In this report, we present the sum-mary of our findings and highlights of the policy discussion with key stake-holders held at a public meeting of the Midwest Comparative Effectiveness Public Advisory Council (CEPAC) on November 20, 2020. Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease. In this issue of NEJM Evidence, Chamie et al.6 report on the third major single-arm trial in BCG-unresponsive NMIBC, which evaluated intravesical administration of an interleukin-15 superagonist, nogapendekin alfa inbakicept, in combination with BCG (NAI/BCG). In such a scenario, two unmet clinical needs could emerge. First, reliable biomarkers could identify early those patients who do not respond to BCG immunotherapy. Second, the current arsenal of new intravesical and systemic treatment candidate agents could be expanded for bladder-sparing strategies. Pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept have been approved for BCG-unresponsive NMIBC since 2020. Detalimogene voraplasmid, cretostimogene grenadenorepvec, and TAR-200 are promising agents in development, showing high complete response rates. Intravesical anti-PD-1/PD-L1 agents like pembrolizumab and nadofaragene firadenovec have demonstrated efficacy and safety in BCG-unresponsive NMIBC, leading to regulatory approval. Additionally, BCG combined with immunostimulatory protein complexes (e.g., N-803) achieved high complete response rates while preserving quality of life. The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of nadofaragene firadenovec, oportuzumab monatox, and pembrolizumab for BCG-unresponsive NMIBC. With agents like pembrolizumab, nadofaragene firadenovec, and N-803 demonstrating promising efficacy, the focus is shifting toward optimizing treatment sequencing, improving durability of response, and refining patient selection criteria. We sought to determine the efficacy of different interventions in recent trials accruing patients fulfilling the strict BCG-unresponsive definition established by the US Food and Drug Administration. Nadofaragene firadenovec-vncg received US Food and Drug Administration approval for bacille Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bla….