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
Presenter: Shirish Madhav Gadgeel, Unknown Session: Phase 0 and First-in-Human Phase I Clinical Trials Time: 4/20/2026 2:00:00 PM → 4/20/2026 5:00:00 PM
Authors
Ravit Geva 1 , Ofra Maimon 2 , Aaron Hansen 3 , Jeong Eun Kim 4 , Javier Garcia-Corbacho 5 , Enriqueta Felip 6 , Sook Hee Hong 7 , Kyriakos Papadopoulos 8 , Guru Sonpavde 9 , Alexandre Desjonqueres 10 , Yulin Li 11 , Christoph Mancao 12 , Jochen Schulze 12 , Stephen Ducray 12 , Andrea Frohwann 10 , Lidia Sacchetto 10 , Huijuan Su 13 , Laura Hunt 14 , Stefanie Reif 10 , David A. Schaer 15 , Helge Roider 10 , Leila Khoja 10 , Shirish Madhav Gadgeel 16 , Tae Min Kim 17 1 Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel, 2 Hadassah Hebrew University Hospital Ein Kerem, Ein Kerem, Israel, 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 4 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of, 5 Hospital Clinic de Barcelona, Barcelona, Spain, 6 Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 7 The Catholic University of Korea-Seoul St. Mary’s Hospital, Seoul, Korea, Republic of, 8 START Cancer Center, San Antonio, TX, 9 AdventHealth Medical Group, Orlando, FL, 10 Bayer AG, Berlin, Germany, 11 Bayer HealthCare Pharmaceuticals, Whippany, NJ, 12 Bayer AG, Basel, Switzerland, 13 Bayer, Beijing, China, 14 Bayer PLC, Reading, United Kingdom, 15 Bayer, Whippany, NJ, 16 Henry Ford Cancer Center, Detroit, MI, 17 Seoul National University Hospital, Seoul, Korea, Republic of
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.
Disclosure
R. Geva, None.. O. Maimon, None.. A. Hansen, None.. J. Kim, None.. J. Garcia-Corbacho, None.. E. Felip, None.. S. Hong, None.. K. Papadopoulos, None.. G. Sonpavde, None. A. Desjonqueres, Bayer Employment. Y. Li, Bayer Employment. C. Mancao, Bayer Employment. J. Schulze, Bayer Employment. S. Ducray, Bayer Employment. A. Frohwann, Bayer Employment. L. Sacchetto, Bayer Employment. H. Su, Bayer Employment. L. Hunt, None. S. Reif, Bayer Employment. D. A. Schaer, Bayer Employment. H. Roider, Bayer Employment. L. Khoja, None. S. Gadgeel, Astra-Zeneca Other, Consultant; Ad Board. Genentech/Roche Other, Consultant. Pfizer Other, Consultant. Bayer Other, Consultant. Regeneron Other, Consultant. Daichii Other, Consultant. Astellas Other, Consultant. Boehringer-Ingelheim Other, Consultant. Ellipses Other, Consultant. Amgen Other, Consultant. BMS Other, Consultant. Gilead Other, Consultant. J&J Other, Consultant. Arrivent Other, Manuscript support. T. Kim, None.
Cited in
Control: 10693 · Presentation Id: 12056 · Meeting 21436