Immunotherapy and Nodal-Sparing Irradiation for T-Cell Induction and Unmasking of Tumor Antigenicity in the Microenvironment for Head and Neck Cancer

Patients with surgically resectable HPV‐negative HNSCC with no prior history of head andneck radiation and a life expectancy of at least 12 months will be enrolled.Patients will undergo pre‐radiation pembrolizumab for two cycles followed bypre‐operative radiotherapy and two additional cycles of pembrolizumab. Radiation will begiven to a total dose of 35 Gy in 5 fractions to gross disease, followed byresponse‐directed surgery approximately eight weeks after completion of radiation.Patients randomized to ENI will concurrently receive 27 Gy in 5 fractions to electivenodal regions during radiation to gross disease.Baseline symptom evaluation will be obtained using validated surveys for head and neckcancer patients: the Functional Assessment of Cancer Therapy for the Head and Neck(FACT‐HN) and the MD Anderson Dysphagia Inventory for Head and Neck (MDADI‐HN). Tumorbiopsies will be performed serially across treatment for translational study at thefollowing time points: baseline, after induction pembrolizumab, on the final day ofradiation, and at the time of surgery. If patients sign a secondary consent, quantitativeMRI (qMRI) will be performed prior to radiation, on the day of the last fraction ofradiation and six weeks after the completion of radiation, prior to surgery.