Background: Locoregionally advanced (LA) HNSCC treated with surgery can carry significant functional morbidity, further intensified by adjuvant (adj) radiation (RT) often with concurrent chemotherapy. Although the pathologic response rate of anti-PD1 therapy is modest, combination approaches may provide enhanced clinical benefit. This pilot study evaluates whether the combination of neoadjuvant cemiplimab + platinum-doublet chemotherapy + cetuximab is safe, feasible, and effective in pathologic down-staging to reduce the extent of surgery and justify omission of adj RT. Methods: 10 patients (pts) with resectable LA HNSCC who would warrant adj RT per clinical stage were enrolled. Neoadjuvant treatment consisted of cetuximab loading dose with cemiplimab followed by 3 cycles of chemotherapy (cisplatin or carboplatin + docetaxel) with cetuximab and cemiplimab prior to definitive surgical resection. Standard of care adj RT+/- chemotherapy was administered based on pathologic staging. Pts with ypT0-2N0 tumors without adverse features or ypT0-1N1 tumors with minimal residual disease ( < 10% viable tumor) were offered 6 months of adj cemiplimab in lieu of RT. Primary endpoint was safety (defined by dose limiting toxicity (DLT) related to the addition of cemiplimab to this combination regimen). Secondary endpoints included feasibility (defined as no surgical delay > 20 weeks from start of neoadjuvant therapy due to treatment toxicity) and pathologic down-staging allowing for omission of adj RT. Results: 10 pts completed treatment with no DLTs and surgical delays. 8/10 (80%) pts were clinically staged as T3/T4 and 5/10 (50%) were N2b/c (AJCC 7^th Ed). Pathologic down-staging was observed in 9/10 (90%) pts after neoadjuvant therapy. 60% had a major pathologic response and 40% had a complete pathologic response. 6/8 pts and 7/10 pts who would have required a mandibulectomy and free flap, respectively, did not require it following neoadjuvant treatment. Of the 5/10 (50%) pts who were eligible for omission of adj RT, 4 did not undergo RT and 3 received adj cemiplimab. All pts remain disease-free at a median follow-up of 16 months. The most common adverse events (AEs) of any grade (G) were rash (80%), nausea (70%), fatigue (50%), and diarrhea (50%). 2/10 (20%) pts experienced a G3 or G4 immune-related AE attributed to the addition of cemiplimab. One pt developed G3 transaminase elevation prior to surgery and 1 pt experienced G3 myasthenia gravis and G4 myocarditis (resolved) outside the DLT window. Conclusions: Neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab has an acceptable toxicity profile, is feasible in pts with LA HNSCC, and led to notable pathologic down-staging allowing for reduction in extent of surgery and omission of adj RT. Further evaluation of this regimen is clearly warranted. Clinical trial information: NCT04722523.