BAY 2965501 / Bayer, German Cancer Research Center - LARVOL DELTA

Bayer has cleared out four cancer candidates from its early-stage pipeline, including a STAT3 inhibitor acquired as part of its buyout of Vividion Therapeutics. (FierceBiotech) - "Vividion and Bayer 'made the strategic decision to discontinue the development' of VVD-130850 'based on the totality of the data, which includes safety, PK/PD and activity of the drug,'...The program consisted of a DGK-alpha inhibitor dubbed BAY 2862789 along with a DGKzeta Inhibitor called BAY 2965501....The final cancer drug thrown on the scrap heap was an anti-human CCR8 antibody called BAY 3375968 or lanerkitug."

Discontinued • P1 data • Colorectal Cancer • Melanoma • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Acute Myeloid Leukemia: A Key Role of DGKα and DGKζ in Cell Viability. (PubMed, Cells) - "This study investigated the effects of ritanserin, a DGKα-specific inhibitor, and DGKζ-IN4 or BAY 2965501, DGKζ-selective inhibitors, on a panel of AML cell lines...These findings indicate that DGKs targeting can effectively reduce AML cell viability. However, AML heterogeneity and the limited selectivity of current inhibitors underscore the need for predictive biomarkers and combinatorial strategies to translate DGK inhibition into effective therapy."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Treatment with Diacylglycerol Kinase (DGK) Alpha specific inhibitor BAY2862789 exhibits combination potential with DGK zeta inhibition in biomarker assays during FIH monotherapy Trial (SITC 2025) - P1 | "Accordingly, ex vivo assays performed on a subset of patients (n=>10), including the addition of BAY2965501, demonstrated synergistic elevation in IFNγ and IL2 production on-treatment compared to baseline.Conclusions Specific inhibition of DGKα by BAY2862789 alone does not lead to substantial immune modulation in patients, despite reaching sufficient exposure to synergize with BAY2965501 in ex vivo assays. Data suggests that BAY2862789 should be combined with DGKζ inhibition to achieve the greatest T cell activation in patients."

Biomarker • Biomarker assay • First-in-human • IO biomarker • Monotherapy • Oncology • IFNG • IL2

Selective Inhibition of Diacylglycerol Kinase Zeta exhibits increased T cell activation and anti-tumor immunity, demonstrating pharmacodynamic proof of mechanism in the FIH trial of BAY2965501 (SITC 2025) - P1 | "Thus, selective blocking of DGKζ could represent an attractive strategy to overcome the limitations of first generation immunotherapies.Methods BAY2965501 is being investigated in a FIH dose-escalation and expansion study (NCT05614102) to evaluate safety, pharmacokinetics and pharmacodynamics, in patients with solid tumors as a monotherapy and in combination with anti-PD-1 antibody pembrolizumab. BAY2965501-induced T cell activation coincided with expansion of newly detected T cell clones both in monotherapy and anti-PD-1 combination as measured by TCRseq. In evaluable paired biopsies, >50% of patients demonstrated >2-fold increase of T cell infiltration/activation confirming DGK inhibition dependent changes in anti-tumor immunity.Conclusions BAY2965501 demonstrates pharmacodynamic PoM in monotherapy and combination, providing evidence that specific inhibition of DGKζ in patients is sufficient to modulate anti-tumor immunity.Acknowledgements Acknowledgments:..."

First-in-human • IO biomarker • PK/PD data • Oncology • Solid Tumor • DGKZ

A First-in-human Study to Learn How Safe the Study Drug BAY2965501 is, Find the Best Dose (Single Drug & Combination), How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, How it Acts on Different Tumors in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=284 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Jun 2027 ➔ Sep 2027

First-in-human • Monotherapy • Trial completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • PD-L1

A First-in-human Study to Learn How Safe the Study Drug BAY2965501 is, Find the Best Dose (Single Drug & Combination), How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, How it Acts on Different Tumors in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=284 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • PD-L1

Optimal enhancement of anti-tumor T-cell immunity through the combined use of selective DGK zeta and DGK alpha inhibitors (CIMT 2025) - "We previously presented the discovery and pharmacology of the DGKζ-selective inhibitor BAY 2965501 (5). In parallel, we developed the DGKα-selective inhibitor BAY2862789, and analyzed its impact on T-cell activation and anti-tumor immunity, both as single agent and in conjunction with DGKζ inhibition, PDL1-blockade and/or depletion of CCR8-positive T-regulatory cells (6)... The availability of DGKζ and DGKα selective inhibitors allows for hypothesis-driven pharmacology and toxicology studies, and – in combination with the forthcoming single-agent patient exposure data - for a rationally designed dual-agent clinical study."

Infectious Disease • Oncology • CCR8 • TGFB1

A First-in-human Study to Learn How Safe the Study Drug BAY2965501 is, Find the Best Dose (Single Drug & Combination), How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, How it Acts on Different Tumors in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=284 | Recruiting | Sponsor: Bayer | Trial completion date: Aug 2026 ➔ Jun 2027 | Trial primary completion date: Aug 2026 ➔ Jun 2027

Monotherapy • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Optimal enhancement of anti-tumor T-cell immunity through the combined use of selective DGK zeta and DGK alpha inhibitors (SITC 2024) - "Further experimental evidence suggests that dual DGKα/ζ inhibition may result in enhanced T-cell activation compared to selective inhibition alone.1–4 We previously presented the discovery and pharmacology of the DGKζ-selective inhibitor BAY 2965501.5 In parallel, Bayer has developed the DGKα-selective inhibitor BAY2862789, and analyzed its impact on T-cell activation and anti-tumor immunity, both as single agent and in conjunction with DGKζ inhibition, PDL1-blockade and/or depletion of CCR8-positive T-regulatory cells.6 First-in-human clinical trials with selective DGK inhibitors are currently ongoing.7–8 Methods and Results Both inhibitors are human/mouse cross-reactive compounds that enhance in vitro T-cell activation and T-cell mediated tumor cell killing. The model now offers the opportunity to identify optimal combinations that pair maximal enhancement of T-cell immunity with minimal probability for on- and off-target adverse events. Conclusions The availability of..."

Oncology • CCR8 • TGFB1

BAY 2965501: a highly selective DGK zeta inhibitor for cancer immunotherapy (SITC 2023) - P1 | "A first-in-human clinical trial of BAY 2965501 in solid tumors is currently enrolling patients (NCT05614102). This study will evaluate the safety, tolerability, maximum tolerated or administered dose, pharmacokinetics, pharmacodynamics, and tumor response profile of BAY 2965501."

IO biomarker • Oncology • Solid Tumor • CD8 • DGKZ • HAVCR2 • IL2

A First-in-human Study to Learn How Safe the Study Drug BAY2965501 is, Find the Best Dose (Single Drug & Combination), How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, How it Acts on Different Tumors in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=284 | Recruiting | Sponsor: Bayer | N=179 ➔ 284

Enrollment change • Metastases • Monotherapy • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • IL2 • PD-L1

BAY 2965501: A highly selective DGK- ζ inhibitor for cancer immuno-therapy with first-in-class potential (AACR 2023) - P1 | "Collectively, the preclinical data support first in human (FiH) phase I testing of therapeutic potential.A FiH trial with BAY 2965501 in patients with advanced solid tumors including NSCLC, gastric/GEJ AdCa, ccRCC, and melanoma patients, is currently enrolling patients (NCT05614102). This study will evaluate the safety, tolerability, maximum tolerated or administered dose, pharmacokinetics, pharmacodynamics, and tumor response profile of BAY 2965501."

Clear Cell Renal Cell Carcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DGKZ

Phosphorylated extracellular signal-regulated kinase (pERK) activation in T effector cells as a target engagement biomarker for the DGKζ inhibitor BAY2965501 in clinical trials (AACR 2023) - "These findings support implementing the pERK+CD8+ assay in T cells as a target engagement biomarker during early phase clinical trials."

Biomarker • Clinical • IO biomarker • Oncology • CD8 • MAPK1

Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting (Bayer Press Release) - "Bayer will present latest research across its oncology portfolio at the American Association for Cancer Research (AACR) 2023 Annual Meeting....In the New Drugs on the Horizon session at AACR, Bayer will present preclinical data on its novel selective diacylglycerol kinase (DGK) zeta inhibitor BAY 2965501....An inhibition of DGKzeta has been demonstrated to enhance T-cell priming against suboptimal tumor antigens and has the potential to overcome multiple immune-suppressive mechanisms in the tumor microenvironment."

Preclinical • Oncology

A First-in-human Study to Learn How Safe the Study Treatment BAY2965501 is, to Find the Best Dose, How it Affects the Body, What Maximum Amount Can be Given, How it Moves Into, Through and Out of the Body, and How it Acts on Different Tumors in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=179 | Recruiting | Sponsor: Bayer

New P1 trial • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • IL2