First in human trial of BAY2965501, a selective inhibitor of intra-cellular T cell checkpoint diacylglycerol kinase zeta (DGKζ), as monotherapy and combination with anti-PD-1

Background: The ability of immunotherapies to boost anti-cancer immunity is limited by the immune system's capacity to recognize tumor-associated antigens. DGKζ acts as an intra-cellular immune checkpoint, attenuating the intensity of T cell receptor signaling through phosphorylation of the secondary messenger diacylglycerol. Preclinically, BAY2965501 was shown to block DGKζ and enhance T cell anti-tumor function as a monotherapy and in combination with anti-PD-1. Here we report results of the first selective DGKζ inhibitor FiH trial. Methods: A FiH trial (NCT05614102) of BAY2965501 was conducted comprising dose escalation in monotherapy (MDE) and combination with pembrolizumab (CDE) in solid tumor patients, parallel biomarker cohorts in selected tumors, and a monotherapy expansion (ME) in NSCLC, to determine safety (MTD/MAD), pharmacokinetics (PK), pharmacodynamics (PD) and to explore evidence of proof of mechanism (PoM) through T cell modulation. BAY2965501 was administered orally once daily in 21 day cycles. Results: 124 patients were dosed (52% male, 69% ECOG 1, 75% white, aged 30-91 years); 9 cohorts in MDE (N=48) & 5 cohorts in CDE (N=26). Schedules tested included either 1) same dose level or 2) step up to target dose level over 2 or 3 weeks. Selected dosages were tested in biomarker cohorts (monotherapy N=19, combination N=9) and NSCLC ME (N=22) based on PK/PD analysis.BAY2965501 showed similar PK in MDE and CDE. Plasma concentrations above preclinically defined EC50/EC80 required for increased T cell function, coinciding with >2-fold increase in peripheral T cell activation (Ki67+) compared to baseline, were achieved. Consistent with biologic changes in anti-tumor immunity, paired biopsy analysis demonstrated >2-fold increase change of T cell activation/infiltration in ~50% of evaluable patients. Safety at dosages associated with observed PD was manageable. Overall, dose modifications / discontinuation due to TEAEs occurred in 55% / 6%, and due to TRAEs in 28% / 3%. Four DLTs occurred in MDE (G4 tonic-clonic seizure, G3 muscular weakness, G2 hallucinations and G2 dyskinesia), and one in CDE (G2 dyskinesia). Neurological and psychiatric TRAEs occurred infrequently across all cohorts and resolved on interruption of BAY2965501. Most common TRAEs (>15%) were gastrointestinal (Diarrhea, Nausea, Decreased appetite, Vomiting). 2 responses (PR) in ME and 3 PRs, including 1 post progression in CDE were observed (1 confirmed in each), with a disease control rate of 40% and 53.1% in ME and CDE, respectively. Conclusions: BAY2965501 monotherapy and combination with anti-PD-1 demonstrated acceptable safety, despite neurological DLTs, with MAD/MTD determined in MDE and CDE. PD effects provide evidence of PoM with modest signals of single agent and combination activity supporting further testing in combination with anti-PD-1.