Motolimod did not improve progression-free survival in head and neck cancer, but questions remain

However, post-hoc analysis suggests that participants who experienced injection site reactions showed benefit from the addition of motolimod to the standard regimen.

“In the Activ8 study, we did not show an improvement in PFS with the addition of motolimod,” reported Professor Ezra Cohen, Associate Director, Moores Cancer Center, UC San Diego Health, La Jolla, California, US. “However, we did see that the drug was doing something – the cytokine profile of the experimental versus the control arm showed toll-like receptor 8 engagement, and likewise with other biomarkers, but the problem was, it did not have an effect on PFS.”

“Patients were able to mount a local response to the drug and appeared to benefit from the drug.”
Professor Ezra Cohen, Associate Director, Moores Cancer Center, UC San Diego Health, La Jolla, California, US.

Activ8 is based on the principle that stimulating the immune system with motolimod would improve efficacy to standard therapy by increasing antigen-specific T cell responses against epidermal growth factor receptor. Standard of care therapy in head and neck cancer is the EXTREME regimen (platinum, 5-fluorouracil (5FU), cetuximab (CTX)) for first-line treatment of recurrent or metastatic SCCHN. Activ8 investigated the clinical outcomes of when motolimod is added to EXTREME in SCCHN.

Professor Cohen highlighted the tremendous unmet medical need in this group of patients, with most treated with palliative intent because their cancers are beyond cure. “Many patients have symptoms related to cancer such as pain, neck and throat masses, and this impacts quality of life massively.” Median overall survival is only 10 months currently. “We need to reach a point where we can improve survival to one or two years or more and improve symptoms for many of these patients.”

Professor Cohen explained that the randomised phase II study was predicated on prior data showing that motolimod was well tolerated with cetuximab, and that there was some immunologic activity of motolimod that suggested improvement on the first-line regimen.
Patients were randomised 1:1 to EXTREME plus motolimod (n=100) or EXTREME plus placebo (n=95). In this study, clinicians could choose either cisplatin or carboplatin for the platinum component of EXTREME, with 80% opting for carboplatin. Motolimod was added in week 2 and extended for all cycles of chemotherapy and maintenance with cetuximab. Patients were stratified by ECOG (Eastern Cooperative Oncology Group) 0 versus 1, prior systemic therapy for SCCHN and choice of cisplatin or carboplatin.
The primary endpoint was PFS (by immune-related Response Evaluation Criteria In Solid Tumors (RECIST)). OSl and safety were secondary endpoints, as were PFS by both immune-related RECIST and RECIST. “We focussed on immune-related adverse events and the cytokine profile in the two arms,” said Professor Cohen.
Median PFS was 185 days in the motolimod group and 181 days in the control group (p=0.474). OS was 412 days in the motolimod group and 343 days in the controls (p=0.395).
“In the Activ8 study, we did not show an improvement in PFS with the addition of motolimod, when examined by central and independent review,” said Professor Cohen. “Nor was there a difference by RECIST or by immune-related RECIST.”

With respect to adverse events, observations were generally as expected from the EXTREME regimen including hematological toxicity, nausea and vomiting, and the cutaneous toxicity that is seen with 5FU and cetuximab. Pyrexia occurred in 10 patients in the control arm and 38 in the motolimod arm, chills in 5 and 33 patients respectively, and injection site reactions in 35 patients in the motolimod group.

“Interestingly, in the experimental arm we saw evidence of toxicity related to toll-like receptor 8 agonism,” noted Professor Cohen. The study found that patients experienced fever and minor cytokine syndrome and injection site reactions, but the rate of these toxicities was much lower than in previous studies. “For example we would expect to see injection-site reactions in around 80% of patients, but we only saw them in 40% which was striking to us and right now remains unexplained.”

Professor Cohen highlighted that in patients with injection site reactions, improvement was seen in OSl and PFS, compared to the placebo arm (motolimod patients with injection site reactions had a PFS of 216 days versus 181 days in control, p=0.055). “Patients were able to mount a local response to the drug and appeared to benefit from the drug. We don’t know why this did not translate into the whole population, or why those particular patients were able to mount that response, and why there’s a disconnect between the cytokine profile across the board and only 40% of patients experienced injection site reactions, but we’re trying to investigate.”

Next, with tumour samples and clinical data, Professor Cohen and his colleagues want to understand the connection between the injection site reactions and response. “We could hypothesise that in order to form a local reaction to the toll-like receptor 8 agonist, a patient has to have certain parameters in their immune system,” he noted, adding that, “maybe the local response correlates with something in the tumour environment that we can look at that might indicate which patients are the best candidates for the next trial with the drug.”

“There’s a clear sign that the drug is doing something positive, but in an unselected population it was diluted quite a bit,” concluded Professor Cohen.

Based on Cohen E, Saba N et al. Active8: A randomized, double-blind, placebo-controlled study of chemotherapy plus cetuximab in combination with motolimod immunotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (LBA37). Presented on Friday 7 October 2016.

[button link=“https://medonline.at/infocenter-esmo/“ color=“blue“ target=“blank“ size=“large“]<< Back to Infocenter ESMO 2016[/button]