Abstract CT058: Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative "window of opportunity" study
Authors: Duvvuri Umamaheswar , George Jonathan , Kim Seungwon , Alvarado Diego , Neumeister Veronique , Chenna Ahmed , Hawthorne Thomas , LaVallee Theresa , Grandis Jennifer R. , Bauman Julie E. 
Published: August 2018

Abstract
Background: ErbB3 (HER3) and its ligand, neuregulin-1 (NRG1), are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. Preclinically, treatment of primary tumor and cell line tumor models of HNSCC with CDX-3379, an anti-ErbB3 monoclonal antibody, results in significant tumor reduction and reduced tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3), and antitumor activity is enhanced when combined with cetuximab. In a Phase 1 clinical study, a patient (pt) with cetuximab- refractory HNSCC experienced a durable complete response to CDX-3379 and cetuximab. A “window-of-opportunity” study was conducted to evaluate the effect of CDX-3379 on pErbB3 and other potential tumor biomarkers in pts with HNSCC.
Methods: Pts with newly diagnosed, operable HNSCC received CDX-3379 (1000 mg IV) at a 2-week interval prior to tumor resection. Pre- and post-treatment tumor samples were evaluated for expression of pErbB3 (VeraTag®); ErbB3 and NRG (quantitative in situ hybridization); and Ki67 and phosphatase and tensin homolog (PTEN) (quantitative immuno-fluorescence). Primary study objective was to demonstrate ≥ 50% reduction in pErbB3 in ≥ 30% of pts. Toxicity, pharmacokinetics, and tumor measurements were also assessed.
Results: 12 pts with HNSCC (5 oral cavity, 4 oropharynx, 3 larynx; 3 HPV+, 9 HPV-; 10 stage IVA) received 2 CDX-3379 doses. Radiographic assessments and tumor resection were performed at a median (range) of 20.5 (15-26) and 27.5 (18-35) days from first CDX-3379 dose. CDX-3379 reduced pErbB3 levels in 10/12 (83%) pt samples, with ≥ 50% decreases in 7/12 (58%, P=0.04). Ki67 decreased in 5/12 (42%). In this small sample, NRG, ErbB3 or PTEN expression did not clearly correlate with changes in pErbB3, Ki67 or tumor measurements. Target trough CDX-3379 serum levels (50 µg/ml based on mouse xenograft models) were achieved in all pts. Treatment-related toxicity included diarrhea (n=6), fatigue (n=2), and acneiform dermatitis (n=2). 11/12 (92%) pts had RECIST stable disease prior to resection. A pt with HPV- HNSCC experienced significant tumor shrinkage (26% decrease in nodal metastasis radiographically; 92% in primary tumor by physical exam) on day 16, as well as marked improvement in pain and ability to eat. Tumor pErbB3 reduced from 0.45 to &lt;0.14 ng/ml.
Conclusions: CDX-3379 is associated with molecular and clinical activity in HNSCC. CDX-3379 administration was well-tolerated and induced a significant decrease in pErbB3. In this small study of 2 CDX-3379 doses over 14 days, one pt experienced a marked clinical effect including reduced tumor size and symptomatology and 92% had RECIST stable disease pre-resection. A Phase 2 study has been initiated to evaluate the combination of CDX-3379 and cetuximab for pts with progressive HNSCC after prior cetuximab and checkpoint inhibition.
Citation Format: Umamaheswar Duvvuri, Jonathan George, Seungwon Kim, Diego Alvarado, Veronique Neumeister, Ahmed Chenna, Thomas Hawthorne, Theresa LaVallee, Jennifer R. Grandis, Julie E. Bauman. Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative "window of opportunity" study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT058.