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JAMA Oncol. 2018 Nov 1;4(11):1583-1588. doi: 10.1001/jamaoncol.2018.1888.

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

Author information

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

Abstract

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.

PMID:
29931076
PMCID:
PMC6248084
[Available on 2019-06-21]
DOI:
10.1001/jamaoncol.2018.1888

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