BMS-986408 / BMS - LARVOL DELTA

Design, Synthesis, and T Cell Checkpoint Combination Potential Of First-In-Class DGKα/ζ Inhibitor BMS-986408. (PubMed, J Med Chem) - "The lead molecule BMS-502 was optimized to the first-in-class dual DGKα/ζ inhibitor BMS-986408 (BMS-408), starting with the replacement of an aryl nitro group that posed a potential liability. In preclinical studies, BMS-408 demonstrated dose-proportional pharmacokinetics and pharmacodynamics in mice, as well as robust efficacy in combination with either anti-PD-1 and/or anti-CTLA-4 in MC-38 and 1956 tumor models. Given the favorable in vitro and in vivo profiles, as well as in vivo pharmacology, BMS-408 was advanced to clinical development."

Journal • Oncology

Blocking Diacyl-Glycerol Kinase (DGK) Allows for Enhanced T-Cell Priming in Tumor-Draining Lymph Nodes Bolstering Immunotherapy Efficacy in Mesothelioma (IMIG 2025) - "MethodsWildtype C57BL/6 mice were inoculated with AE17-OVA mesothelioma tumors intraperitoneally and treated with a novel clinical-grade DGK-alpha and -zeta isoform-specific small molecule inhibitor (BMS-986408) daily by oral gavage with or without anti-PD-1/anti-PD-L1 (every 3-4 days)...ConclusionCollectively, we found DGKi to strongly induce lymph node accumulation of T-cells, which combined with anti-PD-1 and/or peptide vaccination allowed for immunotherapy efficacy in previously insensitive models including AE17-OVA mesothelioma. These findings provide new treatment opportunities to bolster immunotherapy efficacy in mesothelioma patients."

Clinical • Lung Cancer • Melanoma • Mesothelioma • Oncology • Solid Tumor • CD69 • CD8 • DGKI

A Study to Evaluate the Safety and Tolerability of BMS-986408 Alone and in Combination With Nivolumab or Nivolumab and Ipilimumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=68 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=101 ➔ 68

Enrollment change • Trial completion • Melanoma • Solid Tumor • BRAF • NRAS

Discovery of BMS-986408, a First-In-Class Dual DGKα and DGKζ Inhibitor That Unleashes PD-1 Checkpoint and CAR T-Cell Immunotherapies. (PubMed, Cancer Immunol Res) - "BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypo-functionality, insufficient expansion, and lack of co-stimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in cancer patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of BMS-986408 Alone and in Combination With Nivolumab or Nivolumab and Ipilimumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=101 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | N=402 ➔ 101 | Trial primary completion date: Oct 2025 ➔ Aug 2024

Combination therapy • Enrollment change • Metastases • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

First disclosure of BMS-986408: A dual inhibitor of Diacylglycerol kinases alpha and zeta for cancer therapy (ACS-Fall 2024) - "Our preclinical efforts culminated in the discovery of BMS-986408, an orally bioavailable, potent dual inhibitor of DGKs α and ζ (IC50s < 20 nM). The favorable PK profile across species was predictive of once daily dosing in human, and BMS-986408 is currently in Phase 1/2 clinical trials in patients with solid tumors."

Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of BMS-986408 Alone and in Combination With Nivolumab or Nivolumab and Ipilimumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=402 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | N=113 ➔ 402 | Trial completion date: Mar 2027 ➔ Oct 2025 | Trial primary completion date: Mar 2027 ➔ Oct 2025

Combination therapy • Enrollment change • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

A Study to Evaluate the Safety and Tolerability of BMS-986408 Alone and in Combination With Nivolumab or Nivolumab and Ipilimumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=113 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

A Study to Evaluate the Safety and Tolerability of BMS-986408 Alone and in Combination With Nivolumab or Nivolumab and Ipilimumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=122 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

Combination therapy • New P1/2 trial • Melanoma • Oncology • Solid Tumor • BRAF • NRAS