Abstract CT003: Initial results of a phase 1 study of AMG 355, a novel anti-CCR8 antibody as a single agent and in combination with pembrolizumab in patients with solid tumors

Abstract Background: Prior clinical strategies to target regulatory T cells (Tregs) have been limited by lack of tumor selectivity and efficacy. Chemokine receptor 8 (CCR8) is selectively enriched on intratumoral Tregs, providing a rationale to evaluate targeted Treg depletion in a first-in-human study using AMG 355, an afucosylated monoclonal antibody to CCR8. Methods: This multicenter, open-label, phase 1 study evaluated the safety, tolerability and preliminary antitumor activity of AMG 355 in adult patients (pts) with advanced solid tumors (non-small cell lung cancer, colorectal cancer, gastric cancer and melanoma) who had failed to respond or were intolerant to standard treatment. Participants were administered intravenous (IV) AMG355 given alone (Part 1A) or with 200 mg pembrolizumab Q3W (Part 1B). Both parts included dose escalation and backfilled cohorts with mandatory pre- and on-treatment tumor biopsies. The primary endpoints were safety, maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary endpoints were pharmacokinetics, preliminary antitumor activity, and pharmacodynamic effect on tumor CCR8+ cells on paired tumor biopsies. Results: As of December 7, 2025, 77 pts received AMG 355 alone (n=47) or in combination with pembrolizumab (n=30). Treatment-related adverse events (TRAEs) occurred in 74. 5% and 80. 0% of pts (including 4. 3% and 16. 7% grade ≥3 TRAEs) in Part 1A and Part 1B, respectively. Most common (%, all grades/grade ≥3) AEs were: infusion-related reactions (40. 4/0) and pyrexia (21. 3/0) in Part 1A; infusion-related reactions (36. 7/0), ALT increase (23. 3/3. 3) and AST increase (23. 3/0) in Part 1B. No dose-limiting toxicity was observed. MTD was not reached. Serum AMG 355 levels increased dose-proportionally in both monotherapy and pembrolizumab combination arms. Spanning multiple dose levels (70-700mg), the median %IPS (Immune cell Proportion Score: percentage of CCR8+ cells among immune cells measured by IHC) was 5 (range 0-25) prior to AMG 355 treatment (N=47). In pts whom paired biopsies were available with clinical activity (N=26), the baseline median CCR8 %IPS was 12. 33 (range 2-20) in 7 pts with stable disease (SD) or partial response (PR), and 5 (range 0-25) in 19 pts with progressive disease (PD). For on-treatment (cycle 2) biopsies, the median CCR8 %IPS was 1 (range 0-5) in pts with SD/PR and 1 (range 0-6) in pts with PD. Objective responses were limited to two partial responses (one with melanoma in Part 1A and one with gastric cancer in Part 1B). SD was the best response in 9 pts (19. 1%) in Part 1A and 10 pts (33. 3%) in Part 1B. Conclusions: AMG 355 was safe and tolerable at doses up to 700 mg, but clinical activity as a single agent or combined with pembrolizumab was limited. Pharmacodynamic activity was observed, and further examination of the immune contexture is underway using digital pathology approaches. Citation Format: Antoine Hollebecque, Pilar Garrido Lopez, Marwan Fakih, Yasutoshi Kuboki, Markus Joerger, Jeong Eun Kim, Iwona Lugowska, Ivan Manuel Victoria Ruiz, Chia-Chi Lin, Fredericus Eskens, Ingrid Desar, Ming-Huang Chen, Caio Max Rocha Lima, Antoine Italiano, Haeseong Park, Abdulazeez Salawu, Kyriakos Papadopulos, Timothy Price, Tae Min Kim, Martina Imbimbo, Irene Vuu, Jackie Zhang, Theresa Alexander, Kumiko Isse, Elizabeth Finger, Olivier Mir, Oriol Mirallas. Initial results of a phase 1 study of AMG 355, a novel anti-CCR8 antibody as a single agent and in combination with pembrolizumab in patients with solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT003.