While the addition of motolimod to the EXTREME regimen did not improve progression-free or overall survival in first-line recurrent or metastatic squamous cell carcinoma of the head and neck, post hoc analysis suggests that subjects with injection-site reactions benefited from the addition of this agent.

— Ezra Cohen, MD

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In the phase II Active8 trial, a novel immunotherapy agent, motolimod, failed to improve outcomes over chemotherapy plus cetuximab (Erbitux) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. In a post hoc analysis, however, patients with injection-site reactions did appear to benefit, according to Ezra Cohen, MD, of the University of California, San Diego, Moores Cancer Center in La Jolla, California.

“In patients with injection-site reactions, there was a difference. This is completely hypothesis-generating, and we need to interpret these results with caution. There are various ways to explain this, and we are working to do that,” Dr. Cohen said in his presentation at the 2016 European Society for Medical Oncology (ESMO) Congress.¹

Motolimod, a toll-like receptor 8 (TLR8) agonist, stimulates myeloid dendritic cells, monocytes, and natural killer cells in the blood and tumor microenvironment, inducing a proinflammatory immune response. In a phase Ib study of previously treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck, motolimod combined with cetuximab was safe and well tolerated and produced “some interesting efficacy results,” Dr. Cohen noted. Motolimod was therefore tested for its additional benefit when added to the first-line standard-of-care EXTREME regimen. (EXTREME was a randomized, controlled multicenter trial conducted in Europe using European Union–approved cetuximab.)

Active8 was a randomized, double-blind, placebo-controlled phase II study in 195 patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients received the EXTREME regimen, which included a platinum, fluorouracil (5-FU), and cetuximab, or the same chemotherapy plus motolimod. Motolimod was continued with cetuximab as maintenance after six cycles, while the control arm received maintenance cetuximab.

Endpoint Not Met

The primary endpoint of progression-free survival per independent central review in the intent-to-treat population was not met. “The primary and secondary endpoints did not change in the intent-to-treat population. As more data surfaces, it looks like human papillomavirus–positive patients had a progression-free and overall survival benefit,” Dr. Cohen reported. The investigators evaluated outcomes by independent central assessment, Response Evaluation Criteria in Solid Tumors (RECIST), and immune-related ­RECIST (ie, criteria developed to more accurately reflect the antitumor activity of immunotherapeutic agents, given their distinct mechanism of action).

Median progression-free survival was 185 days in the motolimod arm and 181 days in the control arm, by independent central assessment and according to immune-related RECIST (hazard ratio [HR] = 0.99; P = .474). The analysis was similar according to traditional RECIST criteria, a median of 184 and 181 days, respectively (HR = 1.01; P = .516). A secondary endpoint, overall survival, was also not different, 412 vs 343 days (HR = 0.95; P = .395).

“The median overall survival was what we would expect to see with the EXTREME regimen, and the addition of motolimod did not improve survival,” he commented.

The adverse-event profile was typical of the EXTREME regimen, except for a greater incidence of pyrexia (43% vs 12%), chills (37% vs 6%), and injection-site reactions (39% vs 0%) in the motolimod arm.

Biomarker of Response?

“We saw a 40% rate of injection-site reactions in the motolimod arm, whereas in all other studies using motolimod on its own and in combination with different agents (n = 276 total), the rate is typically 80%,” Dr. Cohen said. “This struck us, and we began to ask, what’s different in this study?”

“With that in mind, we did a post hoc unplanned analysis looking at patients who developed injection-site reactions on motolimod, and we saw a separation of the progression-free survival curves; the same effect held for overall survival,” he said.

Motolimod-treated patients experiencing injection-site reactions had a median progression-free survival of 216 days, vs 181 days for the placebo arm (HR = 0.69; P = .055). Median overall survival was 570 vs 382 days, respectively (HR = 0.56; P = .023).

“Again, this was an unplanned post hoc analysis, but it’s of interest because we feel injection-site reactions are a parameter of the agent’s activity,” Dr. ­Cohen explained.

Analysis of serum biomarkers showed TLR8 engagement, with mean changes in plasma mediators (chemokines, interleukins) comparable to what has been shown in previous studies of this drug. Serum cytokine responses demonstrated engagement of TLR8, he said.

“We did additional correlative studies, but, in short, none revealed the promise of a predictive biomarker for motolimod. The pharmacology was typical of prior studies, with pharmacokinetics showing considerable interpatient variability but no correlation with outcome. CD3- or CD8-positive lymphocyte infiltration at baseline did not predict response rate or progression-free survival,” Dr. Cohen said. “We are investigating whether this unique combination with platinum or 5-FU could have dampened the immune response.”

He concluded: “While the addition of motolimod to the EXTREME regimen did not improve progression-free survival or overall survival in first-line recurrent or metastatic squamous cell carcinoma of the head and neck, post hoc analysis suggests that subjects with injection-site reactions benefited from the addition of this agent, and we could hypothesize that there were some patients who translated TLR8 administration into a clinical benefit.”

Going forward, he said, “In a sense, it’s back to the drawing board with this agent.” The researchers are now especially interested in outcomes for motolimod in combination with other immunomodulating agents. In those studies, they will obtain tumor biopsies before and during treatment, “which may answer some of the questions in terms of what is happening to different cell populations in the microenvironment,” he added. ■

Disclosure: Dr. Cohen has served on the advisory boards of Bristol-Myers Squibb, AstraZeneca, Pfizer, Merck, Merck Serono, Aspyrian, Human Longevity, Amgen, and Genmab.

Reference

1. Cohen E, Saba NF, Gitlitz B, 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. 2016 ESMO Congress. Abstract LBA37. Presented October 7, 2016.