Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma

Purpose: ErbB3 and its ligand neuregulin-1 (NRG1), are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 monoclonal antibody, in patients with HNSCC. Experimental Design:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1000 mg) at a two-week interval prior to tumor resection. The primary study objective was to achieve ≥ 50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥ 30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed. Results:pErbB3 was detectable in all tumors prior to treatment and decreased for 10/12 (83%) patients following CDX-3379 dosing, with ≥ 50% reduction in 7/12 (58%, p=0.04, 95% CI=27.7%, 84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. 5/12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with HPV-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment. Conclusions:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase 2 study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.