What’s Next for NMIBC: The Immunotherapy and Gene Therapy Pipeline

EP: 1.Current Standards of Care and Shifting Strategies in NMIBC

EP: 2.NMIBC Treatment Decisions in the Age of BCG Shortages

EP: 3.Expert Discussion on BCG-Unresponsive NMIBC

EP: 4.Bladder-Sparing Breakthroughs: Novel FDA-Approved Treatment Options for NMIBC

EP: 5.Weighing the Risks and Benefits of Bladder-Sparing Agents vs Cystectomy

Now Viewing

EP: 6.What’s Next for NMIBC: The Immunotherapy and Gene Therapy Pipeline

EP: 7.Topline Data From the BOND-003 Trial in NMIBC

EP: 8.Immunotherapy in NMIBC: Key Results Safety Profile From BOND-003 Trial

EP: 9.Diving Deeper: Discussing Results From Cohort C in the BOND-003 Trial

EP: 10.Ongoing Investigations: Expanding the Role of Cretostimogene in NMIBC Care

EP: 11.In the Pipeline: Novel Treatment Delivery Methods for NMIBC

EP: 12.Rethinking First-Line Treatments: Will BCG Continue to Be the Standard in NMIBC?

Currently, several FDA-approved agents treat BCG-unresponsive carcinoma in situ (CIS), with or without papillary disease. Pembrolizumab, a single-agent checkpoint inhibitor, has a complete response rate of less than 20% at 12 months and is thus marginally effective and not widely used in practice.

Nadofaragene firadenovec (Adstiladrin), a gene therapy that overexpresses interferon beta administered every 3 months, has shown improved response rates compared to pembrolizumab, with approximately 30% of patients responding at 12 months. However, this still leaves room for improvement.

The third FDA-approved agent is the combination of BCG with an IL-15 superagonist (N-803), which showed approximately a 40% complete response rate at 12 months, with some patients maintaining responses up to 24 months. Its clinical use is limited currently by the ongoing BCG shortage.

To improve outcomes beyond single-agent therapy, new combination immunotherapies are being investigated, including intravesical oncolytic immunotherapies like cretostimogene. This agent is a conditionally replicating adenovirus that selectively targets tumors with RB pathway alterations and induces tumor lysis and immune stimulation via expression of GM-CSF. Trials show promising results with a 45% response rate at 12 months, making it the most effective intravesical immunotherapy currently under FDA review for BCG-unresponsive CIS.

Further studies are exploring combinations of intravesical agents with systemic checkpoint inhibitors to boost efficacy. For example, combination BCG plus PD-1 inhibitors like durvalumab and sasanlimab are under investigation. The CREST trial demonstrated improved efficacy of BCG plus sasanlimab in BCG-naive high-risk non–muscle-invasive bladder cancer, suggesting combination therapies may play an important future role in this disease space.