4.3 Review

Immunotherapy in urothelial cancer: current status and future directions

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Immune mechanisms and molecular therapeutic strategies to enhance immunotherapy in non-muscle invasive bladder cancer Invited review for special issue Seminar: Treatment Advances and Molecular Biology Insights in Urothelial Carcinoma

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Summary: Intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) has been the standard care for high-risk non-muscle invasive bladder cancer (NMIBC) for over four decades, but disease recurrence and progression are still common. Current research focuses on developing alternative treatments and salvage bladder preservation therapies after BCG failure. This review synthesizes the current understanding of NMIBC's molecular biology and tumor immune microenvironment to identify existing and emerging therapeutic targets. Combination regimens and predictive molecular biomarkers are being investigated to overcome treatment resistance and discover new targets for NMIBC.

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Extended follow-up results from the CheckMate 274 trial.

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Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advancedtransitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial

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Summary: This study aimed to evaluate the safety and efficacy of nivolumab induction and high-dose ipilimumab combination therapy in patients with metastatic urothelial carcinoma. The results showed that compared to nivolumab monotherapy, the combination of nivolumab and high-dose ipilimumab significantly improved the objective response rate. This study provides evidence for the potential value of using high-dose ipilimumab as a treatment strategy in patients with metastatic urothelial carcinoma.

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Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up

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Summary: Bladder cancer (BCa) is a common malignancy that often leads to death. The majority of BCa cases develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guerin (BCG) is the standard treatment for NMIBC, but there is a significant portion of patients who do not respond to BCG. Some drugs, such as valrubicin and pembrolizumab, have been approved by the FDA for the treatment of BCG-unresponsive NMIBC, but their complete remission rates are not satisfactory. ALT-803, a new drug that promotes the proliferation and activation of certain immune cells, has shown promising clinical efficacy and safety compared to other treatments for BCG-unresponsive NMIBC.

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Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial

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Summary: The study demonstrates the efficacy of intravesical nadofaragene firadenovec, a novel therapy using a replication-deficient recombinant adenovirus, in patients with BCG-unresponsive non-muscle-invasive bladder cancer, with a favorable benefit:risk ratio. The treatment led to a complete response in a significant proportion of patients with carcinoma in situ, and the adverse events were generally mild, with no treatment-related deaths reported.

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Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

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Summary: Several immune checkpoint inhibitors have been approved for the treatment of patients with metastatic urothelial carcinoma, showing promising efficacy in first-line or second-line therapy. PD-L1 expression may be a predictive factor for response to ICIs. Anti-PD-1 and PD-L1 antibodies have demonstrated durable responses in some mUC patients.

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Summary: Urothelial bladder cancer is the most common malignancy of the urinary system, and the use of immunotherapy and immune checkpoint inhibitors has transformed treatment strategies, showing improvements in metastatic disease but posing challenges for locally invasive disease.

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Summary: IMvigor010 is the largest adjuvant study evaluating a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not show improved disease-free survival with atezolizumab compared to observation. Atezolizumab was generally well tolerated, but higher rates of adverse events leading to discontinuation were reported compared to previous studies on metastatic urothelial carcinoma.

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Summary: The study demonstrates the long-term durable remission effect of atezolizumab in patients with mUC after platinum-based chemotherapy, with fewer treatment-related adverse events and treatment discontinuation. This supports the use of atezolizumab in this patient population.

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Summary: Neoadjuvant chemotherapy can improve outcomes in cisplatin-eligible MIBC patients, but the increase in overall survival is modest; for cisplatin-ineligible patients, the standard treatment is still RC, and more effective systemic therapies are needed.

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Summary: Bladder cancer is a significant burden to global public health, with urothelial carcinoma accounting for nearly 90% of cases. Despite advances in immunotherapy, only a small subset of patients benefit from it. The TGF-beta pathway has been identified as a potential resistance mechanism to immunotherapy, and therapies targeting this pathway are being explored for the treatment of bladder cancer.

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Summary: This study evaluated the efficacy and safety of pembrolizumab, a PD-1 inhibitor, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. The results showed that pembrolizumab monotherapy was well-tolerated and demonstrated promising antitumor activity in this patient population.

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Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma

D. F. Bajorin et al.

Summary: In a trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, adjuvant nivolumab showed longer disease-free survival compared to placebo, especially among patients with a PD-L1 expression level of 1% or more, despite an increase in treatment-related adverse events.

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Summary: Recent targeted therapy trials have expanded options for ICI sequencing in mUC. Immune checkpoint inhibitors (ICIs) combined with first-line platinum-based chemotherapy did not improve overall survival in platinum-eligible patients, but ICI monotherapy as switch-maintenance significantly improved overall survival in mUC patients who had achieved at least stable disease following first-line platinum-based chemotherapy.

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