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Brief Report
June 21, 2018

Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and NeckThe Active8 Randomized Clinical Trial

Author Affiliations
  • 1University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania
  • 2Winship Cancer Institute, Emory University, Atlanta, Georgia
  • 3Keck School of Medicine, University of Southern California, Los Angeles
  • 4Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5Karmanos Cancer Institute, Detroit, Michigan
  • 6University of Kansas Medical Center, Kansas City
  • 7University of Cincinnati Cancer Institute, Cincinnati, Ohio
  • 8Mount Sinai Medical Center, New York, New York
  • 9West Cancer Center, University of Tennessee, Memphis
  • 10University of Colorado Cancer Center, Aurora
  • 11Washington University School of Medicine, St. Louis, Missouri
  • 12Abramson Cancer Center, Philadelphia, Pennsylvania
  • 13VentiRx Pharmaceuticals, Seattle, Washington
  • 14Hollings Cancer Center, Charleston, South Carolina
  • 15Denver Veterans Affairs Medical Center, Denver, Colorado
  • 16University Hospitals Seidman Cancer Center, Cleveland, Ohio
  • 17Cleveland Clinic, Cleveland, Ohio
  • 18Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 19Moores Cancer Center, University of California San Diego, La Jolla
JAMA Oncol. Published online June 21, 2018. doi:10.1001/jamaoncol.2018.1888
Key Points

Question  Does the addition of the toll-like receptor 8 agonist motolimod to standard chemotherapy/cetuximab combination treatment (the EXTREME regimen) improve outcomes in patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN)?

Findings  In this randomized clinical trial that included 195 patients, adding motolimod to the EXTREME regimen was well tolerated but did not improve survival in the overall population. However, significantly improved outcomes were observed in subsets of patients, including those with human papillomavirus–positive disease and those experiencing injection site reactions.

Meaning  There was a lack of synergy between motolimod and the EXTREME regimen in the overall study population, but certain subsets of patients may benefit from the combination.


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.