A Phase 1 Multiple Expansion Cohort Trial of MRTX1719 in Patients With Advanced Solid Tumors With Homozygous MTAP Deletion

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Overview

BMS-986504 (also known as MRTX1719) is an oral, selective MTA‑cooperative PRMT5 inhibitor being developed for tumors with homozygous MTAP deletion (MTAP‑del), a genomic alteration present in roughly 10% of cancers. The agent originated at Mirati Therapeutics as MRTX1719 and is now being advanced by Bristol Myers Squibb; multiple medicinal chemistry reviews explicitly note the synonymy BMS‑986504 = MRTX1719. Early clinical experience has shown antitumor activity across MTAP‑del solid tumors, and dedicated phase 2/3 trials in NSCLC are underway. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: Protein arginine methyltransferase 5 (PRMT5).
• Modality: “MTA‑cooperative” inhibition—BMS‑986504 preferentially binds PRMT5 when methylthioadenosine (MTA) is present. In MTAP‑del tumors, MTA accumulates, enabling tumor‑selective PRMT5 inhibition (and sparing normal tissues). This exploits a synthetic‑lethal vulnerability created by MTAP loss adjacent to CDKN2A. Preclinical and translational studies show selective suppression of PRMT5‑dependent symmetric di‑methyl arginine (SDMA) and robust antitumor activity in MTAP‑del models. (aacrjournals.org)

Key translational evidence from a peer‑reviewed study (Cancer Discovery, 2023): - >70‑fold selectivity for MTAP‑del vs MTAP‑WT cells; dose‑dependent SDMA inhibition in MTAP‑del tumors with minimal effects in hematopoietic cells. (aacrjournals.org)

Clinical development

• First‑in‑human, phase 1/2 basket (NCT05245500; protocol 1719‑001/CA240‑0007) in MTAP‑del solid tumors; ongoing. (dana-farber.org)
• NSCLC programs:
• Phase 2 monotherapy after prior therapy (NCT06855771; MountainTAP‑9). (bmsclinicaltrials.com)
• Phase 2/3 first‑line in combination with pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy (NCT07063745). (bmsclinicaltrials.com)
• Additional/adjacent studies:
• Early‑phase PK/ADME with radiolabeled drug (NCT06672523). (cdek.pharmacy.purdue.edu)
• Phase 0/1 in recurrent glioblastoma with MTAP loss (NCT06883747). (ivybraintumorcenter.org)

Efficacy

• Basket phase 1/2 (peer‑reviewed preliminary clinical data): In the initial publication cut (as of June 13, 2023), 6 confirmed objective responses were described among 18 evaluable MTAP‑del patients treated at ≥100 mg QD; responses occurred across melanoma, gallbladder adenocarcinoma, mesothelioma, NSCLC, and malignant peripheral nerve sheath tumors. (aacrjournals.org)
• NSCLC cohort update (conference presentation press release, WCLC 2025): Among evaluable MTAP‑del NSCLC patients (n=35), overall response rate (ORR) 29% and disease control rate (DCR) 80%; responses included patients with EGFR‑ and ALK‑positive disease after prior TKIs. Median duration of response was 10.5 months; median time to response 4.3 months (median follow‑up 11.7 months). (Conference data; not yet peer‑reviewed.) (iaslc.org)

Safety

• Early phase basket (to 2023 cut): Well tolerated; no dose‑limiting toxicities observed up to 400 mg QD, and without the dose‑limiting hematologic toxicities (thrombocytopenia, anemia, neutropenia) often seen with earlier PRMT5 inhibitors. (aacrjournals.org)
• WCLC 2025 NSCLC update: Most treatment‑related adverse events (TRAEs) were grade 1–2; grade ≥3 TRAEs in 14% of solid‑tumor patients. Reported treatment‑related hematologic AEs included anemia (8%), neutropenia (7%), and thrombocytopenia (7%). No new safety signals were reported. (Conference data.) (iaslc.org)

Other notes and combinations

• Preclinical work in pancreatic ductal adenocarcinoma (PDAC) suggests BMS‑986504 disrupts RNA splicing and shows enhanced efficacy when combined with KRASG12C/G12D inhibitors, supporting rational combinations in MTAP‑del, KRAS‑mutant tumors. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Peer‑reviewed translational/clinical report: MRTX1719 (BMS‑986504) in MTAP‑deleted cancers (Cancer Discovery, 2023). https://aacrjournals.org/cancerdiscovery/article/13/11/2412/729848/MRTX1719-Is-an-MTA-Cooperative-PRMT5-Inhibitor (aacrjournals.org)
• Medicinal chemistry perspective confirming BMS‑986504 = MRTX1719. https://pubmed.ncbi.nlm.nih.gov/39919252/; https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03067 (pubmed.ncbi.nlm.nih.gov)
• Phase 1/2 basket trial (NCT05245500). https://www.dana-farber.org/clinical-trials/22-150 (dana-farber.org)
• NSCLC phase 2 monotherapy (NCT06855771). https://www.bmsclinicaltrials.com/us/en/clinical-trials/NCT06855771 (bmsclinicaltrials.com)
• NSCLC phase 2/3 combination (NCT07063745). https://www.bmsclinicaltrials.com/us/en/clinical-trials/NCT07063745.html (bmsclinicaltrials.com)
• Recurrent GBM Phase 0/1 (NCT06883747). https://www.ivybraintumorcenter.org/brain-tumor-clinical-trials/current-trials/bms-986504-in-recurrent-glioblastoma/ (ivybraintumorcenter.org)
• WCLC 2025 NSCLC update (press release). https://www.iaslc.org/iaslc-news/press-release/bms-986504-demonstrates-durable-responses-mtap-deleted-nsclc-including (iaslc.org)

Notes: Where conference or company communications are cited, results should be considered preliminary until peer‑reviewed full manuscripts are available.

Last updated: Oct 2025

Inclusion Criteria

* Histologically confirmed diagnosis of a solid tumor malignancy with homozygous deletion of the MTAP gene detected in tumor tissue.

* Unresectable or metastatic disease.

* Presence of a tumor lesion amenable to mandatory biopsy for pharmacodynamic evaluation at baseline and on-study unless Sponsor-confirmed as medically unsafe or infeasible.

* Age ≥ 18 years.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Adequate organ function.

Exclusion Criteria

* Prior treatment with a PRMT5 or MAT2A inhibitor therapy.

* Active brain metastases or carcinomatous meningitis.

* History of significant hemoptysis or hemorrhage within 4 weeks of the first dose of study treatment.

* Major surgery within 4 weeks of first dose of study treatment.

* History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions (eg, uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications.

* Cardiac abnormalities.

* Other protocol-defined Inclusion/Exclusion criteria apply.