Phase 2 OSPRI tests pembrolizumab (PD‑1 inhibitor) with proton SFRT vs photon SBRT

Mayo Clinic is running this randomized Phase 2 neoadjuvant study in oral cavity squamous cell carcinoma to compare two “immune‑priming” radiation approaches added to pembrolizumab (Keytruda; an anti‑PD‑1 monoclonal antibody from Merck/MSD) before definitive surgery. Patients are assigned to either proton spatially fractionated radiotherapy (SFRT; grid-like high/low dose pattern intended to concentrate tumor dose while sparing adjacent mucosa/mandible) or photon stereotactic body radiotherapy (SBRT; highly conformal hypofractionated x‑ray RT), each delivered every other day for up to 3 fractions over ~1 week, followed by pembrolizumab every 3 weeks for up to 2 cycles, then resection within 8 weeks. Eligible patients include radiation‑naïve, non‑metastatic, locally advanced (e.g., T3/T4) or locoregionally recurrent, HPV/p16‑negative oral cavity SCC. The key scientific angle is whether spatial fractionation with protons can improve major pathologic response versus a modern photon SBRT comparator while keeping pre‑op toxicity acceptable; today’s care for resectable locally advanced oral cavity SCC is upfront surgery with neck management followed by risk‑adapted adjuvant RT or chemoradiation, with immunotherapy mainly used in recurrent/metastatic settings rather than routinely pre‑op.