Immunotherapy in Head and Neck Squamous Cell Carcinoma With PD-L1 Combined Positive Score Less Than 1

Importance: Immune checkpoint inhibitors (ICIs) are recommended for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), including patients with tumors with a programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS) of less than 1. However, the benefit of ICIs in this population remains uncertain. Objective: To quantify the probability that ICIs are associated with improved or reduced survival in HNSCC with a PD-L1 CPS of less than 1 compared with standard non-ICI therapy. Data Sources: Systematic search of PubMed, Embase, Web of Science, and ClinicalTrials.gov from database inception to January 11, 2026. Study Selection: Phase 3 randomized clinical trials comparing ICI-based regimens vs standard non-ICI control in HNSCC reporting outcomes in the subgroup with a PD-L1 CPS of less than 1. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. Bayesian random-effects meta-analysis estimated hazard ratios (HRs) with 95% credible intervals (CrIs) and the posterior probability of HR being greater than 1.0 (favoring control), a continuous measure of evidence. Frequentist random-effects meta-analysis also estimated HRs with 95% CIs and P values to assess statistical significance. All processes were performed independently by at least 2 reviewers, with discrepancies resolved through discussion or adjudication by a senior investigator. Main Outcomes and Measures: The primary outcome was overall survival (OS), and the secondary outcome was a composite of disease-free survival (DFS), progression-free survival (PFS), and event-free survival (EFS). Results: The meta-analysis included 7 randomized clinical trials from 2018 to 2025 involving 630 patients with tumors with a PD-L1 CPS of less than 1. In the recurrent/metastatic setting (3 trials), the bayesian HR for OS was 1.42 (95% CrI, 0.93-2.06), with a posterior probability of an HR exceeding 1.0 of 95.6%. The frequentist HR was 1.46 (95% CI, 1.17-1.83; P < .001). In the locally advanced setting (4 trials), the bayesian HR for the composite of DFS, PFS, and EFS was 1.19 (95% CrI, 0.72-2.06), with posterior probability of an HR exceeding 1.0 of 76.8%. Across all trials, the bayesian HR was 1.43 (95% CrI, 0.97-2.07) for OS (4 trials) and 1.30 (95% CrI, 0.94-1.75) for the composite of DFS, PFS, and EFS (6 trials), with posterior probability of an HR exceeding 1.0 of 96.2% and 95.5%, respectively. The frequentist HRs were 1.47 (95% CI, 1.18-1.83) for OS and 1.31 (95% CI, 1.02-1.69) for the composite of DFS, PFS, and EFS. Conclusions and Relevance: This systematic review and meta-analysis found a high bayesian probability, alongside frequentist statistical significance, that ICIs were associated with reduced OS in patients with HNSCC with a PD-L1 CPS of less than 1. These subgroup-derived findings warrant validation and cautious use in this understudied population.