Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.

Abstract

6014 Background: Previously, neoadjuvant PD-1 plus AP followed by surgery and radiotherapy showed promising disease control and laryngeal preservation in resectable LA-HNSCC. Ivonescimab, a PD-1/VEGF bispecific antibody, potentially exerts synergistic anti-tumor activity by normalizing tumor vasculature and enhancing immune infiltration. This study evaluates the efficacy and safety of neoadjuvant Ivonescimab plus AP in resectable LA-HNSCC. Methods: This single-center phase II trial enrolled patients (18-70 yrs) with resectable stage III-IVa LA-HNSCC (oral cavity, oropharynx, hypopharynx, or larynx). Neoadjuvant therapy: 3 cycles of Ivonescimab (20mg/kg Q3W) plus AP, followed by surgery. Postoperative treatment included radiotherapy ± chemotherapy and maintenance Ivonescimab (10mg/kg Q3W) for 14 cycles. Primary endpoints: pCR and 2-year EFS. MRD and PD-L1 CPS were also investigated. Results: By November 2025, 36 patients were enrolled (median age 58; 75% Stage IV). Primary tumor sites were hypopharynx (50.0%), larynx (25.0%) and oral cavity (19.4%). Radiological assessment performed prior to Cycle 3 demonstrated an exceptional objective response rate (ORR) of 100% among 34 evaluable patients. Notably, a remarkably deep radiological response was achieved, with a complete response (CR) rate of 50.0% (17/34) and a partial response (PR) rate of 50.0% (17/34). Deep tumor shrinkage was observed in all cases. 30 patients underwent surgery with a 100% R0 resection rate. The overall pCR rate was 50.0% (15/30). Specifically, pCR was achieved in 70.0% (21/30) of primary lesions and 64.3% (18/28) of lymph nodes. While robust pathological responses were observed in the hypopharynx (64.3%), tongue (57.1%), and oropharynx (50.0%), the pCR rate in the larynx was markedly lower at 12.5%. Crucially, the profound tumor downsizing induced by Ivonescimab enabled volume-reduced resections, achieving 100% successful laryngeal and pharyngeal preservation while maintaining negative margins. High PD-L1 predicted efficacy; median CPS was 30.0 in pCR vs. 10.0 in non-pCR (p=0.18). Notably, 100% of pts with CPS > 30 achieved pCR. Pre-op MRD specificity for pathological conversion was 91.7% (sensitivity 37.5%). Safety: The most common Grade≥3 AEs were pharyngeal fistula (surgical-related) and transient transaminase elevation. Most drug-related AEs were manageable and consistent with the known profiles of PD-1 and VEGF inhibitors. Conclusions: Neoadjuvant Ivonescimab plus chemotherapy demonstrated unprecedented radiological response depth and pathological remission rates in LA-HNSCC. This novel PD-1/VEGF-based dual blockade may redefine neoadjuvant standards for head and neck cancer. High CPS and MRD negativity are robust predictors of deep pathological response. Clinical trial information: NCT06537011 .