Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade.

Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology.

Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study.

Background: Anti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.

FGFR Inhibition in Urothelial Carcinoma.

Background And Objective: The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain.

Methods: Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer".

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.

Background: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.

Methods: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group).

Advancements in the front-line treatment of metastatic urothelial carcinoma.

Both the CheckMate-901 (gemcitabine-cisplatin plus nivolumab) trial and the EV-302 (enfortumab-vedotin plus pembrolizumab; EV+P) trial have shown a significant improvement in OS over standard (cis)platinum-based chemotherapy. The effect size, as well as the broader eligibility criteria for EV+P position this regimen as a compelling preferred candidate for the new standard of care in front-line mUC treatment.

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study.

Background: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1.

Platinum-Based Chemotherapy Induces Opposing Effects on Immunotherapy Response-Related Spatial and Stromal Biomarkers in the Bladder Cancer Microenvironment.

Purpose: Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized.

Treatment patterns and survival outcomes of patients admitted to the intensive care unit due to immune-related adverse events of immune checkpoint inhibitors.

Introduction: Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.

Methods: All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included.

Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) can achieve remarkable responses in urothelial cancer (UC), which may depend on tumor microenvironment (TME) characteristics. However, the relationship between the TME, usually characterized by immune cell density, and response to ICI is unclear. Here, we quantify the TME immune cell densities and spatial relationships (SRs) of 24 baseline UC samples, obtained before pre-operative combination ICI treatment, using multiplex immunofluorescence.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

Background: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.

Methods: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.

Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

Background And Objective: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL).

Methods: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation.

Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation.

Background: Bladder cancer is one of the most common cancer types worldwide. Generally, research relies on invasive sampling strategies.

Methods: Here, we generate bladder cancer organoids directly from urine (urinoids).

Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma.

Background: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy.

Methods: In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival.

Turning up the heat: CTLA4 blockade in urothelial cancer.

Anti-PD1 and anti-PDL1 monotherapies have shown clinical efficacy in stage IV urothelial cancer and are integrated into current clinical practice. However, only a small number of the patients treated with single-agent checkpoint blockade experience an antitumour response. Insufficient priming or inhibitory factors in the tumour immune microenvironment might have a role in the lack of response.

Disease-Free Survival of Patients With Muscle-Invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder-Preserving Therapy: A Nationwide Study.

Purpose: Although level I evidence is lacking that radical cystectomy (RC) is superior to bladder-preserving therapy (BPT), RC is still advocated as the recommended treatment in patients with nonmetastatic muscle-invasive bladder cancer (MIBC). This study sought to compare the survival of patients with MIBC treated with BPT versus those treated with RC.

Methods And Materials: All patients with nonmetastatic MIBC diagnoses were identified via the population-based Netherlands Cancer Registry.

Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial.

Purpose: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT).

Patients And Methods: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer.