According to the results of a randomized trial, the addition of a toll-like receptor agonist (TLR8) to standard care failed to improve progression-free survivial (PFS) for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Conventional treatment with or without motolimod therapy resulted in a median PFS of about six 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, M.D., 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 2 Active8 trial, a follow-up to an earlier phase 1b study that demonstrated the safety and tolerability of motolimod in combination with Erbitux (cetuximab) for patients with recurrent or metastatic SCCHN. Evidence from that study and others suggested that motolimod engagement with TLR8 could enhance SCCHN responsiveness to Erbitux.
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 Erbitux (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 percent of the patients, 81 percent 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 percent 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. Median OS in the ITT population was 412 days with motolimod and 343 days with placebo, also not significant.
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 percent of patients treated with motolimod, but the incidence of grade 3/4 reactions was 2.2 percent.
Overall, the most common adverse events (any grade) were neutropenia (54.3 percent), thrombocytopenia (53.1 percent), anemia (52.6 percent), fatigue (44.0 percent), stomatitis (43.4 percent), dermatitis acneiform (42.3 percent), leukopenia (38.3), nausea (37.1 percent), hypomagnesemia (32.6 percent) and vomiting (32.0 percent). The most common grade 3 or higher adverse events were neutropenia (37.7 percent), anemia (20.0 percent), leukopenia (18.3 percent), thrombocytopenia (16.0 percent), fatigue (11.4 percent) and stomatitis (11.4 percent).
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 percent reduction in the hazard for progression or death, which fell just short of statistical significance.
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 percent reduction in the hazard ratio.
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.”