Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR 
agonists may be important for augmenting the efficacy of therapies for squamous 
cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective 
small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic 
cells, and monocytes. A phase Ib clinical trial assessed the safety and 
antitumor activity of motolimod in combination with cetuximab in patients with 
SCCHN. Correlative biomarkers of immune activity were explored.Experimental 
Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in 
this open-label, dose-escalation study using a standard 3 + 3 design. Doses of 
motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in 
combination with fixed weekly doses of cetuximab in 28-day cycles.Results: There 
were no protocol-defined dose-limiting toxicities, drug-related deaths, or 
evidence of synergistic toxicities between motolimod and cetuximab. Clinical 
tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and 
3.0 mg/m2 was identified as the MTD. Two patients achieved partial responses for 
an overall response rate of 15%. Five patients had disease stabilization 
equating to a disease control rate of 54%. Statistically significant increases 
in plasma cytokines and in the frequency and activation of circulating NK cells 
were observed.Conclusions: Motolimod can be safely administered in combination 
with cetuximab with an acceptable toxicity profile. Encouraging antitumor 
activity and robust pharmacodynamic responses were observed. Motolimod is being 
further investigated in a phase II trial in patients with SCCHN 
(ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442-50. ©2016 
AACR.