Phase 2 pembrolizumab PD-1 inhibitor plus hypofractionated RT tests ENI nodal-sparing strategy

Medical College of Wisconsin is running this non-comparative randomized Phase 2 “INITIUM” platform in resectable, locally advanced head and neck squamous cell carcinoma (HPV-negative oropharynx and resectable oral cavity primaries), asking whether elective nodal irradiation (ENI) helps or hurts immune priming when PD-1 blockade is paired with short-course pre-op radiation. All participants receive pembrolizumab (Merck/MSD; anti–PD-1 monoclonal antibody that releases inhibitory signaling on activated T cells) for two induction cycles, then hypofractionated pre-operative radiation to gross disease (7 Gy × 5 fractions), then two more pembrolizumab cycles, followed by surgery; patients are randomized to receive ENI to clinically/radiographically uninvolved draining nodal basins versus omit ENI (nodal-sparing). The scientific angle is the deliberate tradeoff between nodal control and preserving lymph-node antigen presentation/T-cell expansion (“in situ vaccination” concept) in the neoadjuvant window. Today’s care for these patients is surgery with risk-adapted adjuvant radiation or chemoradiation, and for unresectable disease definitive chemoradiation; this trial explores whether a short pre-op immuno-radiotherapy sequence can deepen pathologic response without broadly sterilizing elective nodal basins.