EACH: A randomised phase II study evaluating the safety and anti-tumour activity of the combination of avelumab and cetuximab relative to avelumab monotherapy in recurrent/metastatic head and neck squamous cell cancer.

Abstract

TPS6091 Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) have low response rates to licensed second line therapies, including PD-1 inhibitors nivolumab and pembrolizumab, and represent an area of unmet clinical need. The chimeric IgG1 epithelial growth factor receptor (EGFR) monoclonal antibody cetuximab potentiates the activity of radiotherapy in locally advanced HNSCC and chemotherapy in R/M HNSCC and is also licensed with modest activity as a single agent. Cetuximab initiates Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), resulting in an anti-tumour immune response and the potential to augment the activity of PD-1/PD-L1 inhibition. EACH aims to examine the safety and efficacy of the potentially synergistic interaction between cetuximab and avelumab, a fully human IgG1 anti-PD-L1 monoclonal antibody in R/M HNSCC. Methods: EACH is a randomised phase II trial preceded by a safety run-in phase. Eligible patients have histologically or cytologically confirmed measurable recurrent or metastatic squamous cell carcinoma of any site in the safety run-in phase, and HNSCC in phase II, that is considered incurable by local therapies. The safety run-in has a single arm de-escalating design, aiming to establish the safety of cetuximab with avelumab and determine the optimal dose of cetuximab within this combination. The safety run-in has a dosing schedule of avelumab (10 mg/kg) + cetuximab (500 mg/m2) intravenously every 2 weeks, with de-escalation of cetuximab to 400 mg/m2 and 300 mg/m2 if necessary. The safety run-in phase commenced recruitment in July 2018 and is ongoing. The phase II component will randomize 114 HNSCC patients between either avelumab + cetuximab at the dose determined by the safety run-in phase or avelumab (10 mg/kg) alone. Treatment will be in 4-week cycles for up to one year. The primary endpoint in the safety run-in phase is the occurrence of dose limiting toxicities, and in phase II is Disease Control Rate at 24 weeks, using iRECIST. Blood and fresh tissue will be collected for exploratory translational studies, which will focus on the identification of potential novel predictive biomarkers for response. Clinical trial information: NCT03494322.