Abstract CT131: Global first-in-human (FiH) monotherapy dose escalation trial of BAY2862789, a diacylglycerol kinase alpha (DGKα) selective intra-cellular T cell checkpoint inhibitor in solid tumors

Abstract Background: The limited ability of a patient’s immune system to recognize tumor mutations as foreign antigens is a key constraint on the effectiveness of immunotherapies to improve anti-cancer immunity. DGKα is an isoform of DGK in T cells, that like DGKζ acts as an intra-cellular immune checkpoint to down-modulate the strength of T cell receptor signaling through phosphorylation of the critical secondary messenger diacylglycerol. Preclinically, inhibition of DGKα with the specific inhibitor BAY2862789 results in enhanced T cell function as monotherapy and in combination with immunomodulatory agents leading to increased anti-tumor effects in vitro and in vivo murine models, albeit to a lesser degree than DGKζ inhibition. Methods: A FiH trial (NCT05858164) of BAY2862789 was performed using a keyboard design for dose escalation (DE) in patients with solid tumors, with an additional parallel biomarker cohort (BC) of select tumor types, to evaluate safety (MTD/MAD), pharmacokinetics and pharmacodynamics (PD) and to determine a recommended dose for expansion (RDE). BAY2862789 was administered orally in continuous 21-day cycles until disease progression or treatment discontinuation. Here we report results of the first selective DGKα inhibitor global FiH study. Results: Thirty-nine patients were dosed: N=27 DE, and N=12 BC (NSCLC=9, GOJ N=2 and CRC N=1). Baseline characteristics were 46% female (N=18) with age range 21-84 years and ECOG 0 (N=15), ECOG 1 (N=24). Three dosages were tested in 5 cohorts. Patients received between 1-16 cycles in total. Plasma concentrations of BAY2862789 were in the predicted pharmacologically active exposure range in all cohorts. Percentage worst grade TEAEs and TRAEs G1/2 were 51% and 79%; ≥ Grade 3 were 24% and 18% respectively. The most common TRAEs (>15% of patients) were Nausea, (79% G1-2, 3% G3), Dizziness (72% G1-2, 3% G3), Vomiting (59% G1-2, 3% G3), and Diarrhea (21% G1-2, 3% G3). Possible immune-related AEs were observed in 5 patients including raised CK G4 and myositis G2, myalgia G1, Hyperthyroidism G1, Hypothyroidism G2, erythema/pruritus G1. Two separate DLTs were observed (hypertension G3, dizziness G3). TRAE leading to dose modification or discontinuation occurred in 26% and 5% of patients, respectively. Despite plasma concentrations higher than in vitro EC80 in all patients, no consistent evidence of peripheral T cell activation (Ki67+) was observed. No measurable increase in intra-tumor T cells was seen in evaluable paired biopsies (N=5). The overall disease control rate was 43.6% with no RECIST 1.1 response observed. Conclusions: At tested doses, treatment with BAY2862789 was tolerable. Whilst MAD and RDE were determined, analyses of PD biomarkers suggest that specific inhibition of DGKα as a monotherapy is clinically insufficient to effectively modulate anti-tumor immunity. Citation Format: Ravit Geva, Ofra Maimon, Aaron Hansen, Jeong Eun Kim, Javier Garcia-Corbacho, Enriqueta Felip, Sook Hee Hong, Kyriakos Papadopoulos, Guru Sonpavde, Alexandre Desjonqueres, Yulin Li, Christoph Mancao, Jochen Schulze, Stephen Ducray, Andrea Frohwann, Lidia Sacchetto, Huijuan Su, Laura Hunt, Stefanie Reif, David A. Schaer, Helge Roider, Leila Khoja, Shirish Madhav Gadgeel, Tae Min Kim. Global first-in-human (FiH) monotherapy dose escalation trial of BAY2862789, a diacylglycerol kinase alpha (DGKα) selective intra-cellular T cell checkpoint inhibitor in 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(8_Suppl):Abstract nr CT131.