Mark D. Tyson, MD, MPH

Mark D. Tyson II, MD, MPH, contextualizes the cretostimogene data within the broader BCG-unresponsive NMIBC treatment landscape, addresses the methodologic limitations of cross-trial comparison, discusses the heavily pretreated nature of the BOND-003 population, reviews his approach to treatment sequencing across available bladder-sparing options, and offers his central take-home message for urologists managing high-risk BCG-unresponsive disease.

Mark D. Tyson II, MD, MPH, reviews the safety and tolerability profile of cretostimogene in BOND-003, including the absence of grade 3 or higher treatment-related adverse events, a 97% protocol completion rate, and the practical workflow considerations that would govern administration of cretostimogene in a urology practice if the agent receives FDA approval.

In this episode of The UroOnc Minute, Mark D. Tyson II, MD, MPH, discusses the importance of BCG maintenance therapy in NMIBC and shares strategies for navigating treatment barriers and toxicity.

Mark D. Tyson II, MD, MPH, presents the efficacy results from BOND-003, Cohort C, including the 75.5% complete response rate at any time point, durability outcomes at 12 and 24 months, a median duration of response of 27.9 months, re-induction conversion data, and cystectomy-free survival rates of 89.2% and 81.3% at 12 and 24 months, respectively.

Mark D. Tyson II, MD, MPH, describes the design of the phase 3 BOND-003 trial, Cohort C, including the patient eligibility criteria, induction and maintenance dosing schedule, the clinical rationale and immunologic basis for allowing re-induction in patients with persistent disease at 3 months, and the definition and significance of the primary end point.

Mark D. Tyson II, MD, MPH, explains the mechanism of action of cretostimogene grenadenorepvec, including its selective replication in Rb-E2F pathway–altered cancer cells and its dual activity via tumor cell lysis and GM-CSF–mediated immune amplification, and reviews the early clinical evidence that supported its FDA Breakthrough Therapy and Fast Track Designations.

Mark D. Tyson II, MD, MPH, characterizes the clinical landscape for patients with BCG-unresponsive NMIBC, outlines the real-world barriers that make bladder-sparing approaches important despite cystectomy's guideline-preferred status, and describes the efficacy and durability benchmarks he applies when evaluating new bladder-preserving therapies.

Mark D. Tyson II, MD, MPH, discusses findings from the phse 3b PATAPSCO study, evaluating durvalumab plus BCG for patients with BCG-naïve, high-risk NMIBC.

"The implication for real-world decision-making is that this drug appears to hold up to what was seen in the trial," says Mark D. Tyson II, MD, MPH.

Panelists discuss how it would be preferred that BCG monotherapy not remain the first-line treatment for intermediate-risk and high-risk disease within the next 10 years. It is encouraged that the future of first-line treatment be a noninfectious agent that would be easier to develop and include more data.

Panelists discuss how PD-L1 inhibitors such as durvalumab and sasanlimab represent a promising frontier in non–muscle-invasive bladder cancer (NMIBC) treatment. These immunotherapies work by unleashing the body’s immune response against cancer cells, potentially offering new options for patients whose disease doesn’t respond to conventional therapies such as BCG. Their ongoing phase 3 trials could establish immunotherapy as a valuable addition to the NMIBC treatment landscape.

Panelists discuss how both TAR-200 and UGN-102/103 represent innovative approaches to intravesical drug delivery for bladder conditions. TAR-200 uses a novel silicone-based system designed for controlled gemcitabine release, potentially offering extended drug exposure compared with conventional instillations. UGN-102 and UGN-103 employ a proprietary RTGel technology that transforms from liquid to gel form at body temperature, allowing for longer retention of mitomycin (UGN-102) and high-dose botulinum toxin (UGN-103), respectively, in the bladder.

Panelists discuss how cretostimogene grenadenorepvec is an intravesical oncolytic virus therapy targeting BCG-unresponsive bladder cancer through selective replication in tumor cells and immune stimulation via granulocyte-macrophage colony-stimulating factor expression.

Panelists discuss how for patients with BCG-unresponsive bladder cancer, treatment selection depends on key factors including tumor characteristics (carcinoma in situ vs papillary), patient fitness, and preferences. Standard options include radical cystectomy (the gold standard) or bladder-preserving approaches such as pembrolizumab, intravesical chemotherapy, or clinical trials. The decision requires careful individualization based on risk stratification, comorbidities, and shared decision-making.

Panelists discuss how FDA approvals have expanded options for BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC), with pembrolizumab, nogapendekin alfa inbakicept-pmln, and nadofaragene firadenovec-vncg offering new immunotherapy and gene therapy approaches.

Panelists discuss how BCG-unresponsive bladder cancer is defined by disease persistence/recurrence within 6 to 12 months of adequate BCG therapy. Treatment options include cystectomy, intravesical chemotherapy, immunotherapy, or clinical trials.

Panelists discuss how low-risk non–muscle-invasive bladder cancer (NMIBC) requires transurethral resection of bladder tumor (TURBT) with surveillance. Intermediate-risk disease needs adjuvant intravesical chemotherapy. High-risk cases receive BCG induction/maintenance therapy after TURBT, with close monitoring.

Panelists discuss their views on using cretostimogene as monotherapy versus combination therapy, the importance for urologists to stay updated on advances for managing BCG-unresponsive NMIBC, and the potential impact of combining cretostimogene with pembrolizumab on addressing unmet needs in NMIBC care.

Panelists discuss whether the trial results support investigating cretostimogene with other checkpoint inhibitors and provide insights into notable ongoing trials exploring cretostimogene for intermediate- or high-risk NMIBC, such as BOND-003 and PIVOT-006.

Panelists discuss how the combination therapy of cretostimogene plus pembrolizumab offers a promising new approach for managing BCG-unresponsive non-muscle-invasive bladder cancer, highlighting its potential benefits and the implications of its FDA Breakthrough Therapy Designation for clinical practice.

Key opinion leaders examine the comparative safety profiles and response durations of combination therapy versus monotherapy in the treatment of BCG-unresponsive carcinoma in situ with or without papillary disease.

Experts discuss the results of the CORE-001 Trial.

Experts compare Cretostimogene and BCG Administration Methods

Experts discuss the patient quantity and qualifications for the CORE-001 trial.

Experts give an overview of the ASCO 2024 data.

Experts discuss available therapies beyond BCG.

Experts discuss the rate of recurrence following first-line BCG therapy.

Trinity Bivalacqua, MD, PhD and Mark Tyson, MD, MPH discuss the current shortage of BCG therapy and how that has impacted clinical practice management.

After briefly introducing themselves, Trinity Bivalacqua, MD, PhD and Mark Tyson, MD, MPH discuss approximately how many newly diagnosed bladder cancer patients have non-muscle invasive bladder cancer, or NMIBC.

In this final episode, panelists conclude with reflections on the significant progress made in treating NMIBC over the past decade, particularly in the last 5 years. Looking ahead to 2024, experts in urology express excitement about investigational treatments (ie, cretostimogene grenadenorepvec and UGN 102), the potential for personalized medicine, emphasizing the need to understand molecular characteristics of the disease for better treatment customization. The session also highlights the importance of balancing quality of life with effective treatment strategies, and the prospect of utilizing emerging therapies early in the disease process.