BMS‐986504 / BMS - LARVOL DELTA

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

Combination of MTA-cooperative PRMT5 inhibitor BMS-986504 and KRAS inhibitors for the treatment of MTAP-deleted KRAS-mutant pancreatic cancer (AACR 2025) - "We validated co-targeting KRAS as a combination strategy and found that combined small molecule inhibition of PRMT5 and G12C/D-mutant KRAS (using adagrasib and MRTX1133, respectively) effectively suppressed MTAP-del PDAC growth in vitro and in vivo. Further, we determined that, while PRMT5 and KRAS regulate distinct transcriptomes, they converge on common pathways governing cancer cell growth and combined inhibition of PRMT5 and KRAS caused marked downregulation of PDAC-essential genes. These findings provide a rationale for combined inhibition of PRMT5 and KRAS to maximize targeted therapies for MTAP-del and KRAS-mutant biomarker-positive PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MIA • MTAP • PRMT5

Preclinical evaluation of drugs for the treatment of MTAP-deficient cancers [WITHDRAWN] (AACR 2025) - "Subsequently, with in vitro viability assay we showed that the two PRMT5 inhibitors, GSK3326595 and MRTX1719 exhibited strong anti-proliferative effects against MTAP-deficient cells. This selective PRMT5 inhibitor developed a superior anti-tumor effect, achieving a tumor growth inhibition of over 100% after three weeks of treatment. In summary, our findings may advance the development of novel therapeutic strategies for MTAP-deficient cancers."

Preclinical • Bladder Cancer • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • MAT2A • MTAP • PRMT5

Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) (AACR 2025) - "BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del."

Biomarker • Clinical • Metastases • PK/PD data • Oncology • Solid Tumor • EGFR • KRAS • MAT2A • MTAP • PRMT5 • TP53

Developing PRMT5 inhibition-based Immuno-oncology combination therapies in MTAP-loss tumors (AACR 2025) - "Two PRMT5 inhibitors, GSK3326595 (substrate-competitive) and MRTX1719 (MTA-cooperative), were evaluated on tumor and immune cells. The combination also increased CD8+ T cell proliferation in MTAP-KO tumor tissues. Collectively, our results provide a strong rationale for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors."

Combination therapy • Immuno-oncology • Oncology • CD8 • MTAP

Targeting PRMT5 to enhance T cell-mediated antitumor immune responses. (IMMUNOLOGY 2025) - "Our data show that GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of MTAP status. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. Furthermore, the combination of MRTX1719 in combination with immune checkpoint blockade (ICB) leads to superior antitumor activity in two syngeneic murine models with MTAP-loss tumor, providing a strong rationale for the clinical development of PRMT5i-based IO combinations."

Oncology • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss (AACR 2025) - "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases."

Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion ( MTAP-del): Clinical update and first report of pharmacokinetics (PK) and pharmacodynamic (PD) analyses from CA240-0007. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT05245500 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • PK/PD data • Oncology • Solid Tumor • MTAP

Phase 1 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov) - P1 | N=320 | Recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial • Brain Cancer • Hepatology • Lung Cancer • Mesothelioma • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Clinical Trial of BMS-986504 in Recurrent GBM Patients (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: Nader Sanai | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Study to Evaluate the Mass Balance, Metabolism, Elimination, and Drug Levels of [14C]-BMS-986504 (MRTX1719) in Participants With Advanced Solid Tumors With Homozygous Methylthioadenosine Phosphorylase Deletion (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open • Solid Tumor

Clinical Trial of BMS-986504 in Recurrent GBM Patients (clinicaltrials.gov) - P1 | N=9 | Not yet recruiting | Sponsor: Nader Sanai

New P1 trial • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Study of BMS-986504 in Participants With Pre-treated Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) With Homozygous MTAP Deletion (clinicaltrials.gov) - P2 | N=130 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

Monotherapy • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Targeting epigenetic deregulation in pancreatic cancer via Protein Arginine Methyltransferase 5 (PRMT5) inhibition as a promising therapeutic strategy (LCC 2025) - "Patient-derived cell line models of PDAC were screened using cytotoxicity assays with various concentrations of SAM-competitive (LLY-283) and MTA-cooperative (MRTX-1719) PRMT5 inhibitor. Moreover, using 3D tumour cell-cancer associated fibroblast (CAF) co-culture assays, we showed no direct effects of PRMT5 targeting on CAF contractility and matrix remodelling; however, inhibition of PRMT5 as a monotherapy or combination therapy with MAT2A or PARP inhibitor significantly reduced cancer cell invasion in 3D organotypics model. Our ongoing work focuses on understanding the biological determinants, including gene expression and methylation signatures, and mechanisms behind PRMT5 inhibitor response and potential synergy that may allow broader clinical application."

Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HRD • MAT2A • MTAP • PRMT5

Inhibitory Effect of PRMT5/MTA Inhibitor on MTAP-Deficient Glioma May Be Influenced by Surrounding Normal Cells. (PubMed, Cancer Med) - "Due to the complexity of the tumor environment in vivo, the anti-tumor effects of PRMT5/MTA-specific inhibitors may be somewhat attenuated, and their ability to achieve suitable therapeutic effects in the clinic might require more in-depth studies."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MTAP

MRTX1719, an MTA-cooperative PRMT5 Inhibitor, Induces Cell Cycle Arrest and Synergizes With Oxaliplatin and Gemcitabine for Enhanced Anticancer Effects. (PubMed, Anticancer Res) - "MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G0/G1 phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells."

Journal • Oncology • MTAP

Exploring the Clinical Translation of Synthetic Lethality, PRMT5 Inhibitors in MTAP-Deleted Cancers: A Scoping Review (ISPOR-EU 2024) - P1/2 | "Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models...Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours. There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination."

Clinical • Review • Synthetic lethality • Oncology • Solid Tumor • BRCA • MTAP

Discovery of a highly MTA-synergistic series of PRMT5 inhibitors for the treatment of MTAP-deficient tumors by virtual screening technology (EORTC-NCI-AACR 2024) - "TNG-908 & MRTX-1719) and leading to a greater degree of MTA-synergistic binding than for any clinical-stage chemical series. ConclusionsA characteristic, high degree of MTA-synergy has been demonstrated for compounds within a novel chemical series in vitro and in cellular contexts both by manipulating SAM and MTA concentrations through combination with small molecule inhibitors and extensive screening of MTAP wild type and deficient lineages. Optimization of the lead compounds toward selection of a development candidate is underway."

Oncology • MTAP

IDE397 demonstrated deep and durable regressions in combination with PRMT5 inhibitors BMS-986504 and AMG 193 in preclinical models (PRNewswire) - "...IDEAYA had additional poster presentations at ENA 2024 highlighting preclinical data for the MAT2A and PARG programs. In the ENA 2024 concomitant publication, IDE397 demonstrated deep and durable regressions in combination with clinical stage PRMT5 inhibitors BMS-986504 and AMG 193 in multiple MTAP-deletion preclinical models."

Preclinical • Oncology • Solid Tumor

A Study to Evaluate the Mass Balance, Metabolism, Elimination, and Drug Levels of [14C]-BMS-986504 (MRTX1719) in Participants With Advanced Solid Tumors With Homozygous Methylthioadenosine Phosphorylase Deletion (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

Metastases • New P1 trial • Oncology • Solid Tumor

Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers (EORTC-NCI-AACR 2024) - "Ryvu PRMT5 inhibitors have a robust antiproliferative effect on MTAP-deleted cell lines and provide a good safety window for MTAP WT cells, as shown in a wide cell line panel The antitumor activities were compared in vitro and in vivo to MRTX1719 and AMG193 in MTAP null tumors such as HCT116 MTAP KO, DoHH-2 and Lu99. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population."

Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Lung Adenocarcinoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CDKN2A • MTAP

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors. (PubMed, J Immunother Cancer) - "Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors."

Journal • Oncology • MTAP

MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors (J Immunother Cancer) - "GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects....In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors."

Preclinical • Oncology

Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov) - P1/2 | N=580 | Recruiting | Sponsor: Mirati Therapeutics Inc. | N=370 ➔ 580

Enrollment change • Metastases • Brain Cancer • Gastrointestinal Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Mesothelioma • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • MTAP

Chemical development in pharmaceutical industry-Technology and innovation (ACS-Fall 2024) - "It serves to develop practical synthetic routes for making drug substances (API) at various stages of the drug development and to ultimately develop feasible chemical processes to support commercial launch of the drugs. In this lecture, the chemical development of selected drugs: adagrasib (MRTX849), MRTX1719, MRTX1133 featuring asymmetric synthesis, flow chemistry via dynamic kinetic resolution, process optimization and manufacturing will be presented."