Preliminary results of a first-in-human phase 1b (aCCeleR8-001) study of S- 531011, a humanized anti-CCR8 monoclonal antibody, in patients with advanced solid tumors
Recommended Citation
Doi T, Satoh T, Yamamoto N, Hwang C, Hamid O, Olszanski AJ, Zeng F, Katsube T, Chisamore MJ, Harada T. Preliminary results of a first-in-human phase 1b (aCCeleR8-001) study of S- 531011, a humanized anti-CCR8 monoclonal antibody, in patients with advanced solid tumors. 2025; (16_suppl).
Document Type
Conference Proceeding
Publication Date
5-28-2025
Abstract
Background: C-C motif chemokine receptor 8 (CCR8) is selectively upregulated in tumorinfiltrating regulatory T cells (TI-Tregs) in multiple cancers, inhibiting anti-tumor activity of the host immune system. S-531011, a humanized IgG1 monoclonal antibody, is anticipated to deplete CCR8-positive TI-Tregs, restoring anti-tumor immunity without inducing autoimmunity. Methods: An aCCeleR8-001 study is a Phase 1b/2, multicenter, open-label study of S-531011 which consists of Phase 1b Dose Escalation part (Parts A-1 and A-2) and Phase 2 Dose Expansion part. The safety/tolerability, pharmacokinetic (PK), pharmacodynamic, and anti-tumor activity of S-531011 as monotherapy and in combination with pembrolizumab (Merck & Co., Inc.) were evaluated in patients with various types of locally advanced or metastatic solid tumors. S-531011 monotherapy was administered at 8, 24, 80, 240, 800, or 1600 mg/kg intravenously every 3 weeks (Q3W) in Part A-1, whereas patients in Part A-2 received S-531011 at 80, 240, 800, or 1600 mg/kg in combination with pembrolizumab 200 mg/ kg Q3W. The data were analyzed when all patients in Dose Escalation cohorts completed the dose-limiting toxicity (DLT) observation period. Results: As of the data cutoff date (30 Sep 2024), 40 and 35 patients were enrolled in Parts A-1 and A-2, respectively. No DLTs were reported at any dose level and themaximumadministered dose of S-531011 was 1600mgin both parts. One patient reported an infusion-related reaction in Part A. Immune-related adverse events (irAEs) were reported in two patients (5.0%; Grade 1/2 only) in Part A-1, whereas 15 irAEs were reported in 10 patients (28.6%; including four Grade 3 irAEs in four patients) in Part A-2. PK of S-531011 was approximately dose proportional with a terminal elimination half-life of 10 to 12 days regardless of dose level. CCR8 receptors in PBMCs were occupied at doses of 80 mg or higher. PK/CCR8 receptor occupancy modeling analysis indicated that > 90% of receptors in tumor tissues were occupied in the range of 80 to 800 mg. Multiplex immunohistochemistry analysis demonstrated proof of mechanism as evidenced by CCR8-positive Treg depletion in tumor tissue at doses of 24mgor higher. Among 62 evaluable patients dosed at 80 to 1600mgin Part A, four patients (6.5%) had confirmed partial response, three of whom had colorectal cancer (CRC). Twenty patients (32.3%) had disease control for≥6 weeks. Response rate was not correlated with dose (80 to 1600 mg). Following a comprehensive data review, tentative recommended Phase 2 doses were determined to be 80 to 800 mg in both parts. Conclusions: S-531011 was well tolerated up to 1600 mg as monotherapy and in combination with pembrolizumab. A higher response rate in patients with CRC warrants further exploration of this tumor type in Phase 2 Dose Expansion part. Phase 2 CRC cohorts are currently ongoing.
Issue
16_suppl
