E-602 plus cimepilimab elicits preliminary anti-tumor activity and is safe against PD-(L)1-resistant solid tumors

First-in-class engineered human sialidase Fc fusion based on data from the Phase 1/2 GLIMMER-01 trial (NCT05259696) shared at the 2024 SITC Annual Meeting The combination of compound E-602 and cemiplimab elicited preliminary antitumor activity and demonstrated a tolerable safety profile in patients with anti-PD-(L)1-resistant solid tumors, including non-small cell lung cancer [NSCLC] and melanoma.

The data showed that despite a half-life of approximately1 day, the E-602 combination produced tumor devascularization within 2 to 5 days of treatment. When excluding those patients with a baseline HYRDA tissue score of 20 or less, 9 of 10 patients developed tumor separation. CD163-positive tumor-associated macrophages were also reduced after treatment with E-602 plus cimipilimab. Excluding those patients with a baseline hydra tissue score of 20 or less, 8 of 10 patients developed tumor-associated macrophage depletion.

Among 15 patients with hypersialic acid (those with a HYDRA tissue score of 20 or higher), 7% (n=1) had a partial response (PR), 40% (n=6) had stable disease, and 53% (n=8) reported progressive disease. One patient who developed a PR had been receiving study treatment for more than 12 months at the time of analysis. Of the 5 patients who lacked hypersialylation and had polyp tissue scores less than 20, all patients (100%; n=5) experienced disease progression after study treatment. These data suggest that desialylation of tumor cells exhibiting hypersialylation may be a potential therapeutic strategy for such patients.

Glycan editing of cell surface glycans offers a potential new therapeutic approach to treat cancer. E-602, a first-in-class engineered human sialidase Fc fusion, has demonstrated safety, mechanism validation and early anti-tumor activity in combination with cimepilimab in patients with PD-1 and PD-L1 resistant solid tumors. A future goal of this project is to increase the duration of tumor isolation to improve antitumor activity. There are two ways to do this. One is to increase drug exposure by optimizing human sialidase to extend half-life. The other is to enhance tumor targeting by integrating tumor targeting arms. Tumor cell sialylated polysaccharides can suppress innate and adaptive anti-tumor immunity, and desialylation of tumor cells may enhance these types of anti-tumor immunity.

In the monotherapy dose-escalation portion of the GLIMMER-01 trial, patients received escalating doses of E-602 at 1 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg. The researchers determined that the recommended dose for the second phase is 20 mg/kg. atIn part 2 of the GLIMMER-01 trial, patients received 20 mg/kg of E-602 once weekly and 350 mg of cimepilimab every 3 weeks. The primary endpoints were safety and tolerability and objective response rate.

The cohort included 21 patients with PD-L1-resistant disease, with the most common tumor types including non-small cell lung cancer (n=12), melanoma (n=8), and esophagogastric junction cancer (n=1). The median age was 66 years (range 42-82 years), the majority of patients were female (52%), and the ECOG performance status at screening was 1 (67%). Most patients had baseline tumors that were hypersialic acid (75%). The combination of E-602 and cimepilimab increased peripheral cytokine levels compared with E-602 alone.

The treatment combination produced no dose-limiting toxicities, and investigators observed one treatment-related serious adverse reaction (AE), including a Grade 3 infusion-related reaction. Grade 2 toxicities included infusion-related reactions (38%) and fatigue (10%). In addition, grade 1 treatment-related adverse events included nausea (10%), chills (10%), and fatigue (5%).

Reference: https://www.onclive.com/view/e-602-plus-cemiplimab-elicits-preliminary-antitumor-activity-is-safe-in-pd--l-1-resistant-solid-tumors