Impact of PD-L1 and HPV biomarkers on immune checkpoint inhibitor efficacy in locally advanced HNSCC: A systematic review of randomized trials.

e18050 Background: The role of immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains uncertain, with randomized trials showing inconsistent results in heterogeneous populations. We conducted a systematic review of randomized trials evaluating ICI-based strategies in LA HNSCC, with outcomes stratified by PD-L1 expression, HPV/p16 status, and cisplatin eligibility to identify patients most likely to benefit from ICIs. Methods: MEDLINE and EMBASE databases were systematically searched up to January 10, 2026. Randomized controlled trials (RCTs) evaluating ICIs in patients with LA HNSCC were included. The primary outcome was progression-free survival (PFS). A inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for PFS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test. Random effects model was applied. Results: A total of 3,605 patients from 7 randomized trials (5 phase III, 1 phase II/III, and 1 phase II) were included. These studies evaluated ICI-based strategies versus standard therapy in LA HNSCC, including ICI with radiotherapy (RT) in cisplatin-ineligible patients (NRG-HN004, and GORTEC 2015 PembroRad), ICI added to cisplatin-based chemoradiotherapy (KEYNOTE-412, and JAVELIN Head and Neck 100), perioperative pembrolizumab or postoperative nivolumab with standard of care treatment (KEYNOTE-689, and NIVOPOSTOP GORTEC 2018), and atezolizumab maintenance following definitive therapy (IMvoke010). In the overall population, no significant difference in PFS/EFS/DFS was observed between ICI and standard therapy (HR 0.90; 95% CI: 0.77–1.06; p=0.20). However in subgroup analyses stratified by PD-L1 expression, patients with PD-L1 positive tumors demonstrated improved PFS with ICIs compared with control (HR 0.78; 95% CI: 0.67–0.91; p<0.0001). In contrast, PD-L1 negative tumors demonstrated inferior PFS in the ICI arm (HR 1.31; 95% CI: 1.02–1.68; p=0.03). No significant differences in PFS were observed based on HPV or p16 status. A subset analysis of cisplatin-eligible LA HNSCC trials evaluating the addition of ICIs to standard therapy exhibited a similar pattern. ICI use in PD-L1 positive patients demonstrated significantly improved PFS (HR 0.76; 95% CI: 0.63–0.92; p<0.0001) while PD-L1 negative patients demonstrated decreased PFS (HR 1.28; 95% CI: 0.99–1.66; p=0.06). In cisplatin ineligible populations ICI regimens did not improve PFS compared with cetuximab plus RT. Conclusions: This study showed that although there was no significant difference in PFS/EFS/DFS in the overall population, the PDL-1 positive subgroup experienced significantly improved PFS with ICIs compared with control while the PDL-1 negative subgroup demonstrated inferior PFS in the ICI arm; these results were mirrored in the cisplatin-eligible subgroup.