for clinical decision-making; however, they should be interpreted carefully, owing to limitations regarding the retrospective nature of primary data.

• Keywords
• Metastatic urothelial carcinoma, Pembrolizumab, Prognostic factor,
• MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   MeSH
• Carcinoma, Transitional Cell * drug therapy   MeSH
• Humans MeSH
• Urinary Bladder Neoplasms * drug therapy   MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Review MeSH
• Systematic Review MeSH
• Names of Substances
• Antibodies, Monoclonal, Humanized MeSH
• pembrolizumab MeSH Browser