Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet most patients (pts) ultimately develop ICI resistance. Overcoming this resistance is a major clinical challenge. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles administered by a single intratumoral injection, locally amplifies the RT dose without adding toxicity to surrounding healthy tissue. In preclinical models, NBTXR3/RT has been shown to enhance tumor cell death and tumor antigen release and to effectively expand T-cell repertoire, thus potentially triggering both local and systemic immune responses to help improve ICI treatment. A phase I trial is ongoing to evaluate NBTXR3/RT in combination with anti-PD-1 in pts with advanced cancers. Here we report early outcomes in pts with locoregionally recurrent (LRR) or metastatic (M+) head & neck squamous cell carcinoma (HNSCC). Methods: Study 1100 is a phase I dose escalation/expansion trial [NCT03589339] evaluating NBTXR3 activated by stereotactic body radiotherapy (SBRT) followed by anti-PD-1 therapy (nivolumab or pembrolizumab) in 3 cohorts of pts with advanced solid tumors. Pts are either resistant to prior ICI or naïve. Escalation cohorts were defined by site of injection: H&N lesions, lung metastases, or liver metastases. SBRT was delivered as per standard practice. The primary objective of the escalation part was to determine the NBTXR3/RT/anti-PD-1 RP2D for each cohort. Secondary objectives were feasibility, safety, and anti-tumor efficacy (objective responses). Results: 16 pts with LRR or M+ HNSCC were treated in the escalation part. 10 pts were resistant to anti-PD-1, 6 were naïve. 8 pts were HPV+, 7 were HPV-, and 1 had HPV status unknown. 13 pts had M+ disease, of which 9 were anti-PD-1 resistant, 4 were naïve. Overall tumor responses were observed in 31.3% (5/16) with mean duration of response (DOR) for these 5 pts of 14.8 (SD ± 7.64) months, at the time of cut-off (4 pts were still responders). Disease control was observed in 75.0% (12/16). Among M+ pts, overall tumor responses were observed in 23.1% (3/13) with mean DOR for these 3 pts of 12.1 (SD ± 5.83) months (2 were still responders). Disease control was observed in 69.2% (9/13) pts with M+ disease. 25.0% (4/16) pts experienced disease progression, and all had M+ disease. All patients who progressed did so with the appearance of a new (non-treated) lesion. Conclusions: Promising early signs of efficacy were observed in HNSCC pts treated with NBTXR3/RT/anti-PD-1, including responses in pts resistant to anti-PD-1 and with M+ disease. Disease control was observed in M+ pts, highlighting the potential for NBTXR3 in this difficult to treat population. Overall, these results support evaluation of NBTXR3/RT/anti-PD-1 in the ongoing expansion part. Clinical trial information: NCT03589339.