IMPORTANCE: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell 
carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 
(TLR8) agonist motolimod may stimulate innate and adaptive immunity.
OBJECTIVE: To determine whether motolimod improves outcomes for R/M SCCHN when 
combined with standard therapy.
DESIGN, SETTING, AND PARTICIPANTS: The Active8 study was a multicenter, 
randomized, double-blind, placebo-controlled clinical trial enrolling adult 
patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral 
cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. 
Follow-up ended September 2016. Analysis for the present report was conducted 
between June 2016 and December 2017.
INTERVENTIONS: Combination treatment with platinum (carboplatin or cisplatin), 
fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, 
each administered intravenously every 3 weeks. Patients received a maximum of 6 
chemotherapy cycles, after which patients received weekly cetuximab with either 
placebo or motolimod every 4 weeks.
MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) as determined by 
independent central review using immune-related RECIST (Response Evaluation 
Criteria in Solid Tumors). Key secondary end points included overall survival 
(OS) and safety.
RESULTS: Of 195 patients enrolled, 85% were men (n = 166); 82% were white 
(n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 
5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and 
median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) 
for motolimod vs placebo. Increased incidence of injection site reactions, 
pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 
cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. 
In a prespecified subgroup analysis of HPV-positive participants, motolimod vs 
placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 
1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 
1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with 
injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; 
HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 
0.56; 1-sided 90% CI, 0.00-0.81; P = .02).
CONCLUSIONS AND RELEVANCE: Adding motolimod to the EXTREME regimen was well 
tolerated but did not improve PFS or OS in the intent-to-treat population. 
Significant benefit was observed in HPV-positive patients and those with 
injection site reactions, suggesting that TLR8 stimulation may benefit subset- 
and biomarker-selected patients.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01836029.