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

• Type of Material: Article
• Authors: Robert L. Ferris, University of Pittsburgh; Nabil F Saba, Emory University; Barbara J. Gitlitz, University of Southern California; Robert Haddad, Dana-Farber Cancer Institute; Ammar Sukari, Karmanos Cancer Institute; Prakash Neupane, University of Kansas; John C. Morris, University of Cincinnati; Krzysztof Misiukiewicz, Mount Sinai Medical Center; Julie E. Bauman, University of Pittsburgh; Moon Fenton, University of Tennessee; Antonio Jimeno, University of Colorado; Douglas R. Adkins, Washington University; Charles J. Schneider, Abramson Cancer Center; Assuntina G. Sacco, VentiRx Pharmaceuticals; Keisuke Shirai, Hollings Cancer Center; Daniel W. Bowles, Denver Veterans Affairs Medical Center; Michael Gibson, niversity Hospitals Seidman Cancer Center; Tobenna Nwizu, Cleveland Clinic; Raphael Gottardo, Fred Hutchinson Cancer Research Center; Kristina L. Manjarrez, VentiRx Pharmaceuticals
• Language: English
• Date: 2018-11-01
• Publisher: American Medical Association (AMA)
• Publication Version: Final Published Version
• Copyright Statement: 2018 American Medical Association. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1001/jamaoncol.2018.1888
• Title of Journal or Parent Work: JAMA Oncology
• ISSN: 2374-2437
• Volume: 4
• Issue: 11
• Start Page: 1583
• End Page: 1588
• Grant/Funding Information: This trial was supported by VentiRx Pharmaceuticals.
• Keywords: Science & Technology; Oncology; OROPHARYNGEAL CANCER; SOLID TUMORS; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology

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.