Evaluation of the impact of regional lymph node depletion on response to immune checkpoint blockade in recurrent and metastatic head and neck squamous cell carcinoma.

6056 Background: Lymphadenectomy remains a central component of definitive treatment for head and neck squamous cell carcinoma (HNSCC). However, lymphadenectomy disrupts the draining regional lymph node basin where anti-tumor immune cell priming can occur. We hypothesized that history of regional lymph node depletion may be associated with decreased efficacy of immune checkpoint blockade (ICB) in patients who suffer recurrent or metastatic (R/M) HNSCC. Methods: This was a single-institution retrospective cohort study including all patients treated with ICB (anti-PD-1 mAb) for R/M HNSCC from 2015 - 2025. Patients with distant metastatic disease at presentation were excluded. Demographic, clinicopathologic, and treatment history prior to ICB were collated and summarized for each patient. We defined regional lymph node depletion (LN depletion) as history (at any time prior to ICB initiation) of bilateral lymphadenectomy, > 4 levels dissected, or ≥18 lymph nodes excised. We then examined history of LN depletion as a predictor of ICB disease control rate (DCR: SD, PR, or CR) and progression-free survival (PFS) after ICB with Kaplan-Meier method and Cox models alone and controlling for tumor HPV status. Results: Our cohort was comprised of 100 patients (median age 72 years, 71% male). Primary tumor sites included oral cavity (n=38) p16+ oropharynx (n=23), larynx (n=21), p16- oropharynx (n=13) and sinonasal (n = 5). Forty-six were treated with first-line ICB, while 54 were treated after platinum chemotherapy failure. Sixty had a history of lymphadenectomy prior to ICB. Of these 60 patients, 51 (85%) had a history of radiation prior to ICB. History of regional LN depletion was significantly associated with lower DCR with ICB when considering bilateral lymphadenectomy (25.9% vs 54.8%, p = 0.03), > 4 levels dissected (25.0% vs. 54.8%, p = 0.02), or ≥18 lymph nodes excised (25.0% vs. 84.6%, p < 0.0001) analyzed alone and on bivariate analysis controlling for HPV status. In patients meeting all three criteria for LN depletion (n = 24), DCR was the lowest at 16% compared to 75% for patients meeting none of the criteria. On bivariate analyses controlling for HPV status, history of bilateral lymphadenectomy (HR: 2.04 [95% CI 1.1 – 3.8] p = 0.02), > 4 levels dissected (HR: 1.82 [95% CI: 1.0 – 3.3] p = 0.05, and ≥18 lymph nodes excised (HR: 3.35 [95% CI: 1.4 – 8.1] p < 0.01) were independently associated with poorer PFS after ICB. Conclusions: In patients with R/M HNSCC, prior regional LN depletion was associated with lower DCR and PFS after ICB. This suggests that greater surgical disruption of draining regional lymph node basins prior to ICB may affect immune response.