Neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab to de-escalate surgery and omit adjuvant radiation in locoregionally advanced head & neck squamous cell carcinoma (HNSCC).

6019 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 ( 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 .