Background: Anti-PD-1/PD-L1 is now part of first line therapy in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic radiotherapy (SBRT) to metastatic lesions can reduce tumor burden and could be immune-stimulatory. The combination of SBRT with dual-checkpoint blockade with Durvalumab (D, anti-PD-L1) and Tremelimumab (T, anti-CTLA-4) has not previously been tested in HNSCC. We report on the safety and efficacy of this triple treatment combination (TTC) consisting of SBRT sandwiched between cycles of D and T in oligometastatic HNSCC. Methods: This is a phase I/II single arm multi-institutional study powered for 35 patients with oligometatastatic HNSCC (2-10 lesions) (NCT03283605). D (1500 mg) and T (75 mg) were given for 4 monthly cycles, followed by monthly D for 8 monthly cycles. SBRT to 2-5 lesions was administered during cycle 2. The safety of the TTC was the primary endpoint of the phase I and was evaluated through assessment of Grade 3-5 TTC-related adverse events (AE), based on CTCAE (v 4.03). The primary endpoint of the phase II portion was 6-month progression free survival (PFS), with a predetermined 6-month PFS (6moPFS) rate greater than 27% considered as a positive signal to conduct further research on this combination. Results: A total of 33 evaluable patients were recruited (study accrual was interrupted by the COVID pandemic). The table describes patients’ characteristics. Patients had received 1, 2 and 3 prior systemic therapy lines in 48%, 21% and 9% of the cases, including 6 (18%) patients who had received prior anti-PD-1/L1 or anti-CTLA-4 therapies. The median prescribed and maximum SBRT doses were 45 Gy (range: 18-50) and 52.3 Gy (range: 28.1-69) in 3-5 fractions, respectively Fourteen patients (42%) had Grade ≥ 3 AE attributable to D and T. Only 1 patient developed Grade ≥ 3 AE attributable to SBRT. This patient, who had mucosal radionecrosis after re-irradiation and refused surgical debridement and flap reconstruction, specifically developed 2 Grade 3, 1 Grade 4 and 1 Grade 5 AE. Our primary efficacy endpoint, 6moPFS, was 69.7% (95% CI: 55.6-87.3). Median PFS was 11.9 months (6.94-14.5) and median OS was 25.1 months (17.9-28.4). Rates of complete response, partial response, stable disease and progressive disease were 9%, 21%, 33% and 12%, respectively, with 8 (24%) patients with no evaluable non-SBRT treated lesion. Conclusions: The addition of SBRT to dual-checkpoint inhibition led to 1 (3%) additional patient developing severe AE. Best response rates were encouraging. Our primary efficacy outcome, 6mo PFS was attained and was higher than what was expected in this patient population. Clinical trial information: NCT03283605.