Background: ErbB3 (HER3) and its ligand, neuregulin-1 (NRG1), are widely expressed in HNSCC and associated with tumor progression. ErbB3 may provide a key mechanism of resistance to therapies targeting EGFR and HER2. HPV− tumors, typified by poorer prognosis, have shown favorable response to ErbB3-targeted therapy. CDX-3379, an anti-ErbB3 monoclonal antibody with a half-life-extending Fc region YTE mutation, binds a unique epitope, locks ErbB3 in an inactive form, and blocks all ErbB3-dependent downstream signaling. CDX-3379 enhances antitumor activity of targeted therapies in preclinical models (Falchook ASCO 2016). In a phase (ph) 1 trial, CDX-3379 was well-tolerated alone and in combination with targeted agents. A patient (pt) with cetuximab-refractory HNSCC experienced a durable complete response to CDX-3379 + cetuximab, while 2 pts with BRAF-mutant non-small cell lung cancer, one dabrafenib-resistant, experienced partial responses to CDX-3379 + vemurafenib (Falchook ASCO 2016). A newly-initiated trial evaluates CDX-3379 + cetuximab in pts with HPV− cetuximab-resistant advanced HNSCC. Methods: A ph 2, multicenter, open-label clinical trial (NCT03254927) is enrolling ≤30 pts with advanced refractory HNSCC. Eligibility requires: screening biopsy; HPV−; RECIST 1.1 measurable disease; cetuximab resistance (progression within 6 months); prior PD-1-targeted check-point inhibition (if a candidate); no active brain metastases; and no nasal, paranasal sinus, or nasopharyngeal WHO Type III carcinoma. Pts receive CDX-3379 (initial dose 12 mg/kg IV q 21 days) + cetuximab (loading dose 400 mg/m²; 250 mg/m² IV weekly) until progression/toxicity. Tumor assessments occur at 6-week intervals. Endpoints include objective response rate (ORR; primary), progression-free and overall survival, safety, pharmacokinetics, immunogenicity, and biomarkers (NRG, EGFR ligands). It is hypothesized that CDX-3379 + cetuximab will achieve ORR of 20%, with 80% power and a null hypothesis of ORR ≤5% and α = 0.05 based on a Simon’s 2-stage design. Three US sites are actively recruiting pts, with additional sites planned. Clinical trial information: NCT03254927