Efficacy of definitive radiotherapy with concurrent and adjuvant immune checkpoint inhibitors in patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC).

6062 Background: Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancers, associated with a high incidence and mortality. In 2019, the FDA approved pembrolizumab for the treatment of recurrent/metastatic (RM) HNSCC. While many promising results were noted in the RM setting, unfortunately this was not the case for locally advanced HNSCC (LA HNSCC). Multiple studies have yielded negative results. This meta-analysis aims to further explore the efficacy of immune checkpoint inhibitors (ICIs) in the treatment of LA HNSCC. Methods: MEDLINE and EMBASE databases were systematically searched up to December 31, 2024. Randomized controlled trials (RCTs) evaluating ICIs in patients with LA HNSCC were included. The primary outcome was 2-year progression-free survival (PFS). A generic 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. Fixed effects model was applied. Results: A total of 1,687 patients from 2 phase III RCTs (KEYNOTE-412, JAVELIN Head and Neck 100) and 1 phase II/III RCT (NRG-HN004) were analyzed. NRG-HN004 compared durvalumab + radiotherapy (RT) vs cetuximab + RT, while KEYNOTE-412 and JAVELIN Head and Neck 100 compared pembrolizumab or avelumab + chemoradiotherapy (CRT) vs CRT alone, respectively. In PD-L1 positive cohort, longer PFS was noted in the ICIs arm (HR 0.81; 95% CI: 0.67-0.99; P=0.04), while in PD-L1 negative cohort, we noted the opposite with a shorter PFS in the ICIs arm (HR 1.34; 95% CI: 1.02-1.76; P=0.03). PFS was not different between the two treatment arms in the overall population and all the other subgroups, including HPV negative, HPV positive, males, and females. We conducted a subset analysis of cisplatin-eligible (CE) LA HNSCC including KEYNOTE-412 and JAVELIN Head and Neck 100 trials to assess the addition of ICIs to definitive CRT. We also noted increased PFS in PD-L1 positive cohort in the ICIs arm (HR 0.78; 95% CI: 0.63-0.97; P=0.02). However, in PD-L1 negative cohort, PFS was near significant to be decreased in the ICIs arm (HR 1.31; 95% CI: 0.99-1.75; P=0.06). Conclusions: This study showed that definitive radiotherapy with concurrent and adjuvant ICIs in LA HNSCC was associated with increased PFS in the PD-L1 positive group but decreased PFS in the PD-L1 negative arm. NRG-HN004 trial demonstrated that immunoradiotherapy was inferior to radiation plus cetuximab in cisplatin-ineligible LA HNSCC. In the subset analysis of CE LA HNSCC, addition of ICIs to standard CRT has more pronounced significant PFS in the PD-L1 positive cohort, while there is a trend towards decreasing PFS in the PD-L1 negative cohort. Further studies are needed in the future to evaluate the efficacy of ICIs addition to standard definitive CRT in PD-L1 positive or high LA HNSCC.