Emerging Therapies in Pretreated NMIBC

A roundtable discussion, moderated by Christopher Wallis, MD, PhD, FRCSC, focused on patient selection and treatment considerations for non-muscle invasive bladder cancer, including recent data from SUO 2023. Dr. Wallis was joined by Sia Daneshmand, MD; Piyush Agarwal, MD; and Sima Porten, MD, MPH.

In the next segment of the roundtable series, the panel considers emerging therapies across different risk stratifications, including implications from the ATLAS, ENVISION, and BOND-003 studies.

View the next segment on When to Consider Intravesical Therapy Versus Chemoablation in NMIBC.

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Dr. Wallis: I mentioned earlier that there has been significant progress in the non-muscle invasive disease space, particularly in the BCG-refractory or unresponsive category. Dr. Daneshmand, could you provide an overview of the changes observed in the BCG-unresponsive or pre-treated space and how this may transition into earlier stages?

Dr. Daneshmand: Exciting developments have occurred with novel agents and delivery mechanisms, such as oral and intravesical therapies, and even devices implanted in the bladder for drug delivery. The landscape now includes various trials exploring different mechanisms of action, from T helper responses and cytokine release to chemoblative therapies and sustained drug delivery, like TAR-200 gemcitabine. These innovations are building upon our knowledge of molecular targets on cancer cells, with targeted drugs becoming available. The array of options spans intravesical treatments, gene therapy, ablative therapies, drug devices with chemotherapeutics, and systemic therapies, including checkpoint inhibitors. The challenge is to enhance the effectiveness of BCG and explore new therapeutic combinations.

Dr. Wallis: You mentioned BCG-pretreated space. Dr. Agarwal, do you believe patients must have prior BCG exposure to benefit from these new drugs? How extensively should we explore these options in patients who have not received our current standard of care?

Dr. Agarwal: The definition of BCG-unresponsive disease has posed challenges, especially during BCG shortages. While I believe BCG is primarily a means to induce an immune response, the ongoing BRIDGE trial comparing BCG head-to-head with gemcitabine dose may provide insights. If we establish comparable efficacy, we could potentially move away from BCG. However, currently, BCG remains the standard of care for high-risk disease. Timing of BCG administration after resection is crucial, with a suggested optimal window of 2 to 6 weeks post-resection.

Dr. Wallis: Dr. Porten, do you agree with Dr. Agarwal’s perspective on the challenges posed by BCG shortages and the potential for using other drugs in a frontline setting?

Dr. Porten: The BCG shortages affected treatment strategies, leading to difficulties in classifying patients and sequencing treatments. Patients who were initially promised BCG suddenly faced uncertainties. Moving towards a scenario with more than one front-line option could be key for better patient outcomes. However, defining new indications and optimizing sequencing will be critical.

Dr. Daneshmand: If these treatments move into the frontline, the definition of BCG-refractory will need reevaluation. Sequencing and defining patients’ experiences with BCG or other treatments will become complex, requiring careful consideration and academic collaboration to determine optimal sequences.

Dr. Wallis: Let’s shift our focus to recent trial data. Dr. Daneshmand, what are your thoughts on the BOND-003 trial, particularly its implications for BCG-unresponsive patients?

Dr. Daneshmand: The BOND-003 trial data is promising, showing a 75% complete response rate at any time point for cretostimogene grenadenorepvec alone in BCG-unresponsive patients. This is notable for its well-tolerated nature, with low-grade toxicities. The long-term durability of these responses, especially at 12 to 18 months, remains crucial. However, the initial results are exciting and show a departure from the conventional 30% response rates we are accustomed to.

Dr. Wallis: Dr. Agarwal, what is your perspective on the BOND-003 trial and its outcomes?

Dr. Agarwal: The BOND-003 trial, with its combination of cretostimogene grenadenorepvec alone in BCG-unresponsive patients, presents exciting data with high complete response rates, around 75%. While acknowledging the need for 12-month data, the study’s inclusion of salvage therapy with a second induction in case of non-response is a thoughtful approach. Future trials could explore similar strategies to salvage patients based on underlying mechanisms.

Dr. Wallis: Dr. Porten, do you share the optimism regarding the BOND-003 trial, and how does it compare to other recent studies in the field?

Dr. Porten: The BOND-003 trial aligns with other recent studies, showcasing higher response rates in the 70% range. The challenge lies in determining the optimal sequencing of these therapies when multiple options become available. Patients will benefit from having more tools in the toolbox, but it will require careful consideration and discussions to tailor treatments to individual needs and preferences.

Dr. Wallis: Dr. Daneshmand, how do you see the evolving landscape of bladder cancer treatment, particularly with the introduction of multiple therapeutic options?

Dr. Daneshmand: The growing number of therapeutic options demands a shift in our approach to sequencing and defining patient experiences. The future may involve adapting to changing mechanisms of action with each line of therapy. Similar to the complexity seen in prostate cancer, the challenge will be to determine the most effective sequences and engage in discussions with patients to align treatments with their preferences and circumstances.

Dr. Wallis: Dr. Agarwal, let’s turn our attention to the ATLAS study. Could you provide a summary of the study’s design and outcomes?

Dr. Agarwal: The ATLAS study focused on UGN-102, a reverse polymer device delivering mitomycin, in patients with low-grade intermediate-risk non-muscle invasive bladder tumors. The trial compared upfront transurethral resection of bladder tumor (TURBT) to upfront UGN-102. At 3 months, both arms demonstrated response rates around 65%. Recurrent patients underwent salvage TURBT, and recurrence-free survival appeared favorable in the UGN-102 arm. The study suggests chemoablation with UGN-102 is comparable to upfront TURBT.

Dr. Wallis: Dr. Porten, how would you interpret the results of the ATLAS study, and what clinical information do we need to confidently consider chemoablation upfront?

Dr. Porten: The ATLAS study indicated that chemoablation with UGN-102 is comparable to upfront TURBT in terms of response rates, particularly in low-grade intermediate-risk bladder tumors. However, the challenge remains in patient selection, especially concerning the representation of low-grade disease in biopsy samples. Clinicians need to navigate the heterogeneity of these tumors and determine whether upfront TURBT is necessary to avoid under-treatment of potential high-grade lesions.

Dr. Wallis: Dr. Agarwal, we also have data from the ENVISION study. How does this study compare to ATLAS, and what new information does it provide?

Dr. Agarwal: The ENVISION study was a single-arm trial using UGN in patients with intermediate-risk bladder cancer. The study demonstrated a 79% complete response rate at 3 months with low toxicity. While the response rate seems higher than that of ATLAS, we lack comprehensive data on patient selection and factors influencing these outcomes. It emphasizes the need for further research, including 6- and 12-month data, to assess the durability of the response.

Dr. Wallis: Dr. Porten, considering the clinical benefits and potential appeal to patients, how do you envision the utilization of chemoablation with UGN-102 in practice?

Dr. Porten: ENVISION represents a potential strategy for managing patients with low-grade disease where surveillance, occasional ablation in the office, or traditional intravesical chemotherapy are considered. The tool adds another option to discussions with patients, allowing customization based on individual distress factors. Long-term data demonstrating durability will be crucial for making this a viable long-term option.

Dr. Daneshmand: The patient’s perspective is vital. Understanding what distresses them the most, whether it’s the procedure itself, anticipation, or the recurrence risk, will guide discussions. For patients with multiple recurrences and prohibitive factors for TURBT, chemoablation with UGN-102 could offer a valuable option.

Dr. Wallis: In closing, Dr. Daneshmand, which patients would you consider for chemoablation with UGN-102 assuming it becomes available?

Dr. Daneshmand: Ideal candidates for chemoablation with UGN-102 would include those with multiple satellite lesions post-TURBT, especially when resection is challenging or when dealing with elderly patients on anticoagulation. The goal is to prevent progression rather than necessarily achieving complete responses in these cases.