Dr. Joshua Meeks presented at the 2024 Society of Urologic Oncology (SUO) annual meeting, advocating for a shift in trial designs for drugs targeting Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). He argued that the field should move beyond the traditional single-arm registration trials, which have been the basis for all currently approved agents in this space.
Limitations of Single-Arm Trials
Dr. Meeks highlighted that the lack of comparative data on safety and efficacy is a significant drawback of single-arm trials. The heterogeneous nature of patient populations, with varying BCG exposure histories and disease characteristics, further complicates the interpretation of trial results. Some patients receive full BCG doses, while others receive only partial doses. The number of BCG induction and maintenance cycles also varies, as does the time from the last BCG instillation to recurrence. The volume of cancer present at the time of drug therapy can also differ significantly. This variability raises questions about the generalizability of the findings and the optimal treatment strategies for different patient subgroups.
The Role of Biomarkers and Biopsies
To address these limitations, Dr. Meeks suggested incorporating urinary biomarkers, such as utDNA, into the management paradigm to facilitate early detection of more aggressive variants. Data presented at ASCO GU 2024 demonstrated that urinary comprehensive genomic profiling (uCGP) at baseline and after four cycles of atezolizumab treatment can identify genomic patterns associated with an increased risk of high-grade disease persistence, recurrence, or progression in BCG-unresponsive NMIBC treated with immune checkpoint inhibition. He also emphasized the importance of mandated bladder biopsies at set time intervals, as demonstrated in the nadofaragene trial, where several patients with normal cystoscopies were found to have carcinoma in situ (CIS) at the time of protocol-mandated biopsies.
The Shift Towards Randomized Controlled Trials
The rationale for using single-arm trials in the past was based on the lack of effective medical therapies for BCG-unresponsive NMIBC, with radical cystectomy being the only alternative. However, with the availability of multiple FDA-approved standards of care, Dr. Meeks argued that randomized controlled trials are now both feasible and necessary. He proposed that any of these drugs could serve as a control arm in randomized comparison trials, ensuring that all patients receive potentially active drugs. He suggested a 2:1 randomization scheme to maximize the information gained from the investigational drug arm.
SunRISe-5 Trial as a Model
Dr. Meeks cited the SunRISe-5 trial as an example of a well-designed randomized trial in this space. SunRISe-5 is a Phase III trial evaluating the safety and efficacy of TAR-200 compared with investigator's choice of intravesical chemotherapy in patients with papillary-only, high-risk NMIBC that recurs within the first year of BCG treatment who either refuse or are ineligible for radical cystectomy. Patients are randomized 1:1 to either TAR-200 monotherapy or intravesical gemcitabine or mitomycin.
Proposed Framework for Future Trials
Dr. Meeks proposed a framework for future trial designs in BCG-unresponsive NMIBC, where the investigational drug is compared to a standard of care. He emphasized the importance of blue light cystoscopy with mapping biopsies at both 3 and 12 months, with durability as the primary endpoint and complete response as a secondary endpoint. He also suggested exploring the adoption of STAMPEDE-like platform trials to further accelerate drug development in this area.
Mitigating Bias in Single-Arm Trials
Dr. Meeks outlined several measures to mitigate bias in single-arm trials, including mandating central pathology review, using standardized cystoscopy (potentially recorded), mandating mapping biopsies at set intervals, decreasing the heterogeneity of patients, and using clinically meaningful endpoints such as 12-month durability.
Conclusion
Dr. Meeks concluded that the time is now for randomized controlled trials in the BCG-unresponsive NMIBC space. While single-arm trials have been successful in leading to drug approvals, they may lack utility moving forward given the existence of numerous standards of care. He emphasized that funding support from pharmaceutical companies and entities such as the NIH will be crucial moving forward.
