Adding Motolimod to Standard Chemotherapy and Cetuximab in Squamous Cell Carcinoma of the Head and Neck


Key Points

  • Among all patients, the addition of motolimod did not improve progression-free or overall survival.
  • Potential benefits were observed in HPV-positive patients and in motolimod patients with injection site reactions.

In a phase II trial (Active8) reported in JAMA Oncology, Ferris et al found that the addition of the toll-like receptor 8 (TLR8) agonist motolimod to platinum-fluorouracil plus cetuximab (Erbitux) did not improve progression-free survival among all patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), although potential benefit was observed in some subgroups. It is hypothesized that TLR8 agonists may stimulate innate and adaptive immunity, including in the current setting.

Study Details

In the double-blind multicenter U.S. trial, 195 patients with metastatic or recurrent disease of the oral cavity, oropharynx, hypopharynx, or larynx were randomized between October 2013 and August 2015 to receive combination treatment with platinum (carboplatin or cisplatin), fluorouracil, and cetuximab (EXTREME regimen) plus either placebo (n = 95) or motolimod (n = 100), each given intravenously every 3 weeks. Patients received a maximum of 6 cycles of chemotherapy and then weekly cetuximab with either placebo or motolimod every 4 weeks.

The primary endpoint was progression-free survival on independent central review using immune-related RECIST criteria. Follow-up ended in September 2016.

Overall and Subgroup Outcomes

Median progression-free survival was 6.1 months in the motolimod group vs 5.9 months in the placebo group (hazard ratio [HR] = 0.99, P = .47). Median overall survival was 13.5 vs 11.3 months (HR = 0.95, P = .40). Among 83 cases of oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV)–positive. In a prespecified analysis in the HPV-positive group, median progression-free survival was 7.8 months with motolimod vs 5.9 months with placebo (HR = 0.58, P = .046) and median overall survival was 15.2 vs 12.6 months (HR = 0.41, P = .03). In an exploratory analysis among patients experiencing injection site reactions (all in motolimod group), median progression-free survival was 7.1 among motolimod patients vs 5.9 months among all placebo patients (HR = 0.69, P = .06) and median overall survival was 18.7 vs 12.6 months among all placebo patients (HR = 0.56, P = .02).  

Adverse Events

Adverse events of any grade that were ≥ 10% more common in the motolimod group were injection site reactions (39% vs 0%), chills (37% vs 6%), pyrexia (43% vs 12%), dermatitis acneiform (48% vs 36%), and anemia (60% vs 45%). Serious adverse events occurred in 39% vs 40% of patients.

The investigators concluded, “Adding motolimod to the EXTREME regimen was well tolerated but did not improve [progression-free or overall survival] 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.”

The trial was supported by VentiRx Pharmaceuticals.

Ezra E.W. Cohen, MD, of the Moores Cancer Center, University of California, San Diego, is the corresponding author for the JAMA Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.