Ezra Cohen, MD
Adding a Toll-like receptor 8 agonist (TLR8) to standard care for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) failed to improve progression-free survival (PFS), according to results of a randomized trial.
Conventional treatment with or without motolimod therapy resulted in a median PFS of about 6 months. Similar results emerged from investigator assessments and blinded independent review.
A post hoc analysis suggested an association between injection site reaction and improved PFS and overall survival (OS) with motolimod, as reported at the 2016 ESMO Congress.
“The addition of motolimod to the [standard] regimen did not improve progression-free or overall survival in first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck,” said Ezra Cohen, MD, associate director of Translational Science at the University of California, San Diego. “Serum cytokine responses demonstrated engagement of toll-like receptor 8.
“Injection-site reactions were significantly lower in this study compared with prior motolimod experience in different settings and with different combinations. We are currently investigating whether a unique combination with a platinum agent or 5-FU could dampen immune response.”
Cohen reported findings from the phase II Active8 trial, a follow-up to an earlier phase Ib study that demonstrated the safety and tolerability of motolimod in combination with cetuximab (Erbitux) for patients with recurrent or metastatic SCCHN. Evidence from that study and others suggested that motolimod engagement with TLR8 could enhance SCCHN responsiveness to cetuximab.
The Active8 trial involved 195 patients with recurrent or metastatic SCCHN of the oral cavity, pharynx, larynx, or oropharynx. Patients were randomized to standard therapy with a platinum agent, 5-FU, and cetuximab (EXTREME regimen), administered with or without motolimod. The trial had a primary endpoint of PFS by central review, and secondary endpoints included OS, safety, and investigator-assessed PFS.
The study population had a median age of 58. Men accounted for 85% of the patients, 81% of whom were Caucasian. About two-thirds of the patients tested positive for human papillomavirus. Two-thirds had received prior systemic therapy for SCCHN, and 80% of the patients received carboplatin as part of randomized treatment.
Data for the primary endpoint in the intention-to-treat (ITT) population showed a median PFS of 184 days with the addition of motolimod to the EXTREME regimen and 181 days with EXTREME plus placebo (P
= .516). Median OS in the ITT population was 412 days with motolimod and 343 days with placebo, also not significant (P
Adverse event rates (including grade 3/4 adverse events) were similar between groups, as motolimod added little to the toxicity associated with the standard regimen. Injection site reactions occurred in 39.3% of patients treated with motolimod, but the incidence of grade 3/4 reactions was 2.2%.
Overall, the most common adverse events (any grade) were neutropenia (54.3%), thrombocytopenia (53.1%), anemia (52.6%), fatigue (44.0%), stomatitis (43.4%), dermatitis acneiform (42.3%), leukopenia (38.3), nausea (37.1%), hypomagnesemia (32.6%), and vomiting (32.0%). The most common grade 3 or higher adverse events were neutropenia (37.7%), anemia (20.0%), leukopenia (18.3%), thrombocytopenia (16.0%), fatigue (11.4%), and stomatitis (11.4%).
Given evidence from previous studies of a possible association between injection site reaction and outcome with motolimod, investigators examined the relationship in Active8. The post hoc analysis showed a median PFS of 216 days among motolimod-treated patients who had injection site reactions versus 181 days in the placebo group. The difference translated into a 31% reduction in the hazard for progression or death, which fell just short of statistical significance (P
Injection site reaction with motolimod did have a significant association with OS. Patients with injection site reactions had a median survival of 570 days compared with 382 in the control group, representing a 44% reduction in the hazard ratio (P
A serum biomarker analysis provided evidence of motolimod engagement with TLR8 comparable to evidence of engagement observed in prior studies, said Cohen. Repeat dosing of motolimod did not lead to densitization or augmentation of the TLR8 response.
“Serum cytokine changes did not correlate with injection-site reaction,” said Cohen. “Pharmacokinetics showed considerable interpatient variability but no correlation with outcome.”
Cohen EEW, Saba NF, Gitlitz B, et al. Active8: a randomized, double-blind, placebo-controlled phase 2 study of chemotherapy plus cetuximab in combination with motolimod immunotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark.