“BCG failure is defined as any high-grade disease occurring during or after BCG therapy” said Dr. Chiara Mercinelli (IT) in her lecture on ‘Failure after BCG systemic treatment”. How does this happen? According to Dr. Mercinelli, BCG treatment increases the expression of PD-L1, Tregs, and tumour-associated macrophages, creating an immunosuppressive microenvironment over time. “This PD-L1 upregulation is one of the key mechanisms of immune escape and ultimately explains why some patients become BCG-unresponsive.”

What are the options? Dr. Mercinelli shared the key results of several novel therapies, before summarising these key take-home messages:

• Systemic checkpoint inhibitors restore T-cell function and can enhance or complement the anti-tumour activity of intravesical agents.
• Pembrolizumab is already FDA-approved for CIS BCG-unresponsive, confirming a clinical role for systemic therapy (complete clinical response at 6 months: 36%).
• Trials combining local and systemic therapy (CG0070 + pembrolizumab) show the highest clinical response rates in early-phase trials. Targeted therapy is a valid approach in the NMIBC population.
• Robust randomised trials to compare intravesical and systemic versus intravesical alone are urgently needed to define optimal sequencing and combination strategies.

Prof. Carmen Jeronimo (PT) presented on “Urinary biomarkers for monitoring of NMIBC”. She noted that NMIBC represent the majority of all bladder cancers and have a high recurrence (up to 70%) and variable progression (up to 20%), necessitating life-long surveillance. In her opinion, biomarkers offer the potential to reduce unnecessary cystoscopies and anticipate the identification of high-risk patients in NMIBC. “Urinary biomarkers are ideal for risk-adaptive surveillance – balancing patient burden and recurrence detection.”

She emphasised the need for further validation of the best-performing biomarkers in diverse real-world settings (different populations, different hospitals) and their implementation in clinical practice. She also highlighted that combing biomarker panels with AI driven multimodal surveillance could help individualise NMIBC follow-up.

What is the most cost-effective treatment in NMIBC failure?

According to Prof. Ashish Kamat (US), current options for patients in NMIBC failure are extensive and include immunotherapies, chemotherapy, a combination of both, gene therapies, targeted therapies, device-assisted therapies, and radiotherapy plus immunotherapy. But patients face many treatment considerations, including short-term cure versus short-term gain, quality of life, logistical challenges, anxiety, potential long-term side effects from drugs, and financial toxicity.

Prof. Kamat shared new research (Myers, Talwar et al. 2025) assessing the financial toxicity of five treatments: radical cystectomy, nadofaragene, nogapendekin/BCG, pembrolizumab and gemcitabine/docetaxel, as well as the study CISTO (Gore J, et. al 2025) on the financial impact of bladder-sparing therapy versus radical cystectomy.

He concluded that cost-effectiveness varies by treatment strategy and patient goals, but radical cystectomy remains the most cost-effective overall. Among bladder-sparing therapies, gemcitabine/docetaxel is the most-cost effective single-line option. He noted that multiple sequential therapies offer limited (financial) value, and in his final in comment he stressed that shared decision making is as important as ever.

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Prof. Ashish Kamat (US) presented “Systemic versus intravesical drug from high-risk NMIBC naive from BCG”. He stated, “The standard of care for high-risk, high-grade NMIBC is BCG. It reduces the risk of progression. If you use BCG as the standard of care, the risk progression drops from 9.6% to 5.8% for high-risk NMIBC, and from 40% to 14.8% for very high-risk NMIBC.”

Systemic vs. intravesical therapies

Prof. Kamat also enumerated the therapy options for patients with NMIBC: intravesical (e.g. intravesical chemotherapy, enhanced drug delivery, vaccines, and gene therapy) and systemic (e.g. immunotherapy [IO], targeted therapy, radiation, and other).

To demonstrate when to consider BCG-naïve patients with high-risk NMIBC for systemic therapy. He provided a patient case of a 79-year-old patient who is a long-time smoker and has diabetes and hypertension. The tumour characteristics are as follows:

• Largest tumour cluster: 4 cm, widely invasive T1 high-grade (T1HG), with 5% micropapillary component
• Base of tumour: muscularis propria present, no tumour, carcinoma in situ (CIS) present
• Trigone tumour: 2 cm, T1HG, no CIS, no muscularis propria present
• Bladder neck/prostatic urethra: with CIS, stroma present, not involved

Prof. Kamat explained, “Clearly, this is the type of patient you’d recommend for radical cystectomy. However, if the patient refuses the procedure and is worried about systemic disease, combining a systemic agent such as IO with an intravesical therapy such as BCG makes the most sense. This is the kind of patient where I would consider adding systemic therapy and not just intravesical therapy. In my opinion, it’s not a debate between intravesical or systemic therapies, but when to optimise the best treatment for the patient.”

Active surveillance (AS) in NMIBC

AS in NMIBC is “lagging behind schedule” according to Prof. Paolo Gontero (IT). In his lecture “Active surveillance in NMIBC: myth or reality?”, he stated that there are less than 1,000 published cases in over 20 years.

Prof. Gontero pointed out that patients with recurrent low-grade Ta-NMIBC are the ideal candidates as there is a broad population of these potential candidates. He added that the accuracy of patients’ selection and follow-up may be hampered by suboptimal estimation of grading/staging and unreliable markers. Furthermore, current exit criteria are efficient but need to be more relaxed. There is negligible progression event and the duration is short.

Concerning NMIBC, the anticipated course for AS includes longer follow-up because the long-term impact of AS on the disease is still unknown. Prof. Gontero added, “Patients’ acceptance should be explored. There should also be a reduction of the unreliability of visual tumour appearance. In this respect, we can record videos of the procedures. We should also test AS against a competitive comparator such as office fulguration or chemoablation in the future.”

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