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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Motolimod was invented by Array and licensed to VentiRx; in February 2017, Celgene acquired VentiRx and the motolimod program. Dr Ferris: Advisory Board: Astra-Zeneca/MedImmune, BMS, Lilly Merck, Pfizer, Clinical Trial: Astra-Zeneca/MedImmune, BMS, Merck, Research Funding: Astra-Zeneca/MedImmune, BMS, VentiRx Pharmaceuticals. Dr Haddad: Consulting: Merck, BMS, Astra-Zeneca, Pfizer, Eisai, Genentech, Pfizer, Research Funding: BMS, Pfizer, BMS, Astra-Zeneca, Merck. Dr Morris: Speakers Program: Boehringer-Ingelheim, Merck. Dr Adkins: Consultant: Pfizer, Clinical Trials: VentiRx, Gliknik, Cellceutix, Pfizer, Merck, Novartis, Celgene. Dr Gibson: Consulting/Ad Boards: BMS, Merck, Research Funding: National Comprehensive Cancer Network, Astra-Zeneca, Speakers Program: BMS. Dr Nwizu: Speakers Program: Astra-Zeneca, Helsinn, Pfizer, Heron. Dr Gottardo: Income from VentiRx Pharmaceuticals and Celgene. Ms Manjarrez: Former employee of VentiRx Pharmaceuticals and had equity interest and holds patents related to motolimod. Dr Bryan: Employee of VentiRx Pharmaceuticals. Dr Hershberg: Employee and stock ownership: Celgene Corporation. No other disclosures are reported.

Figures

Figure 1.. Study Enrollment and Participation Flowchart

The EXTREME regimen is standard chemotherapy/cetuximab combination treatment. aOne patient assigned to the placebo arm erroneously received a dose of motolimod and was included in the motolimod arm for safety analyses.

Figure 2.. Kaplan-Meier Analyses of Progression-Free Survival and Overall Survival in the Intent-to-Treat Population

The EXTREME regimen is standard chemotherapy/cetuximab combination treatment. Progression-free survival was measured by independent central assessment per immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Hash marks indicate censored.

Figure 3.. Kaplan-Meier Analyses of Progression-Free Survival and Overall Survival in the HPV-Positive Oropharyngeal Cancer Subset of Study Participants

Hash marks indicate censored; HPV, human papillomavirus.