PGE Inhibitor Shows Some Activity in Advanced Malignancies in Phase I Study

PGE Inhibitor Shows Some Activity in Advanced Malignancies in Phase I Study

A first-in-class agent known as E7046 that inhibits the PGE2-receptor type 4 was well tolerated and showed promising clinical activity, especially regarding its potential for combination therapy, in a phase I trial of patients with advanced malignancies (Abstract 49).

Dr. David S. Hong presents Abstract 49.
“This represents a first-in-class investigational compound for a cancer immunotherapy,” said David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, during an Oral Abstract Session on clinical trials on January 25. E7046 is a potent, highly selective small-molecule inhibitor of PGE2-receptor type 4, and preclinical data have shown that it reverses PGE2-mediated tumor immune suppression. In animal models, the agent used alone showed mostly an immune-dependent inhibition of tumor growth, whereas it showed potent antitumor activity in combination with radiation and with immune checkpoint inhibition.

Dr. Hong presented results of a first-in-human phase I study of the agent, which included 30 patients treated in four dose cohorts (125 mg, 250 mg, 500 mg, and 750 mg once daily). All patients had advanced, nonresectable, or recurrent tumors; 13 patients (43.3%) had colorectal cancer, six patients (20.0%) had pancreatic tumors, four patients (13.3%) had squamous cell carcinoma of the head and neck, and seven patients (23.3%) had other malignancies. The median age in the trial was 58.0 years, and most patients were male (63.3%) and white (80.0%). Patients were generally heavily pretreated, with 73.3% having received three or more prior lines of therapy, including 13.3% who had previously received immunotherapy.

The study found no dose-limiting toxicities in any of the four cohorts, and the maximum tolerated dose was not reached. The most common treatment-emergent adverse events (TEAE) of any grade included fatigue (11 patients, 36.7%), diarrhea (10 patients, 33.3%), nausea (nine patients, 30.0%), and decreased appetite (seven patients, 23.3%). In total, 28 patients (93.3%) experienced a TEAE of any grade.

Seventeen patients had a TEAE of grade 3 or higher (56.7%), with abdominal pain (three patients, 10.0%) and vomiting (two patients, 6.7%) among the more common events.

There were no objective responses by irRECIST criteria, but seven patients (23%) had stable disease. Five patients had a duration of treatment of 18 weeks or more and were clinically stable, and 10 patients had a duration of treatment with E7046 that was longer than their most recent prior therapy.

The investigators did observe metabolic responses in three patients. Measured using 18FDG-PET, a partial metabolic response was defined as a reduction in maximum standardized uptake value (SUVmax) of at least 25% after more than one cycle of the therapy.

Dr. Ann W. Silk discusses Abstract 49.
Dr. Hong noted that E7046 was rapidly absorbed across all doses, with Cmax observed approximately 2 hours after a dose. The elimination half-life was 12 hours, and the exposure of the agent was dose-proportional up to the 500 mg level, with no incremental increase at the 750 mg level. There was also evidence of gene expression changes with E7046 treatment, with modulation of 16 out of a 92-immune-gene panel; seven of those genes are known to be modulated by EP4 signaling. Five of those EP4-signaling genes were significantly regulated, which Dr. Hong said implicates target modulation with the drug.

There were also cytokine changes in blood after treatment with E7046, with modulation of 14 cytokines out of a panel of 36. The T-cell recruiting chemokines CXCL10 (p = 0.0015) and CCL5 (p = 0.0292) were significantly upregulated at day 15 of the first cycle, compared with baseline measurements.

There was an increase in tumor T-cell infiltration after treatment with E7046. Immunohistochemistry staining showed increases in both CD3 and CD8 cells from baseline to post-treatment.

Patients with higher baseline tumor infiltration of T cells had better clinical activity with E7046. Patients with higher baseline levels of CD3+ cells were more likely to have stable disease than progressive disease (p = 0.0002), and the same was true for CD8+ cells (p = 0.0041) and for CD163+ macrophages (p = 0.0437).

Dr. Hong said that combinations using this agent are of significant interest moving forward. “We really felt that this would be the best development opportunity for this molecule,” he said.

Ann W. Silk, MD, of the Rutgers Cancer Institute of New Jersey, was the discussant for the abstract, and she noted that there is ample preclinical rationale for using this agent’s approach. “PGE2-receptor type 4 is an abundant prostaglandin that promotes M2 macrophages and suppresses T-cell activation and recruitment, which makes it an ideal target for cancer immunotherapy,” she said.

She pointed out that although no objective responses were observed, the drug did appear to be safe and tolerable, and that the pharmacokinetics of the drug were quite favorable, which would allow for convenient daily oral administration. However, one patient in the trial did experience anaphylaxis, which is of concern with a drug administered at home.

Also, she said that the study “demonstrated strong mechanistic correlatives in blood and tumor, which support the proposed mechanism of action and inform choices for combination approaches.”

The drug may not be effective as monotherapy, but the correlate studies suggest immune modulation is occurring. “The field recognizes tumor-associated macrophages as a valuable target—E7046 joins a growing group of agents that inhibit M2 macrophages and/or promote M1 macrophages,” Dr. Silk said.

–David Levitan