The year 2025 marked a pivotal turning point in the management of urothelial carcinoma (UC). Nowhere has this transformation been more striking than in high-risk non–muscle-invasive bladder cancer (NMIBC), where long-standing limitations of bacillus Calmette–Guérin (BCG) therapy are finally being challenged by innovative strategies—most notably immune checkpoint inhibitors (ICIs) and antibody–drug conjugates (ADCs).Oncology Frontier – Urology Stream invited Prof. Yijun Shen from Fudan University Shanghai Cancer Center to provide an in-depth clinical perspective on the most influential NMIBC studies of 2025.
The Clinical Challenge of High-Risk NMIBC
NMIBC, defined as tumors confined to the bladder mucosa or submucosa, accounts for approximately 75% of newly diagnosed bladder cancer cases. Prognosis is closely linked to risk stratification. High-risk NMIBC carries a particularly heavy burden, with 10-year recurrence rates reaching 74.3% and progression rates up to 33.3%.
BCG induction plus maintenance remains the standard of care. However, more than 40% of patients experience recurrence within two years. The ongoing global BCG shortage has further complicated management, underscoring the urgent need for alternative bladder-preserving strategies.
While risk stratification systems differ slightly among guidelines, patients are broadly categorized into low-, intermediate-, high-, and very high-risk groups. Standardized definitions of BCG response states—such as BCG-naïve, adequate BCG exposure, BCG-intolerant, BCG-refractory, BCG-relapsing, and BCG-unresponsive—have further refined clinical decision-making.
ICI Plus BCG: Balancing Efficacy and Safety
Recent years have seen rapid expansion of treatment options for patients with BCG-unresponsive disease, offering renewed hope for bladder preservation.
Several landmark studies have influenced clinical practice in Western countries:
- Adstiladrin (CS-003): 70% complete response (CR) rate
- Pembrolizumab (KEYNOTE-057): 58% CR rate
- Anktiva + BCG (QUILT-3.032): 84% CR rate
Given evidence that PD-L1 expression is upregulated in BCG-resistant tumors, combining ICIs with BCG may enhance therapeutic efficacy.
At major international meetings in 2025 (ASCO, ESMO), phase III trials including POTOMAC, ALBAN, and CREST evaluated ICI plus BCG versus BCG alone in high-risk NMIBC. Key findings included:
- Significant improvement in event-free survival (EFS) with durvalumab or sasanlimab plus BCG
- No demonstrated overall survival (OS) benefit to date
- Increased incidence of grade ≥3 immune-related adverse events (irAEs) in combination arms
These results highlight the need to carefully balance improved disease control against heightened immune toxicity.
ADC Plus BCG: The Rise of the “China Strategy”
ADCs have already reshaped the treatment paradigm in advanced urothelial carcinoma. The question now is whether their success can be translated into earlier-stage disease.
Two Chinese investigator-initiated studies presented in 2025 provided compelling evidence that ADC-based strategies may indeed redefine bladder preservation in NMIBC.
Disitamab Vedotin (DV) Plus BCG
Presented at ASCO-GU 2025, a prospective, single-center study led by Fudan University Shanghai Cancer Center enrolled BCG-naïve, very high-risk NMIBC patients who either declined or were ineligible for radical cystectomy and had HER2 expression (IHC 1+/2+/3+).
Patients were assigned to:
- Cohort A: Incomplete tumor resection or carcinoma in situ
- Cohort B: Complete tumor resection
All received eight cycles of disitamab vedotin (2 mg/kg every 3 weeks) plus at least one year of intravesical BCG.
Results demonstrated encouraging efficacy:
- At 3 months, 11 patients in Cohort A achieved clinical complete response (cCR)
- At 6 months, 5 patients maintained cCR
- Cohort B demonstrated promising event-free survival (EFS) at 6 months
Treatment-related adverse events (TRAEs) occurred in 65% of patients, most commonly elevated AST/ALT (40%), alopecia (45%), peripheral neuropathy (35%), anorexia (10%), and rash (5%). Overall safety was manageable.
Vidisicatumab (RC48) Plus BCG: Formula-01 Study
At ESMO 2025, the Formula-01 study led by Sun Yat-sen University Cancer Center evaluated vidisicatumab (2.0 mg/kg every 2 weeks for 8 cycles) plus one year of BCG in HER2-overexpressing high-risk or very high-risk NMIBC.
Among 78 patients:
- 1-year disease-free survival (DFS): 92.24%
- In protocol-compliant patients (n=68), 1-year DFS: 95.59%
- Fewer than 5% experienced treatment failure
Most TRAEs were grade 1–2, including anorexia (53.8%), fatigue (51.3%), alopecia (50.0%), peripheral neuropathy (46.2%), ALT elevation (43.6%), and rash (26.9%). Grade 3–4 TRAEs occurred in 12.8%.
These findings represent a significant step forward in HER2-driven bladder preservation strategies and underscore the growing global influence of Chinese-developed ADCs.
Conclusion
In 2025, immunotherapy-based combinations emerged as a dominant research focus in high-risk NMIBC. Phase III trials demonstrated improved event-free survival with ICI plus BCG, though toxicity remains a concern.
Simultaneously, Chinese investigators achieved remarkable progress with ADC-based strategies. Prospective studies of vidisicatumab plus BCG reported 1-year DFS exceeding 92% in selected patients, with manageable safety profiles.
Together, these advances signal the early dawn of a new era in bladder preservation—where precision biomarkers and innovative combination strategies offer renewed hope for patients facing high-risk NMIBC.
Prof. Yijun Shen
