Reply to Editorial Comment: Matching-Adjusted Indirect Comparisons of Gemcitabine Intravesical System vs. Novel Agents in Bacillus Calmette-Guérin–Unresponsive High-Risk Non–Muscle-Invasive Bladder Cancer

We thank Dr. Clark for his thoughtful and balanced editorial perspective1 on our work2 and for underscoring both the progress and the complexity in managing patients with BCG-unresponsive HR-NMIBC. As Dr. Clark notes, the expanding number of FDA-approved bladder-preserving options represents a meaningful advance for patients who are ineligible for or decline cystectomy, but it also introduces challenges regarding treatment selection and sequencing in the absence of head-to-head trials. Our intent in conducting matching-adjusted indirect comparisons (MAICs) was not to advocate for a uniform treatment sequence or to suggest that one therapy should be viewed as a universal first-line option. Rather, our objective was to apply a recognized comparative effectiveness methodology to help contextualize available efficacy data across single-arm trials, acknowledging their limitations, and to provide additional information that may support clinical, payer, and health-technology assessment decision making in the absence of head-to-head comparisons. In the absence of head-to-head randomized controlled trials, the National Institute for Health and Care Excellence (NICE) Decision Support Unit recognizes MAICs as an appropriate population-adjusted methodology to contextualize comparative treatment effects when individual patient-level data are available for at least one intervention.3 As highlighted in both the Methods and Discussion of our work,2 we explicitly recognize the methodological limitations of unanchored MAICs. We fully agree that treatment decisions for BCG-unresponsive HR-NMIBC must remain individualized, incorporating patient-specific factors such as disease characteristics, prior therapies, comorbidities, logistical considerations, and patient preferences. We agree that continued data maturation, longer-term follow-up across trials, and additional evidence generation will be critical to better informing sequencing considerations. We appreciate commentary and believe it appropriately reinforces the need for cautious interpretation of indirect treatment comparisons while recognizing their role in informing clinical judgment until prospective head-to-head trials become available.