Mechanisms, Clinical Trials, and New Treatments for BCG-Unresponsive in Nonmuscle Invasive Bladder Cancer

IF 3.1 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-09-15 DOI:10.1002/cam4.71243

Xiaotong Huang, Xuan Wang, Zihe He, Yishu Huang, Bing Hu, Weiying Chen, Haifang Du

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Abstract

Background

Bacillus Calmette–Guérin (BCG) is the standard adjuvant therapy for high-risk non-muscle invasive bladder cancer (NMIBC), yet treatment failure occurs in 30% to 40% of patients. Those with BCG-unresponsive disease face a high risk of progression and represent a critical unmet need in urologic oncology. This review summarizes the mechanisms of BCG failure and evaluates emerging therapies for BCG-unresponsive NMIBC.

Methods

We conducted a comprehensive literature review of clinical trials and preclinical studies through August 2025, focusing on therapeutic strategies for BCG-unresponsive NMIBC. Mechanisms of BCG resistance, regulatory definitions, and results from recent Phase II/III trials were analyzed.

Results

Multiple novel therapies have demonstrated efficacy in BCG-unresponsive patients. Immune checkpoint inhibitors (e.g., pembrolizumab) achieved complete response (CR) rates of 41% in carcinoma in situ (CIS) patients. Gene therapies such as nadofaragene firadenovec and CG0070 induced CR rates of 51% and 75%, respectively. Device-assisted therapies including hyperthermic intravesical chemotherapy (HIVEC) showed 24-month recurrence-free survival of 57.4%. The IL-15 superagonist Anktiva (nogapendekin alfa inbakicept), recently FDA-approved, achieved a 71% CR rate with a median duration of 26.6 months when combined with BCG.

Conclusions

The treatment landscape for BCG-unresponsive NMIBC is rapidly evolving, with immune checkpoint inhibitors, gene therapies, targeted agents, and advanced drug delivery systems showing promising efficacy. These innovations provide bladder-preserving options for patients ineligible for radical cystectomy. Future directions include biomarker-driven therapy selection, combination regimens, and optimized intravesical delivery platforms to improve long-term outcomes.

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非肌肉浸润性膀胱癌中bcg无反应的机制、临床试验和新治疗方法

卡介苗（BCG）是高危非肌肉浸润性膀胱癌（NMIBC）的标准辅助治疗，但治疗失败发生率为30%至40%。bcg无反应性疾病的患者面临着很高的进展风险，这是泌尿肿瘤学中一个关键的未满足需求。本文综述了卡介苗失败的机制，并评估了治疗卡介苗无应答的NMIBC的新疗法。方法：我们对截至2025年8月的临床试验和临床前研究进行了全面的文献综述，重点关注bcg无反应的NMIBC的治疗策略。本文分析了卡介苗耐药性的机制、调控定义和最近II/III期试验的结果。结果多种新疗法对bcg无反应患者均有疗效。免疫检查点抑制剂（如派姆单抗）在原位癌（CIS）患者中实现了41%的完全缓解（CR）率。nadofaragene firadenovec和CG0070等基因疗法分别诱导CR率为51%和75%。器械辅助治疗包括膀胱内高温化疗（HIVEC）显示24个月无复发生存率为57.4%。最近获得fda批准的IL-15超级激动剂Anktiva （nogapendekin alfa inbakicept）与卡介苗联合治疗时的总有效率为71%，中位持续时间为26.6个月。结论：随着免疫检查点抑制剂、基因疗法、靶向药物和先进的药物传递系统显示出良好的疗效，bcg无应答的NMIBC的治疗前景正在迅速发展。这些创新为不适合根治性膀胱切除术的患者提供了保留膀胱的选择。未来的方向包括生物标志物驱动的治疗选择、联合方案和优化的膀胱内给药平台，以改善长期预后。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.