二酰甘油激酶alpha（DGKalpha）选择性细胞内T细胞检查点抑制剂BAY2862789在实体瘤中的全球首次人体（FiH）单药剂量递增试验

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. DGKalpha 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 DGKalpha 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 DGKalpha 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 DGKalpha as a monotherapy is clinically insufficient to effectively modulate anti-tumor immunity.