Re-evaluating pathologic response as a surrogate endpoint after neoadjuvant immune checkpoint inhibition in resectable mucosal HNSCC: Updated systematic review and meta-analysis.

e18078 Background: Neoadjuvant immune checkpoint inhibition (ICI) is increasingly studied in resectable mucosal head and neck squamous cell carcinoma (HNSCC), where major/partial pathologic response is commonly reported, but its value as a surrogate for survival remains uncertain. We performed an updated systematic review and meta-analysis to evaluate the association of pathologic response with disease-free survival (DFS) and to summarize grade ≥3 toxicity. Methods: We systematically searched five electronic databases from inception to 5 January 2026 for peer-reviewed English-language studies of adults (≥18 years) with mucosal HNSCC treated with neoadjuvant ICI. Prespecified outcomes were DFS by pathologic response (MPR and PPR; pooled as hazard ratios [HRs] with 95% CIs when reported/derivable) and grade ≥3 adverse events (pooled as risk ratios [RRs] with 95% CIs). Random-effects meta-analysis was performed, and heterogeneity was quantified using I². Results: The pooled DFS analysis for partial pathologic response (PPR) showed a non-significant trend toward benefit (HR 0.58, 95% CI 0.28–1.23; I²=1.9%), with a prediction interval of 0.13–2.64. In contrast, DFS for major pathologic response (MPR) was not statistically significant and was highly inconsistent across studies (HR 1.91, 95% CI 0.24–15.36; I²=88.7%), with an extremely wide prediction interval (0.00–9640.39). For grade ≥3 adverse events, neoadjuvant therapy was associated with a significant reduction in severe toxicity (RR 0.54, 95% CI 0.48–0.62; I²=0%), with a prediction interval of 0.24–1.23. Conclusions: Neoadjuvant ICI reduced grade ≥3 toxicity, but MPR/PPR were not reliable surrogates for DFS. Future trials should prioritize DFS endpoints with standardized response definitions and longer follow-up.