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PURPOSE: To evaluate the safety, feasibility, and clinical efficacy of stereotactic body radiation therapy (SBRT) combined with pembrolizumab in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma who progressed on prior PD-1 inhibitor therapy.METHODS AND MATERIALS: This prospective, nonrandomized phase 2 trial enrolled patients with PD-1 inhibitor-refractory R/M head and neck squamous cell carcinoma. In cohort A, a single lesion was treated with SBRT, whereas other sites were left unirradiated. In cohort B, all known oligometastatic lesions were treated with SBRT. Pembrolizumab was administered every 3 weeks in both cohorts. The primary endpoint was 3-month progression-free survival (PFS). Correlative immune analyses were performed on peripheral blood mononuclear cells using mass cytometry and TCRβ sequencing.RESULTS: Eighteen patients were treated (6 in cohort A and 12 in cohort B). The median PFS was 1.8 months in cohort A and 5.7 months in cohort B. The 3-month PFS rate was 17% (1/6) in cohort A and 67% (8/12) in cohort B, with an overall response rate of 25% (3/12) in cohort B and no objective responses in cohort A. Median overall survival was 7.6 months (95% CI, 0.7-32.9) in cohort A and 10.1 months (95% CI, 5.8-49.7) in cohort B. In cohort B, there were 2 (2/12, 17%) grade 4 toxicities observed in the setting of re-irradiation. Correlative studies showed that patients with PFS >3 months had higher baseline frequencies of CD8+ central-memory T cells and elevated CXCR5 expression on memory B cells.CONCLUSIONS: In anti-PD-1-refractory R/M head and neck squamous cell carcinoma, SBRT with pembrolizumab was safe and feasible, suggesting activity when all progressing lesions were treated. Immune profiling describes pre-existing memory T- and B-cell phenotypes that appear to correlate with treatment benefit. These findings support further study and clinical use of comprehensive SBRT plus PD-1 blockade in this hard-to-treat population.