Yair Lotan, MD, is a professor of urology, chief of Urologic Oncology, and holder of the Jane and John Juston Distinguished Chair in Urology, in Honor of Claus G. Roehrborn, MD, the University of Texas (UT) Southwestern Harold C. Simmons Comprehensive Cancer Center; as well as the medical director of the Urology Clinic at UT Southwestern and Parkland Health and Hospital System

Dr Lotan on Guideline-Supported Treatment Decision-Making for NMIBC

“If you look at guidelines, you need to really recommend cystectomy, which has the highest cure rate for any patient with BCG-unresponsive disease.”

Yair Lotan, MD, a professor of urology, chief of Urologic Oncology, and holder of the Jane and John Juston Distinguished Chair in Urology, in Honor of Claus G. Roehrborn, MD, the University of Texas (UT) Southwestern Harold C. Simmons Comprehensive Cancer Center; as well as the medical director of the Urology Clinic at UT Southwestern and Parkland Health and Hospital System, discussed recommended treatment options for patients with BCG-unresponsive NMIBC.

In patients with BCG-unresponsive NMIBC, current guidelines strongly recommend radical cystectomy, as it offers the highest likelihood of long-term cure, Lotan began. However, decisions surrounding bladder-sparing approaches depend on multiple clinical factors, including tumor stage, histologic features, patient comorbidities, and life expectancy, he cautioned.

Patients with high-grade T1 disease—particularly those with multifocal or high-volume tumors—who are young and have a long life expectancy, are considered at elevated risk of disease progression and metastasis, Lotan explained. Therefore, cystectomy is typically advised for this population, he said. Conversely, older or frail patients, especially those with limited high-grade Ta disease or carcinoma in situ, may be more appropriate candidates for bladder-sparing therapies, he stated. Retrospective and limited prospective data support a relatively low short-term risk of progression in these cases, making 1 or 2 additional intravesical or systemic treatment attempts reasonable, according to Lotan.

Treatment selection is multifactorial, with complete response (CR) rates and toxicity profiles being key considerations, Lotan emphasized. Systemic immunotherapy with pembrolizumab has shown CR rates of approximately 40%, with durable responses in approximately 60% of responders, though the rate of sustained responses by 1 year drops to approximately 20%, he reported. These agents are generally considered for patients unable to tolerate intravesical therapy due to poor bladder capacity, as they avoid direct bladder instillation but carry systemic toxicity, he highlighted.

Although intravesical agents, such as nadofaragene firadenovec (Adstiladrin) and N-803 (Anktiva), have favorable tolerability profiles and are associated with low systemic toxicity, they come at a substantial cost—approximately $60,000 and $230,000, respectively, Lotan noted. Adstiladrin may be more convenient for patients with transportation challenges due to its quarterly dosing schedule, he said. Intravesical gemcitabine and docetaxel, though lacking prospective trial data, are widely used based on retrospective evidence and low cost, he added. Furthermore, clinical trials remain a vital consideration and should be discussed with all eligible patients, as they may offer access to innovative therapies and contribute to future treatment advancements, Lotan concluded.

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Yair Lotan, MD, discusses guideline-supported treatment avenues for patients with BCG-unresponsive NMIBC.

The Benefits and Complications Associated With Radical Cystectomy in BCG-Unresponsive NMIBC  

Dr Lotan on the Benefits and Complications Associated With Radical Cystectomy in BCG-Unresponsive NMIBC  

“If a patient has the bladder removed when their cancer is noninvasive, their outcomes are superior to waiting until the cancer becomes invasive. Therefore, there is an opportunity to cure that patient. However, the consequences of bladder removal are lifelong and can have implications on urinary function—because [patients] have to have a urinary diversion;sexual function; and potentially bowel function.”

Yair Lotan, MD, professor, urology, chief, urologic oncology, Jane and John Justin Distinguished Chair in Urology, UT Southwestern Harold C. Simmons Comprehensive Cancer Center; medical director, Urology Clinic, UT Southwestern and Parkland Health and Hospital System, discusses the benefits and complications associated with radical cystectomy for patients with Bacillus Calmette–Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC).

The National Comprehensive Cancer Network and American Urological Association guidelines outline multiple FDA-approved treatment options for patients with BCG-unresponsive NMIBC, along with commonly used non–FDA-approved therapies, Lotan begins. Among these, radical cystectomy remains the definitive treatment option and offers the highest likelihood of cure, particularly when performed at a time when the disease is still noninvasive, he states. Delaying bladder removal until cancer progresses to an invasive state reduces the chance of achieving long-term disease control and cure, underscoring the importance of early intervention, Lotan states.

Despite its curative potential, bladder resection has significant long-term consequences, he notes. Patients undergoing resection require a urinary diversion, which can affect urinary, sexual, and bowel function, he explains, adding that these functional changes are lifelong and can affect quality of life. Radical cystectomy is also associated with a relatively high rate of short-term complications, Lotan adds. It is a major surgical procedure that involves a recovery period spanning weeks to months, he reiterates. Most patients require a hospital stay of approximately 5 to 6 days, regardless of whether the surgery is performed via an open approach or robotically, Lotan concludes.

Yair Lotan, MD, discusses the benefits and complications associated with radical cystectomy for patients with BCG-unresponsive NMIBC.
 

Dr Lotan on the Benefits and Complications Associated With Radical Cystectomy in BCG-Unresponsive NMIBC

Future Research Directions in BCG-Unresponsive NMIBC

Dr Lotan on the Future Research Directions in BCG-Unresponsive NMIBC

“This is a rapidly evolving field. We had [nogapendekin alfa inbakicept plus BCG] approved [for patients with NMIBC in 2024], we will probably have 2 new drugs approved in 2025, and maybe another the following year. [However,] we still have a lot to learn.”

Yair Lotan, MD, professor, urology, chief, urologic oncology, Jane and John Justin Distinguished Chair in Urology, UT Southwestern Harold C. Simmons Comprehensive Cancer Center; medical director, Urology Clinic, UT Southwestern and Parkland Health and Hospital System, discusses the evolving treatment paradigm for patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) and future research directions in this field.

Patients with BCG-unresponsive NMIBC often seek bladder-preserving alternatives to radical cystectomy, Lotan begins. This preference is particularly relevant for older and medically complex patients who face higher risks associated with major surgery, he explains. However, even younger, healthier patients frequently prioritize bladder preservation to maintain urinary and sexual function, Lotan notes.

Bladder-preserving NMIBC management strategies are advancing rapidly, Lotan emphasizes. In 2024, 

nogapendekin alfa inbakicept-pmln (Anktiva) received FDA approval

 for the treatment of patients with BCG-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors. He adds that there could be 2 additional BCG-unresponsive NMIBC drug approvals in 2025 and possibly more in subsequent years. Despite these advancements, most research in this disease has relied on single-arm trials rather than head-to-head comparisons, Lotan says. This limits the ability to draw definitive conclusions about the relative efficacy of new therapies, he explains. Challenges such as population heterogeneity, variations in treatment approaches, and diagnostic nuances in detecting CIS further complicate assessments, he notes.

Although the availability several treatment agents for patients with NMIBC represents a significant step forward, it is crucial for urologists to remain informed about emerging therapies and to discuss these options with patients, Lotan states. This shared decision-making approach empowers patients to make informed choices that align with their clinical and personal priorities, he concludes.

Yair Lotan, MD, discusses the evolving treatment paradigm for Bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer.

Dr Lotan on Ongoing Research With Novel Agents in BCG-Unresponsive NMIBC

Yair Lotan, MD, professor, urology, chief, urologic oncology, Jane and John Justin Distinguished Chair in Urology, UT Southwestern Harold C. Simmons Comprehensive Cancer Center; medical director, Urology Clinic, UT Southwestern and Parkland Health and Hospital System, discusses ongoing research with novel agents in patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC).

Several agents are under investigation in clinical trials in this patient population, many of which may receive FDA approval in the future. First, the phase 2b SunRISe-1 trial (NCT04640623) is evaluating TAR-200, which uses a novel drug delivery system that facilitates the sustained release of gemcitabine directly into the bladder. The device is inserted and removed cytoscopically and is replaced every 3 weeks during the first 6 months of treatment. In data presented during the 

, the complete response (CR) rate was 83.5% (95% CI, 74%-91%) with TAR-200 monotherapy, and the estimated 12-month duration of response rate was 65.7% (95% CI, 45.2%-80.1%).

In cohort A of the single-arm, phase 2 KEYNOTE-057 trial (NCT02625961), at 3 months, the CR rate was 41% with pembrolizumab monotherapy in patients with high-risk disease without carcinoma in situ. Regarding a phase 3 trial (NCT02773849) investigating nadofaragene firadenovec-vncg (Adstiladrin), at 3 months, the CR rate with this agent was 53.4%. At 1 year, the CR rate was 45.5%. Additionally, in cohort A of the phase 2/3 QUILT-3.032 trial (NCT03022825), at a median follow-up of 23.9 months, the rate of CR at any time with nogapendekin alfa inbakicept-pmln (Anktiva; N-803) plus BCG was 71% (95% CI, 59.6%-80.3%). Finally, for those enrolled in the phase 3 BOND-003 trial (NCT04452591), the rate of CR at any time with cretostimogene grenadenorepvec monotherapy was 75.2% (95% CI, 65%-83%), and responses were durable, Lotan explains.

Lastly, the phase 1/2 LEGEND trial (NCT04752722) is evaluating the intravesical therapy EG-70 in patients with high-risk, BCG-unresponsive NMIBC. The phase 1 portion of this trial is complete, and the phase 2 portion is ongoing, he notes. Early data from this trial have shown promising responses with EG-70, and response durability data will help determine whether this agent should join the NMIBC treatment paradigm, Lotan concludes.

Yair Lotan, MD, discusses ongoing research with novel agents in patients with BCG-unresponsive non–muscle-invasive bladder cancer.

Yair Lotan, MD, discusses factors informing treatment selection for patients with BCG-unresponsive non-muscle invasive bladder cancer.  

Dr Lotan on Factors Informing Treatment Selection in BCG-Unresponsive NMIBC

Yair Lotan, MD, professor, urology, chief, Urologic Oncology; Jane and John Justin Distinguished Chair in Urology, UT Southwestern Medical Center; medical director, Urology Clinic, UT Southwestern, Parkland Health and Hospital System, discusses factors informing treatment selection for patients with Bacillus Calmette–Guérin (BCG)–unresponsive non-muscle invasive bladder cancer (NMIBC).

Balancing the associated adverse effects and potential efficacy of treatments against the associated risks is a crucial part of the conversation between oncologists and patients, particularly when discussing treatment options for bladder cancer, Lotan begins. The ultimate decision rests with the patient and depends on several factors, including age, comorbidities, surgical risks, and life expectancy, he emphasizes. For example, a patient with a longer life expectancy might opt for a more aggressive treatment with a higher cure rate, even if it comes with a greater morbidity risk, Lotan says.

The presence of disease invasion also plays a key role in treatment decision-making, Lotan continues. Patients with T1 disease that has invaded the lamina propria face a higher risk of disease progression compared with those who have noninvasive disease confined to the mucosa, Lotan states. He adds that the presence of invasive disease may prompt patients to consider more aggressive interventions. Additionally, the decision-making process can be influenced by the natural history of the disease and the patient’s overall prognosis, he notes.

Another factor that affects treatment selection is the response to initial treatment, Lotan adds. If a patient’s disease recurs after they have received noninvasive therapeutic options, they may need to reconsider their treatment plan, he explains. In some cases, patients initially resist more aggressive treatments, such as bladder removal, but after multiple unsuccessful attempts with other therapies, they may ultimately opt for surgery, Lotan says. Ongoing disease evaluation supports personalized, evolving treatment discussions that adapt to patients’ changing circumstances and preferences, he concludes.

Yair Lotan, MD, discusses factors informing treatment selection for patients with BCG-unresponsive non-muscle invasive bladder cancer.

Yair Lotan, MD

Articles

Dr Lotan on Guideline-Supported Treatment Decision-Making for NMIBC

Dr Lotan on the Benefits and Complications Associated With Radical Cystectomy in BCG-Unresponsive NMIBC

Dr Lotan on the Future Research Directions in BCG-Unresponsive NMIBC

Dr Lotan on Ongoing Research With Novel Agents in BCG-Unresponsive NMIBC

Dr Lotan on Factors Informing Treatment Selection in BCG-Unresponsive NMIBC