^
    13d
    MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario. (PubMed, Cancer Res)
    MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy.
    Journal
    |
    MTAP (Methylthioadenosine Phosphorylase) • MAT2A (Methionine Adenosyltransferase 2A)
    |
    MTAP deletion
    |
    BMS‐986504 • IDE397 • AMG 193
    1m
    A Phase II Study Evaluating BMS-986504 in MTAP-deleted Pancreatic Cancer (clinicaltrials.gov)
    P2, N=60, Not yet recruiting, M.D. Anderson Cancer Center
    New P2 trial
    |
    gemcitabine • albumin-bound paclitaxel • oxaliplatin • irinotecan • BMS‐986504
    2ms
    Clinical Significance of MTAP Deletions and their Overlap with Concurrent Oncogenic Driver Alterations Including EGFR in Non-Small Cell Lung Cancer. (PubMed, J Thorac Oncol)
    MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.
    Journal
    |
    EGFR (Epidermal growth factor receptor) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • MAT2A (Methionine Adenosyltransferase 2A)
    |
    EGFR mutation • CDKN2A deletion • MTAP deletion
    |
    MSK-IMPACT
    |
    Tagrisso (osimertinib) • BMS‐986504
    2ms
    A Study to Assess Safety, Tolerability and Drug Levels of BMS-986504 in Participants With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=32, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting
    Enrollment open
    |
    BMS‐986504
    2ms
    CA240-0007: Phase 1 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov)
    P1, N=336, Recruiting, Bristol-Myers Squibb | Trial completion date: Apr 2026 --> Dec 2027 | Trial primary completion date: Apr 2026 --> Dec 2027
    Trial completion date • Trial primary completion date
    |
    MTAP (Methylthioadenosine Phosphorylase)
    |
    BMS‐986504
    2ms
    PRIME: Clinical Trial to investigate the feasibility, safety, and tolerability of BMS-986504 in patients with recurrent MTAP-deleted Glioblastoma (ACTRN12625001238460)
    P2, N=10, Not yet recruiting, Peter MacCallum Cancer Centre
    New P2 trial
    |
    MGMT (6-O-methylguanine-DNA methyltransferase) • MTAP (Methylthioadenosine Phosphorylase)
    |
    BMS‐986504
    4ms
    A Study Comparing BMS-986504 in Combination With Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine in Participants With Untreated Metastatic Pancreatic Ductal Adenocarcinoma With Homozygous MTAP Deletion (MountainTAP-30) (clinicaltrials.gov)
    P2/3, N=470, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting
    Enrollment open
    |
    gemcitabine • albumin-bound paclitaxel • BMS‐986504
    4ms
    MountainTAP-29: A Study to Compare the Combination of BMS-986504 With Pembrolizumab and Chemotherapy Versus Placebo Plus Pembrolizumab and Chemotherapy in First-line Metastatic Non-small Cell Lung Cancer Participants With Homozygous MTAP Deletion (clinicaltrials.gov)
    P2/3, N=590, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Keytruda (pembrolizumab) • cisplatin • carboplatin • albumin-bound paclitaxel • pemetrexed • BMS‐986504
    6ms
    A Study to Assess Safety, Tolerability and Drug Levels of BMS-986504 in Participants With Advanced Solid Tumors (clinicaltrials.gov)
    P1, N=32, Not yet recruiting, Bristol-Myers Squibb
    New P1 trial
    |
    BMS‐986504
    6ms
    A Study Comparing BMS-986504 in Combination With Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine in Participants With Untreated Metastatic Pancreatic Ductal Adenocarcinoma With Homozygous MTAP Deletion (MountainTAP-30) (clinicaltrials.gov)
    P2/3, N=470, Not yet recruiting, Bristol-Myers Squibb
    New P2/3 trial
    |
    gemcitabine • albumin-bound paclitaxel • BMS‐986504
    6ms
    Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer. (PubMed, Cancer Res)
    While PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-deleted/KRAS-mutant PDAC.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • MTAP (Methylthioadenosine Phosphorylase)
    |
    KRAS mutation • KRAS G12C • MTAP deletion
    |
    BMS‐986504
    6ms
    MountainTAP-29: A Study to Compare the Combination of BMS-986504 With Pembrolizumab and Chemotherapy Versus Placebo Plus Pembrolizumab and Chemotherapy in First-line Metastatic Non-small Cell Lung Cancer Participants With Homozygous MTAP Deletion (clinicaltrials.gov)
    P2/3, N=590, Not yet recruiting, Bristol-Myers Squibb
    New P2/3 trial
    |
    Keytruda (pembrolizumab) • cisplatin • carboplatin • albumin-bound paclitaxel • pemetrexed • BMS‐986504