Search Results (60)

Background/Objectives: Antibody–drug conjugates (ADCs) targeting Nectin-4 (enfortumab vedotin) and TROP-2 (sacituzumab govitecan) have transformed the management of advanced urothelial carcinoma (UC), but evidence on their molecular targets in rare non-urothelial bladder carcinomas (N-UC) is scarce. We evaluated the immunohistochemical expression of TROP-2 and Nectin-4 in muscle-invasive UC and N-UC and assessed their association with tumour stage, nodal status and overall survival. Methods: In this retrospective single-centre study, 111 consecutive patients with primary muscle-invasive bladder carcinoma (73 UC, 38 N-UC including squamous, adenocarcinoma, neuroendocrine and sarcomatoid variants) were analysed. TROP-2 and Nectin-4 expression was quantified using the H-score; positivity was defined as ≥15. Marker expression was correlated with clinicopathological characteristics and overall survival (OS) using chi-squared, linear-by-linear, log-rank, and Cox regression analyses. Results: TROP-2 positivity was observed in 46.6% of UC and 36.8% of N-UC (p = 0.925); Nectin-4 positivity in 17.8% and 28.9%, respectively (p = 0.275). Among positive cases, TROP-2 H-scores were higher in N-UC than in UC (mean 109 vs. 70; Mann–Whitney p = 0.045; Cliff’s delta 0.37, 95% CI 0.05–0.66); as no adjustment for multiple testing was applied, this difference is regarded as nominally significant and exploratory. Nectin-4 H-scores were numerically higher in UC (mean 82 vs. 53) but did not reach statistical significance (p = 0.84). Across the cohort, TROP-2 expression increased with advancing T stage (linear-by-linear p = 0.026) and was associated with nodal involvement (p = 0.043). Nectin-4 showed no significant stage association. Sarcomatoid carcinomas were negative for both markers. Median OS was 41 months in UC versus 19 months in N-UC (p = 0.668). Neither marker independently predicted OS, whereas advanced T stage (p = 0.003) and nodal involvement (p = 0.021) were significantly associated with poorer survival; T stage remained independently prognostic in multivariable analysis. Conclusions: TROP-2 and Nectin-4 are expressed at comparable rates in muscle-invasive UC and rare N-UC, except in sarcomatoid variants. TROP-2 expression increased with advancing tumour stage, suggesting stage-dependent regulation in muscle-invasive disease. Therefore, both markers should be interpreted as potential therapeutic targets whose expression can be demonstrated in these tumours, rather than as prognostic biomarkers or as validated predictive biomarkers of ADC response; because no patient received an ADC, the present study cannot determine whether expression predicts clinical benefit, and this distinction requires prospective, treatment-linked evaluation that includes patients with N-UC. Full article

Background: Next-generation sequencing (NGS)-detected ERBB2 amplification occurs in a subset of urothelial carcinomas, but its role as a treatment-selection marker for trastuzumab deruxtecan (T-DXd) remains uncertain. Methods: We retrospectively reviewed four patients with metastatic urothelial carcinoma treated with T-DXd in routine practice from 2024. Treatment selection was based on NGS-detected ERBB2 amplification because HER2 immunohistochemistry and in situ hybridization were unavailable. Results: Four men aged 65–76 years received T-DXd: one in the second line and three in the fourth or fifth line. The best radiological responses, abstracted from contemporaneous radiology reports and oncology medical records, were complete response in one patient, partial response in one, and stable disease in two. Three patients had previously received enfortumab vedotin. Documented adverse events included fatigue, anemia, diarrhea, rash, and leukopenia. No interstitial lung disease or pneumonitis was documented in the available records. Conclusions: These observations are descriptive and hypothesis-generating. They do not establish the efficacy or safety of T-DXd or validate ERBB2 amplification as a predictive biomarker, but they support prospective evaluation of genomic ERBB2 amplification when standard HER2 testing is unavailable. Full article

Background and Clinical Significance: Enfortumab vedotin combined with pembrolizumab has emerged as an effective first-line therapy for advanced urothelial carcinoma. While immune checkpoint inhibitors are associated with digestive tract toxicities, upper gastrointestinal involvement such as esophagitis remains rare, and its presentation in combination with enfortumab vedotin is not well characterized. Case Presentation: A 72-year-old man with metastatic urothelial carcinoma presented with generalized weakness, poor oral intake, odynophagia, dysphagia, anemia, and systemic symptoms following the second cycle of combination therapy of enfortumab vedotin and pembrolizumab. Endoscopic evaluation revealed diffuse circumferential ulcerative esophagitis involving the entire esophagus, with associated duodenitis. Infectious workup, including Clostridioides difficile, cytomegalovirus, and human immunodeficiency virus testing, was negative, and HSV-1 IgG was positive, consistent with prior exposure rather than active infection; however, tissue-based testing for active HSV infection was not performed. Lower gastrointestinal evaluation demonstrated nonspecific rectal inflammation. The patient was treated with high-dose intravenous corticosteroids (intravenous methylprednisolone 1 mg/kg/day) with rapid clinical improvement within 48–72 h, followed by a steroid taper and supportive care. Conclusions: This case represents a severe and diffuse manifestation of esophagitis associated with enfortumab vedotin and pembrolizumab therapy. While immune-mediated esophagitis is rare, the combination of antibody–drug conjugate therapy with immune checkpoint inhibition may contribute to synergistic mucosal injury. Early recognition and prompt initiation of immunosuppressive therapy are critical for favorable outcomes. Clinicians should be aware of severe esophagitis as a potential complication of enfortumab vedotin and pembrolizumab therapy. Timely diagnosis and management with corticosteroids can lead to rapid symptom resolution and may prevent serious complications. Full article

Background: Urothelial carcinoma (UC) is a significant clinical problem, especially in locally advanced and metastatic stages, where the prognosis remains poor despite advances in immunotherapy. Enfortumab vedotin (EV), an antibody–drug conjugate (ADC) targeting Nectin-4, extends beyond direct cytotoxicity by actively modulating the immunosuppressive tumor microenvironment (TME) in preclinical models, creating a strong rationale for combination strategies. This systematic review aimed to evaluate the clinical efficacy, safety, and hypothesized immune-modulating potential of EV in the treatment of UC, particularly in combination with immunotherapy. Materials and Methods: The review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Web of Science, and ClinicalTrials.gov databases were searched to identify interventional clinical studies published between 2020 and 2026. Studies evaluating EV used as monotherapy or in combination with immunotherapy in adult patients with UC were analyzed. ORR, PFS, OS, and the incidence of treatment-related adverse events were evaluated. Individual publications originating from the same clinical trial programs were treated as linked records and analyzed collectively. Results: The analysis was primarily based on key clinical trial programs, including EV-103, EV-301, and EV-302, along with their subgroup analyses, follow-up reports, and patient-reported outcomes. EV demonstrated significant clinical efficacy in the treatment of locally advanced UC (laUC). In the EV-301 study, EV therapy significantly prolonged overall survival compared to chemotherapy (12.88 vs. 8.97 months). In the EV-302 study, EV combination therapy with pembrolizumab showed a significant improvement in progression-free survival and overall survival compared to platinum-based chemotherapy. Conclusions: EV represents a significant therapeutic advance not only as a cytotoxic agent but as a potent immune modulator with clinical efficacy that may be enhanced by its biologically hypothesized immunomodulatory mechanisms in mUC. Its clinical development reflects a critical shift from later-line monotherapy toward earlier-line combination strategies designed to target both tumor cells and the microenvironment. Further studies are needed to better define its role in the context of alternative treatment approaches and across different stages of disease. Full article

Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform’s migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies. Full article

The management of urothelial carcinoma (UC) is undergoing a paradigm shift from static anatomical staging to molecularly guided dynamic approaches that integrate time as a critical therapeutic variable. This evolution is driven by liquid biopsies, particularly circulating tumor DNA, which allow real-time tumor interrogation. We conducted this expert review to synthesize landmark evidence, enabling technologies, and implementation challenges in dynamic precision oncology for UC. In this non-systematic narrative review, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library for articles published between January 2015 and February 2026. Studies were selected based on their relevance to dynamic precision oncology, clinical actionability, and translational implementation, prioritizing landmark randomized controlled trials providing level 1–2 evidence, large prospective cohorts, and key translational studies. Enfortumab vedotin plus pembrolizumab established the new first-line standard for metastatic UC, achieving a median overall survival of 33.8 months versus 15.9 months (hazard ratio [HR] 0.51, 95% confidence interval 0.43–0.61). Circulating tumor DNA demonstrates robust prognostic value for molecular residual disease (MRD) detection (Level 2a evidence), stratifying recurrence risk with hazard ratios of approximately 4.5. Critically, the IMvigor011 trial has now provided Level 1b evidence that ctDNA-guided adjuvant atezolizumab improves both disease-free survival (DFS) (HR 0.64, p = 0.0047) and OS (HR 0.59, p = 0.0131) in ctDNA(+) patients, while validating treatment de-escalation in ctDNA(−) patients (1-year DFS 95%). Erdafitinib in patients harboring FGFR2/3 alterations (HR 0.64) confirms the value of genomic profiling. Major limitations include the inherent selection bias of this non-systematic approach, substantial platform heterogeneity, and lack of standardization. In conclusion, dynamic precision oncology has transformed UC management, with the IMvigor011 trial establishing ctDNA-guided MRD status as the first phase 3-validated predictive biomarker framework for adjuvant therapy selection in a solid tumor. Implementation requires adherence to established standardization frameworks, cross-platform and cross-agent validations, and tiered implementation strategies to ensure equitable access across diverse resource settings. Full article

Background and Clinical Significance: Bladder cancer is common, with urothelial carcinoma (UC) comprising most cases in Western countries. Metastases usually involve pelvic structures, lymph nodes, and organs such as the liver, lungs, bones, and adrenal glands. Identifying unusual metastatic sites is critical for accurate diagnosis and treatment planning. Case Presentation: A 65-year-old man with a history of high-grade (G3) UC and carcinoma in situ, previously treated with TURBT, second-look resection, and SWOG-protocol BCG, presented with a new bladder lesion (pT1). Staging CT revealed extravesical spread and a 1.5 cm pancreatic body nodule. EUS-guided biopsy confirmed metastatic UC with concordant immunohistochemistry (GATA3+), excluding primary pancreatic cancer. The patient was referred for systemic therapy with immune checkpoint inhibitors and Enfortumab Vedotin. Conclusions: This case demonstrates the rare occurrence of pancreatic metastasis from bladder UC. EUS-guided biopsy with immunohistochemistry is essential to distinguish secondary lesions from primary pancreatic tumors. Accurate diagnosis is crucial to guide systemic therapy, particularly with emerging immunotherapy and antibody–drug conjugates. Full article

Background: This study describes treatment patterns and clinical outcomes in patients with advanced urothelial carcinoma (aUC) in the US following the approval of avelumab for first-line maintenance treatment. Methods: This retrospective cohort study used deidentified patient data from the Tempus database. Eligible patients had completed first-line systemic anticancer treatment for aUC between July 2020 and March 2023. Results: In total, 974 eligible patients were identified; most (72%) were male. Median age at diagnosis was 70 years. Among patients who completed first-line platinum-based chemotherapy (644 [66%]), 574 (89%) had no evidence of disease progression. Of 219 patients who received first-line maintenance, 135 (62%) received avelumab. Median (95% CI) overall survival (OS) and progression-free survival (PFS) from avelumab maintenance start were 14.9 months (13.1—not estimable [NE) and 6.4 months (4.6—NE), respectively. Enfortumab vedotin (EV) was the most common second-line treatment after avelumab (70%). Median (95% CI) OS and PFS from second-line EV start were 11.6 months (6.1—NE) and 6.6 months (4.1—NE), respectively. Conclusions: Results provide insights into the impact of avelumab first-line maintenance treatment in patients with aUC in the US. Effectiveness data are consistent with previous findings, supporting the use of avelumab maintenance in patients without disease progression following first-line platinum-based chemotherapy. Second-line EV after progression on avelumab maintenance had similar effectiveness to results from other real-world studies. Full article

Background: Enfortumab vedotin plus pembrolizumab (EVP) has become a first-line standard for metastatic or unresectable urothelial carcinoma. However, EVP is associated with distinct toxicities, particularly cutaneous adverse events, and prophylactic systemic corticosteroids were not permitted in pivotal trials. Therefore, the safety and early effectiveness of EVP with routine dexamethasone premedication in real-world practice remain unclear. Methods: This multicenter retrospective study included consecutive patients with metastatic or unresectable urothelial carcinoma who received first-line EVP at five institutions in Japan between September 2024 and September 2025. All patients received routine intravenous dexamethasone premedication before enfortumab vedotin administration. Safety and early clinical outcomes were evaluated, with exploratory subgroup analyses according to clinical trial eligibility and EVITA criteria. Results: Seventy-seven patients were included, with a median age of 75 years, and more than half would have been ineligible for pivotal clinical trials. Cutaneous toxicity was the most frequent adverse event (52.0%), whereas grade ≥3 skin reactions were uncommon (3.9%). With a median follow-up of 6.7 months, the objective response rate was 73.0%. The 6-month progression-free survival and overall survival rates were 73.9% and 78.7%, respectively. Early progression-free survival was generally maintained across subgroups stratified by clinical trial eligibility and EVITA category, with no evidence of excess early progression. Conclusions: In this real-world multicenter cohort, first-line EVP with routine dexamethasone premedication was feasible, with manageable toxicity and encouraging early clinical activity, including in patients with comorbidities commonly encountered in routine clinical practice. Longer follow-up and prospective comparative studies are warranted to clarify long-term outcomes and the impact of dexamethasone on efficacy and toxicity. Full article

Antibody–drug conjugates (ADCs) have reshaped the treatment landscape of urothelial carcinoma (UC) by enabling selective delivery of highly potent cytotoxic agents to tumor cells. Enfortumab vedotin, sacituzumab govitecan, and HER2-directed ADCs have demonstrated meaningful clinical activity across metastatic and earlier disease settings, with enfortumab vedotin plus pembrolizumab now established as a first-line standard of care. Despite these advances, therapeutic responses remain heterogeneous, and resistance frequently limits durability. This review summarizes current knowledge on predictors of response and mechanisms of resistance to ADCs in UC, highlighting the roles of target antigen expression and heterogeneity, genomic alterations, payload sensitivity, drug efflux transporters, and tumor microenvironmental factors. We discuss emerging biomarkers beyond antigen abundance, patterns of cross-resistance and treatment sequencing, and evolving strategies to overcome resistance, including next-generation ADC design and rational combination therapies. Advancing biomarker-driven patient selection and addressing mechanisms of resistance will be critical to maximizing the durability and clinical impact of ADCs in urothelial carcinoma. Full article

Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options. Advances in genomic and transcriptomic research have deepened the understanding of mUC biology, leading to the identification of clinically relevant molecular alterations that represent potential actionable targets. This has broadened the treatment landscape of the disease to include novel agents, such as antibody–drug conjugates (e.g., enfortumab vedotin) and targeted therapies, including the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib. Genomic alterations in FGFR3 are well-established oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR-targeted therapies. The phase III THOR trial demonstrated the clinical benefit of erdafitinib in previously treated mUC patients harboring FGFR3 alterations and supported its subsequent approval by the European Medicines Agency. In this context, accurate molecular profiling is essential to guide patient selection for FGFR inhibitor therapy. Equally important is the standardization and timely implementation of FGFR3 testing in clinical practice to optimize treatment planning. This review addresses key considerations in FGFR3 testing in mUC and discusses how it can be routinely incorporated into clinical practice. Full article

Avelumab maintenance therapy is approved in Japan for patients with aUC without progression after PBC. This report presents subgroup analysis data from the JAVEMACS chart review of avelumab maintenance in patients who received 1L ddMVAC and GC. This retrospective study reviewed medical charts of patients with aUC (February 2021–December 2023). Overall, 350 patients (ddMVAC, n = 32 and GC, n = 196) were included in the study. Baseline characteristics were balanced between the two PBC groups. Median duration from PBC start to avelumab start was 13.2 and 21.1 weeks; median overall survival (OS) was not reached (both groups), progression-free survival (PFS) was 12.0 and 7.4 months, and PFS2 was 27.6 and 21.3 months for the ddMVAC and GC groups, respectively. At data cutoff (June 2024), 25.0% of patients in the ddMVAC and 17.3% in the GC groups were ongoing avelumab treatment. Second-line treatments included EV (64.3% ddMVAC; 64.5% GC), pembrolizumab (21.4% ddMVAC; 8.3% GC), and PBC (14.3% ddMVAC and 21.5% GC). This real-world data from patients with aUC in Japan showed consistent OS patterns with avelumab maintenance across treatment subgroups vs. the overall population despite their inherent heterogeneity. Although patients were not resistant to PBC, 2L EV was more common than 2L PBC. Full article

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody–drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. Methods: We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. Results: ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Conclusions: Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care. Full article

Urothelial carcinoma in situ (UCIS) is a high-grade non-muscle-invasive neoplasm with significant clinical implications due to its potential for progression to muscle-invasive disease. Accurate diagnosis and risk stratification are crucial for appropriate management, particularly given the variability in response to intravesical Bacillus Calmette-Guérin (BCG) therapy. While the diagnosis of UCIS primarily relies on morphological criteria, immunohistochemical (IHC) markers serve as valuable ancillary tools, particularly in challenging cases. Markers such as CK20, CD44, p53, and Ki-67 have been extensively studied, though none demonstrate complete sensitivity or specificity. Additionally, molecular classification has identified luminal and basal subtypes, with potential prognostic and therapeutic implications. Recent studies have also explored predictive biomarkers for BCG response, including PD-L1, whose expression correlates with recurrence and potential responsiveness to immune checkpoint inhibitors. Emerging targeted therapies, such as enfortumab vedotin, have shown promise, with nectin-4 overexpression observed in most UCIS cases. Despite these advancements, challenges remain, including interobserver variability in morphological assessment, heterogeneous IHC methodologies, and the need for standardized molecular testing. This review highlights the current understanding of diagnostic, prognostic, and predictive tissue biomarkers in UCIS, underscoring the potential role of molecular profiling in guiding personalized treatment strategies. Future research should focus on refining biomarker-driven classification systems to improve risk stratification and therapeutic decision-making in UCIS patients. Full article

Background/Objectives: Upper tract urothelial carcinoma (UTUC) is a rare and biologically distinct subset of urothelial malignancies, comprising approximately 5–10% of urothelial cancers. UTUC presents unique diagnostic and therapeutic challenges, with both a higher likelihood of invasive disease at presentation and a less favorable prognosis compared to urothelial carcinoma of the bladder. Current treatment strategies for UTUC are largely derived from bladder cancer studies, underscoring the need for UTUC-directed research. This review provides a comprehensive overview of UTUC, encompassing diagnostic approaches, systemic and intraluminal therapies, surgical management, and future directions. Methods: A narrative review was conducted synthesizing evidence from guideline-based recommendations, retrospective and prospective clinical studies, and ongoing trials focused on UTUC. Results: Neoadjuvant cisplatin-based chemotherapy is increasingly preferred in UTUC due to the risk of postoperative renal impairment that may preclude adjuvant cisplatin use. Surgical management includes kidney-sparing approaches and radical nephroureterectomy (RNU), with selection guided by tumor risk and patient comorbidities. While endoscopic management (EM) preserves renal function, it carries a higher recurrence and surveillance burden; RNU remains standard for high-risk cases. Systemic therapy for advanced and metastatic UTUC mirrors that of bladder urothelial carcinoma. Enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy over chemotherapy in the EV-302 trial, with improved response rate, progression-free survival, and overall survival across subgroups, including UTUC. For patients ineligible for EV, the CheckMate-901 study supported first-line chemoimmunotherapy with gemcitabine, cisplatin, and nivolumab. Further systemic therapy strategies include maintenance avelumab post-chemotherapy (JAVELIN Bladder 100), targeted therapies such as erdafitinib (THOR trial), and trastuzumab deruxtecan (DESTINY-PanTumor02) in FGFR2/3-altered and HER2-positive disease, respectively. Conclusions: Historically, the therapeutic landscape of UTUC has been extrapolated from bladder cancer; however, ongoing research specific to UTUC is deriving more precise regimens involving the use of immune checkpoint inhibitors, antibody–drug conjugates, and biomarker-driven therapies. Full article