Editor’s Note: Transurethral resection of bladder tumors (TURBt) is the conventional treatment for non-muscle-invasive bladder cancer (NMIBC). Patients are stratified into low, intermediate, high, and very high risk categories, with different postoperative bladder instillation treatments and follow-up monitoring strategies for different risk patients. Several advancements in NMIBC research were presented at the recent EAU conference, and “Oncology Frontier-Urology Frontier” invited Professor Wei Yu from Peking University First Hospital to share related research findings.
01
Abstract No: A0729
Comparison of Transurethral Resection of Bladder Tumors (TUR-BT) versus Laser Resection in Outpatient Low-Intermediate Risk Bladder Cancer Patients: Results from a Non-Inferiority Randomized Controlled Trial (RCT) at 12 Months and Long-Term Follow-up
Background: Recurrent low-intermediate risk bladder cancer poses a significant burden on patients and healthcare systems. Researchers have found that for recurrent Ta low-grade bladder cancer patients, outpatient bladder tumor photodynamic therapy (PC-BT) is non-inferior to the gold standard TUR-BT in terms of 4-month recurrence-free survival (RFS). PC-BT is preferred by patients over TUR-BT, with fewer postoperative complications and higher postoperative quality of life. The main objective of this study was to evaluate the 12-month RFS rate in recurrent Ta low-grade bladder cancer patients after PC-BT and TUR-BT. Secondary objectives included analyzing the long-term RFS rate and stage progression after PC-BT and TUR-BT.
Methods: A single-center randomized controlled clinical trial was conducted from 2016 to 2022 at a hospital in Denmark comparing outpatient PC-BT using 980 nm bipolar laser under local anesthesia with the gold standard TUR-BT under general anesthesia. The sample size was 300 cases, with pre-defined non-inferiority margins for 12-month RFS rate and stage progression of 15% and 5%, respectively. A total of 300 patients histologically confirmed to have recurrent Ta low-grade bladder cancer were randomized in a 1:1 ratio to receive either PC-BT or TUR-BT, and were followed up for 7 years.
Results: Of the 300 patients, 154 received PC-BT and 146 received TUR-BT. Follow-up data at 12 months were available for 299 patients. The 12-month RFS rate was higher in the TUR-BT group than in the PC-BT group (44.1% vs. 42.2%), with a difference of 1.9% (95% CI: -9.3 to 13.2), meeting the non-inferiority criteria. The median long-term follow-up times for the PC-BT and TUR-BT groups were 47.2 months and 49.5 months, respectively; the 36-month RFS rates were 26.8% (95% CI: 20.5 to 34.9) and 32.4% (95% CI: 25.5 to 14.3), respectively, with no significant difference (P=0.35); and the cumulative stage progression rates at 60 months were 1.0% (95% CI: 0 to 3.0) and 0.9% (95% CI: 0 to 2.5), respectively, with a difference of 0.2% (95% CI: -2.4 to 2.7), meeting the non-inferiority criteria.
Conclusion: At 12 months of follow-up, outpatient PC-BT had non-inferior RFS rates to TUR-BT. The long-term stage progression rates after PC-BT were non-inferior to those after TUR-BT, and both treatments had very low stage progression rates. Outpatient PC-BT for recurrent Ta low-intermediate risk bladder cancer appears to be a safe alternative to TUR-BT.
(Abstract No: A0736)
02
Sequential Mitomycin C (MMC) Plus Bacillus Calmette-Guérin (BCG) Does Not Offer Superior Efficacy Compared to BCG Alone in Adjuvant Therapy for High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC): Midterm Analysis Results from a Prospective Randomized Trial
Background: Previously, it was believed that sequential MMC followed by BCG could improve disease recurrence risk (DRR) and disease-free interval (DFI) in high-risk NMIBC patients. This study aimed to evaluate whether MMC followed by BCG was superior to BCG alone in reducing DRR in high-risk NMIBC patients.
Methods: A prospective randomized comparative trial was conducted from March 2021 to June 2023, enrolling a total of 72 high-risk NMIBC patients. Patients were randomly assigned to receive either BCG monotherapy (n=31) or MMC+BCG (n=41). Both groups received BCG instillation (81 mg, once weekly for 6 weeks of induction instillation; maintenance instillation at 3, 6, and 12 months), with the MMC+BCG group receiving 4 mg MMC the day before BCG instillation. The primary endpoint was DRR. Secondary endpoints included DFI, treatment-related genitourinary symptoms, and adverse events (AEs).
Results: In the midterm analysis, there were 6/31 (19%) patients who experienced recurrence in the BCG group and 10/41 (24%) in the MMC+BCG group (P=0.611). MMC+BCG did not improve DFI (HR 1.23, 95% CI: 0.46–3.50, P=0.640). Patients receiving sequential treatment experienced more AEs (P > 0.05) and genitourinary symptoms (P < 0.05).
Conclusion: The midterm analysis of this study indicates that the use of MMC the day before BCG instillation during the induction phase does not confer clinical superiority in terms of DRR.
03
(Abstract No: A0738)
TRUCE04: Phase II Clinical Trial of RC48 in the Treatment of High-Risk Non-Muscle-Invasive Bladder Cancer (HR-NMIBC)
Background: RC48 is a novel antibody-drug conjugate targeting HER2 protein, demonstrating efficacy in advanced urothelial carcinoma. However, its efficacy and safety in early-stage urothelial carcinoma need further exploration. Therefore, a phase II clinical trial aimed to evaluate the value of RC48 in HR-NMIBC.
Methods: This prospective study recruited 19 HER2-expressing (IHC 2+ or 3+) HR-NMIBC patients who were either ineligible for complete tumor resection or intolerant to surgery. Patients received either RC48 monotherapy at 120 mg or RC48 in combination with trastuzumab monotherapy at 200 mg intravenously every three weeks until disease progression (PD), unacceptable toxicity, or study termination. The efficacy of RC48 was assessed through cystoscopy, random biopsy, urine cytology, and imaging. Complete response (CR) was defined as all assessments being negative, indicating no evidence of disease. Stable disease (SD) was defined as at least one positive assessment, with a maximum tumor size increase of no more than 20%, while excluding evidence of any muscle-invasive bladder cancer.
Results: All 24 patients completed efficacy and safety assessments. The median age of patients was 69 years (range: 58–81 years). Eight patients (33.3%) received RC48 monotherapy, while 16 patients (66.7%) received RC48 in combination with trastuzumab monotherapy. Sixteen patients (66.7%, 95% CI: 44.7–84.4) achieved CR, and 8 patients (33.3%, 95% CI: 15.6–55.3) were in SD. In the SD group, one patient’s bladder tumor significantly decreased in size, and another patient was diagnosed with low-grade non-invasive bladder cancer (LG/Ta) during evaluation. The PR rates in patients with HER2 IHC 3+ and HER2 IHC 2+ were 73.3% (11/15, 95% CI: 44.9–92.2) and 55.6% (5/9, 95% CI: 21.2–86.3), respectively. One patient died due to reasons unrelated to treatment. The most common grade 1–2 treatment-related adverse events (TRAEs) were itching (58.3%), rash (41.7%), hair loss (37.5%), fatigue (37.5%), anorexia (33.3%), and peripheral neuropathy (33.3%). Four patients (16.7%) reported grade 3–4 TRAEs, including fatigue, itching, leukopenia, and neutropenia. No grade 5 adverse events were reported.
Conclusion: The results of this study demonstrate that both RC48 monotherapy and RC48 in combination with trastuzumab monotherapy are effective in the treatment of NMIBC, with a high objective response rate, tolerable, and manageable TRAEs. These findings suggest that RC48 monotherapy and RC48 in combination with trastuzumab monotherapy may be successful strategies for treating NMIBC.
04
(Abstract：A0731）
Preliminary Results of the BladderGATE Clinical Trial: Intravenous Atezolizumab Plus BCG Bladder Instillation as Frontline Combination Therapy in BCG-Unresponsive High-Risk NMIBC Patients
Background: Bacillus Calmette-Guérin (BCG) induction followed by BCG maintenance therapy post transurethral resection of bladder tumor (TURBT) is the current standard of care for high-risk NMIBC patients. However, the recurrence rates at 2 and 5 years are approximately 30%-40% and 70%-80%, respectively. Atezolizumab, a PD-L1-targeting IgG1 monoclonal antibody, has demonstrated long-lasting responses in metastatic urothelial carcinoma patients. Previous reports have shown significant efficacy of atezolizumab in BCG-unresponsive NMIBC patients. Combining atezolizumab with standard BCG may offer synergistic benefits for NMIBC patients. BladderGATE (NCT04134000) is a phase Ib/II study aimed at evaluating the safety and efficacy of upfront atezolizumab plus BCG bladder instillation therapy in high-risk NMIBC patients.
Methods: Patients with histologically confirmed high-risk NMIBC, BCG-unresponsive or discontinued for more than 2 years, WHO PS 0-2, and normal hematologic and organ function were included. A dose escalation design was employed to determine dose-limiting toxicities and the maximum tolerated dose (MTD) in 9 patients, followed by assessment of safety and efficacy in an expansion cohort of 30 patients. Patients received 6 weeks of induction instillation, followed by maintenance instillation at months 3, 6, and 12, along with intravenous administration of 1200 mg atezolizumab every 3 weeks for up to 1 year. Urine/blood and tissue samples were collected for translational and biomarker-related studies. The primary endpoint was disease-free survival (DFS). Secondary endpoints included safety and quality of life.
Results: A total of 36 patients were enrolled, with a median age of 70 years, 86% being male, 61% former smokers, 22% current smokers, and 17% never smokers. Forty-four percent of patients had tumors ≥3 cm. At a median follow-up of 22 months, 56% of patients completed BCG treatment, and 89% of patients received adequate BCG treatment (5 induction instillations + at least 2 maintenance instillations). Thirteen patients discontinued atezolizumab, including 7 with immune-related adverse events (irAEs; 1 case each of grade 2 dermatitis, grade 3 hepatitis, encephalitis, pneumonia, myocarditis, adrenal insufficiency, and psoriasis), 3 with early relapse disease, and 3 with disease progression. All irAEs were manageable, with no reported deaths. Among the 36 analyzed patients, 5 (14%) experienced local high-grade recurrence, 1 had low-grade NMIBC, 1 had upper tract urothelial carcinoma (UTUC), and 3 had progressive disease with local muscle-invasive bladder cancer (8%). The preliminary 2-year DFS rate was 72.8% (95% CI: 56.1%-89.5%).
Conclusion: Combination therapy with atezolizumab plus BCG bladder instillation appears feasible and safe for high-risk NMIBC patients. The 2-year local recurrence rate of 14% and local disease progression rate of 8% are promising results, pending confirmation by data from the phase III randomized ALBAN study.
05
（abstract：A0741）
Application of Durvalumab Bladder Instillation in BCG-Treated Failure High-Risk NMIBC Patients: Final Results of a Phase II Study by the Hellenic Genitourinary (GU) Cancer Group
Background: Bladder preservation in the era of immunotherapy is an area of great interest for high-risk NMIBC and BCG-treated failure patients. This study aimed to present the final results of a phase I/II trial evaluating the efficacy and safety of durvalumab bladder instillation in such patients, along with in vivo data regarding the stability of durvalumab post-instillation.
Methods: The Hellenic GU Cancer Group conducted an open-label, single-arm, multicenter, phase II clinical trial. The run-in period determined the maximum tolerated dose (MTD) of durvalumab set at 1000 mg. The phase II regimen consisted of 6-week instillation therapy with durvalumab at the MTD dose, with the primary endpoint being the 1-year high-grade recurrence-free survival (HG-RFR) after completion of treatment. Secondary endpoints included toxicity and HG-RFR at 30 days, 3 months, and 6 months after the last durvalumab bladder instillation. Data on the stability of durvalumab post-instillation were also collected.
Results: Thirty patients were recruited across two stages (9 in the run-in period and 21 in phase II). The median age at baseline was 66 years. In the phase II cohort of 21 patients, 1 withdrew consent, and 1 died of Covid-19, leaving 19 patients for assessment of the study’s primary endpoint. At 1 year post-durvalumab instillation, 7 out of 19 evaluable patients remained free from high-grade recurrence (1-year HG-RFR: 38.5%, 95% CI: 17.7%-59.1%). HG-RFR at 1, 3, and 6 months post-treatment completion was 70% (95% CI: 45.1%-85.3%), 55% (95% CI: 31.3%-73.5%), and 38.5% (95% CI: 17.7%-59.1%), respectively. No serious adverse events were observed except for local irritation in the bladder. In an efficacy analysis of the overall study population, 4 patients (21%) experienced ≥T2 disease recurrence at 1, 3, 7, and 13 months post-last durvalumab instillation. The 1-year ≥T2 recurrence-free survival rate was 83.9% (95% CI: 57.9%-94.5%). Seven patients (37%) underwent radical cystectomy between 3 and 13 months after completing study treatment. The proportion of patients undergoing radical cystectomy at 1 year was 25% (95% CI: 10.2%-49.6%), with a median bladder preservation survival of 19.9 months. The recovery amounts of durvalumab post-instillation (calculated in mg) were 749.65 mg and 751.43 mg for 2 patients treated with 750 mg and 998.83 mg and 999.18 mg for 2 patients treated with 1000 mg, respectively.
Conclusion: Bladder instillation of 1000 mg durvalumab is a safe treatment option for BCG-treated failure high-risk NMIBC patients, with negligible toxicity. The efficacy results of this study are encouraging, indicating further investigation of this strategy in the NMIBC field.
06
（Abstract：A0728）
ElectroMotive Drug Administration of Mitomycin C for Primary BCG-Unresponsive High-Risk NMIBC: A Single-Arm Phase II Multicenter Prospective Study
Background: In a single-arm phase II multicenter retrospective study, investigators observed the effect of intravesical mitomycin C electroMotive Drug Administration (EMDA/MMC) on primary BCG-unresponsive high-risk NMIBC patients who were ineligible for or unwilling to undergo radical cystectomy.
Methods: From January 2006 to December 2018, patients histologically diagnosed with BCG-unresponsive high-risk NMIBC (with or without carcinoma in situ) were included. After transurethral bladder tumor resection (TURBT) and repeat TURBT, patients initially received weekly bladder EMDA/MMC treatment for 6 weeks, continued weekly treatment for non-responders for the subsequent 6 weeks, and responders received monthly treatment for 9 months. Patients were followed up every 3 months for the first 2 years and every 6 months thereafter, with a maximum follow-up of 5 years. The primary endpoints were the 3-month complete response (CR) rate in carcinoma in situ patients (no high-risk NMIBC or progressive disease) and recurrence-free survival (RFS) in patients with completely resected papillary disease. Secondary endpoints included progression-free rate, disease-specific survival, and overall survival.
Results: From January 2006 to December 2018, a total of 191 patients were enrolled. According to the FDA definition of BCG-unresponsive NMIBC, 89 patients (48 with carcinoma in situ and 41 with pure papillary disease) were included in the efficacy and safety analysis. The median follow-up time was 40 months (IQR 58-27). Among the 48 patients with carcinoma in situ, 23 (47.9%), 26 (54.2%), 19 (39.6%), 12 (25%), and 11 (22.9%) achieved CR at 3, 6, 12, 18, and 24 months, respectively. Among the 41 patients with BCG-unresponsive papillary disease, 38 (92.7%), 32 (78.1%), 29 (70.7%), 20 (48.8%), and 17 (41.5%) were free from recurrence at 3, 6, 12, 18, and 24 months, respectively. Overall, patients with pure papillary disease had lower rates of high-grade recurrence (24.4% vs. 64.6%; P=0.0002), disease progression (14.6% vs. 41.7%; P=0.0554), overall mortality (39% vs. 68.7%; P=0.9379), and disease-specific mortality (4.9% vs. 20.8%; P=0.1465) compared to patients with carcinoma in situ. Treatment-related adverse events were negligible and primarily occurred in the bladder.
Conclusion: Bladder EMDA/MMC is a safe treatment option for BCG-treated failure high-risk NMIBC patients.
Professor Wei Yu
Deputy Director, Department of Urology
Peking University First Hospital
Chief Physician, Professor, Doctoral Supervisor
Vice Chairman, Prostate Specialty Committee of China Anti-Cancer Association of Traditional Chinese and Western Medicine Integration
Standing Committee Member, Urinary Tract Cancer Committee of Chinese Society of Clinical Oncology
Member, Basic Science Group of Chinese Urological Association
Member, Oncology Group of Chinese Association of Traditional Chinese and Western Medicine Integration, Urology Specialty Committee
Vice Chairman, Familial and Hereditary Tumor Committee of Beijing Anti-Cancer Association
Standing Committee Member, Urinary Specialty Committee of Beijing Cancer Prevention and Treatment Association
Vice Chairman, Youth Committee of Oncology Branch of Beijing Medical Association
Expertise: Minimally Invasive and Comprehensive Treatment of Genitourinary Tumors
