Background: This phase 2 study investigated whether durvalumab plus tremelimumab with proton therapy improves objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) via boosting abscopal effect. Methods: Thirty-one patients who have previously received more than one chemotherapy regimen, including at least one platinum-based regimen and have at least two measurable lesions enrolled at Samsung medical center. Patients received durvalumab 1500mg intravenously (IV) in combined with tremelimumab 75 mg IV every four weeks for four cycles followed by durvalumab 1500mg every four weeks. After one cycle of durvalumab and tremelimumab combination, proton therapy was performed with a total dose of 25 Gy in 5-Gy daily fractions to one of the measurable lesions. We assessed the target lesion response outside the radiation field by RECIST criteria 1.1 to evaluate the abscopal effect. Results: Between March 2018 and July 2020, 31 patients were enrolled. The median age was 59 years, and median two prior chemotherapy regimens were administered. With 24.8 months of follow-up, the median number of cycles of immunotherapy was three. The ORR was 27.3%, including one complete response and five partial responses. Median OS was 6.4 months (95% CI, 1.0 to 11.8), and median PFS was 2.4 months (95% CI, 0.6 to 4.2). Median duration of response was 15.9 months (range 3.7 – 21.2). Grade 3 or higher adverse events were observed in 6 (27.3%) patients; anemia (n = 1), constipation (n = 1), electrolyte imbalance (n = 2), hyperglycemia (n = 1), pneumonia (n = 1). Conclusions: Combination of durvalumab/tremelimuab with proton therapy is well tolerable and shows encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients. These results suggest that the combination of immunotherapy with proton therapy might enhance the abscopal effect. Clinical trial information: NCT03450967