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

Abstract

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 mAb, in patients with HNSCC.

Patients and methods: Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-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 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 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. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-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 II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.

©2019 American Association for Cancer Research.

Figures

Figure 1.. Pharmacokinetics.

CDX-3379 serum concentration over time is individually displayed for each patient. All 12 patients received CDX-3379 (1000 mg/kg) at a two-week interval for a total of two doses. Dotted line represents target trough concentration of 50 μg/mL which resulted in maximal antitumor efficacy in preclinical models.

Figure 2.. Phospho-tyrosine 1289-ErbB3 Expression by VeraTag®.

(A) Change in pErbB3 level in individual patient tumor samples. Post-treatment pErbB3 levels were below the assay level of detection for four patients (108–01, 110–02, 111–02 and 112–02); values were set at the assay level of detection of 0.14. (B) Mean tumor pErbB3 levels for all patients (n=12) before and after CDX-3379 treatment.

Figure 3.. Waterfall Plot of Change in Tumor Burden.

Percent change from baseline in the sum of longest diameters of target lesion(s) for each study patient. Radiographic assessments were performed at a median (range) of 20.5 (15–26) days from first CDX-3379 dose. HPV status is denoted by + and − signs.