Single-arm design in a heterogeneous cohort limits causal inference

The trial references historical controls (eg, BC2001)2 but includes a distinct population with 28% T3/T4 tumors and 11% node-positive patients—groups under-represented in prior CRT studies.3 This heterogeneity complicates attribution of outcomes solely to nivolumab. For instance, patients with ≥3 high-risk features (eg, T4, N+) had a median FFS of 8.2 months versus 45.2 months in lower-risk groups, suggesting intrinsic tumor biology may dominate over therapeutic benefit.4 A single-arm design cannot disentangle treatment effect from confounding by baseline risk. Future trials should adopt randomized designs comparing CRT±nivolumab, stratified by molecular subtypes (eg, basal vs luminal)5 and predefined risk criteria (eg, genomic instability scores).

Methodological gaps in cfDNA biomarker validation

The reliance on shallow whole-genome sequencing (sWGS) to derive copy number instability (CNI) scores lacks validation against tissue-based genomics or orthogonal cell-free DNA (cfDNA) assays (eg, targeted sequencing). While CNI ≤25 correlated with improved OS (49.6 vs 20.5 months, p=0.0024), the threshold appears arbitrary and may not reflect tumor evolution dynamics. Recent studies demonstrate that integrating single-nucleotide variants (SNVs) and methylation signatures enhances circulating tumor DNA detection sensitivity in urothelial cancer.5 Longitudinal sampling beyond Cycle 4 is also needed to track clonal adaptation under immunotherapy pressure. A multiomics approach (sWGS+SNVs+methylation) would better capture residual disease biology and refine prognostic utility.

Survivorship bias in Quality of Life assessments

Quality of Life analyses showed no significant decline (p=0.94), but only 39% of patients completed 12 nivolumab cycles, with 18% discontinuing due to progression. Survivorship bias likely skews results, as patients with early progression or toxicity were excluded from later assessments. The FBSI-18 tool, while validated, lacks sensitivity to immune-related symptoms (eg, chronic fatigue, subclinical inflammation). Incorporating immunotherapy-specific patient-reported outcomes (PROs) (PRO-Common Terminology Criteria for Adverse Events)6 would provide a more nuanced evaluation of treatment tolerability.

In conclusion, the NEXT trial highlights the feasibility of adjuvant nivolumab in MIUC but underscores critical gaps in study design, biomarker validation, and clinical translation. Addressing these through randomized trials, advanced cfDNA profiling, and biomarker-driven therapeutic escalation will clarify nivolumab’s role in bladder preservation paradigms. We urge the authors to respond to these points to enrich the ongoing discourse.