Gary Steinberg: Treatment guidelines continue to evolve for bladder cancer due to the unmet need.

Bladder cancer is the eleventh most common cancer worldwide and it can be stratified based on the depth of penetration, with the major division between muscle-invasive and non-muscle-invasive cancers. Non-muscle-invasive bladder cancer, or NMIBC, accounts for around 75% of newly diagnosed bladder cancers.

Neal Shore: Current treatment approaches for NMIBC, outlined in the AUA, SUO, and EAU treatment guidelines, show strong similarities.

The initial standard-of-care treatment involves transurethral resection of bladder tumor, followed by intravesical chemotherapy or Bacillus Calmette-Guérin, also known as BCG, depending on patient risk stratification.

In response to past BCG shortages, treatment guidelines advise that first-line BCG should be reserved for high-risk NMIBC patients and intermediate-risk patients should be treated with intravesical chemotherapy. The unmet need for these NMIBC patients suggests further research for new and effective alternatives to BCG is required.

Several novel treatments that interact with the immune system are at various stages of development. Increased expression of programmed cell death-ligand 1, or PD-L1, is a mechanism used by tumors to evade the immune response. In high-risk NMIBC patients, PD-L1 expression in tumor cells, and the T-cell population in the tumor microenvironment, were shown to be predictive factors of BCG response.

Gary Steinberg: High PD-L1 expression in BCG-relapsing tumors was also associated with the disease progression and reduced 5-year survival rates. However, the use of PD-L1 testing remains controversial.

Anti-PD1/PD-L1 antibodies sasanlimab, pembrolizumab, durvalumab, and atezolizumab are being investigated in combination with BCG in phase 3 trials in high-risk, BCG-naïve patients with NMIBC.

Neal Shore: What sort of progress is being made on targeted therapies with alternative mechanisms of action for BCG-naïve patients?

Gary Steinberg: Several therapies have demonstrated preclinical efficacy and are in clinical investigation. These include N-803, an IL-15 receptor superagonist that promotes innate and adaptive immune responses, which is under investigation in combination with BCG.

Alpha1H, a synthetic peptide derived from the human breast milk protein alpha-lactalbumin, which has tumoricidal activity, the mammalian target of rapamycin inhibitor, sirolimus, APL-1202, an inhibitor of methionine aminopeptidase 2, and the pan tyrosine kinase inhibitor sunitinib.

Neal Shore: What are the options for recurrent disease?

Gary Steinberg: In terms of immune checkpoint inhibitors, pembrolizumab + BCG is under investigation in a phase 1 trial in high-risk, BCG-recurrent NMIBC.

In the phase 3 KEYNOTE-676 trial, patients with high-risk, recurrent NMIBC after 1 BCG induction course will receive pembrolizumab + BCG or BCG alone. This trial was also updated to include a BCG-naïve population.

TMX-101, a toll-like receptor agonist with immunostimulatory properties, has also demonstrated promising anti-tumor activity in a phase 2 trial in recurrent carcinoma in situ NMIBC, where 50% of patients had received 2 or more prior courses of BCG.

Fibroblast growth factor receptor, or FGFR, inhibitors have shown clinical efficacy in advanced bladder cancer. Pemigatinib, an FGFR1-3 inhibitor, is a targeted therapy for BCG-recurrent NMIBC under investigation in phase 2 trials.

What are options of BCG-unresponsive NMIBC?

Neal Shore: Pembrolizumab is FDA approved for patients with high-risk, BCG-unresponsive NMIBC with carcinoma in situ.

Many immune checkpoint inhibitor trials are now underway in BCG-unresponsive NMIBC. It will be very interesting to see the outcome of these important studies. Various trials are also underway for a range of immunomodulators that have shown preliminary clinical activity.

Targeted therapies for BCG-unresponsive NMIBC include, as examples, the FGFR 1 through 4 inhibitor erdafitinib, APL-1202 + BCG, and vicinium, a fusion protein consisting of an epithelial cell adhesion molecule–specific antibody fragment fused to Pseudomonas exotoxin that inhibits protein synthesis.

Gary Steinberg: Examples of other novel approaches, gene therapies, vaccines, viral- and bacterial-based therapies under investigation include intravesical nadofaragene firadenovec, an interferon-α2b gene-mediated therapy, Ty21a, a commercial vaccine for typhoid fever that improved survival in bladder tumor–bearing mice, and CG0070, an oncolytic adenovirus with a GM-CSF transgene that is replication-selective for retinoblastoma pathway-defective tumors.

Neal Shore: A meta-analysis of patients with NMIBC reported that intravesical chemotherapy + BCG improved clinical outcomes versus BCG alone. Many chemotherapy trials are ongoing, for example, mitomycin C with BCG and alone; lenalidomide + BCG; gemcitabine + docetaxel; paclitaxel; or cisplatin-gemcitabine in BCG-naïve disease.

In BCG-recurrent disease, metformin and gemcitabine + BCG are being investigated. A combination of cabazitaxel, gemcitabine, and cisplatin is under investigation in BCG-unresponsive disease.

Gary Steinberg: Next-generation sequencing and multi-omics analyses of NMIBC tissue samples have identified potential new therapeutic targets, including those involved in DNA damage repair, p53 pathways, cell cycle, chromatin remodeling, and hormone receptor signaling.

Neal Shore: In terms of drug delivery, intravesical device-assisted therapies are showing improvements in drug tissue penetration versus passive-diffusion therapies, with encouraging clinical data emerging.

The most common include electromotive drug administration, conductive hyperthermic chemotherapy, and radiofrequency-induced thermochemotherapeutic effect.

Gary Steinberg: The current standard-of-care surveillance for NMIBC is cystoscopic evaluation using white light cystoscopy. However, it is limited in detecting carcinoma in situ and thus can lead to disease recurrence or progression.

Neal Shore: In a meta-analysis, blue light cystoscopy, which involves an intravesical instillation of a hexaminolevulinate and blue light to enhance tumor detection, significantly improved tumor detection with a subsequent reduction in tumor recurrence versus white light cystoscopy.

Gary Steinberg: In conclusion, several clinical trials with immune checkpoint inhibitors or other immunomodulators, targeted therapies, chemotherapy regimens, vaccines, or viral- and bacterial-based therapies with evidence of clinical activity in NMIBC are ongoing or have completed.

Advances in lesion detection and intravesical drug delivery systems are also improving the management of patients with NMIBC.