In a groundbreaking development in the fight against non-small cell lung cancer (NSCLC), researchers have unveiled promising results from a novel targeted therapy known as BMS-986504. This innovative agent is specifically designed to exploit a unique vulnerability present in certain cancer cells—namely, the homozygous deletion of the gene MTAP, which encodes the enzyme methylthioadenosine phosphorylase. The findings, presented at the 2025 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC), reveal that BMS-986504 exhibits encouraging antitumor activity in patients with heavily pretreated, advanced NSCLC, opening new avenues for precision oncology.
The molecular rationale behind BMS-986504’s mechanism of action hinges on the metabolic consequences of MTAP loss within cancer cells. MTAP deficiency results in accumulation of methylthioadenosine (MTA), a metabolite that normally undergoes enzymatic breakdown mediated by MTAP. Elevated intracellular levels of MTA have significant biological implications, particularly concerning their interaction with protein arginine methyltransferase 5 (PRMT5), an enzyme essential for post-translational modification of target proteins involved in gene expression regulation, RNA splicing, and cellular survival pathways. BMS-986504 selectively targets the PRMT5 enzyme when it is bound by accumulated MTA, thereby inhibiting its function in MTAP-deleted cells while sparing normal tissues where this complex does not exist.
This therapeutic strategy represents a sophisticated form of synthetic lethality, exploiting the metabolic derangements caused by specific genetic deletions present in approximately 10-15% of all human cancers. Within this subset, NSCLC stands out as a disease with a notable prevalence of MTAP deletion, comprising up to 27% of these cases. The clinical trial evaluated BMS-986504 in a cohort of patients with advanced solid tumors harboring homozygous MTAP deletions, with NSCLC patients forming the majority group. Results indicated a substantial overall response rate of 29%, meaning nearly one-third of patients experienced significant tumor shrinkage or stable disease as a result of the therapy.
Importantly, the drug’s activity extended to patients bearing well-known oncogenic drivers such as EGFR mutations and ALK rearrangements, both of which often become refractory to existing tyrosine kinase inhibitors (TKIs). Among the NSCLC cohort evaluated, responses were observed in four out of seven EGFR-positive patients and two out of four ALK-positive patients, suggesting that BMS-986504 could provide clinical benefit even in otherwise treatment-resistant molecular subtypes. Additionally, one out of three patients with squamous histology responded, indicating a potential broad spectrum of efficacy across histological variants.
The durability of responses to BMS-986504 is noteworthy. The median duration of response extended to over 10 months, highlighting the agent’s capacity not only to induce tumor regression but to maintain disease control over several treatment cycles. Patients generally achieved responses within approximately four months of initiating therapy, underscoring a relatively swift onset of clinical benefit. Median follow-up for these outcomes reached nearly a year, lending confidence to the stability and sustainability of the observed effects.
Safety and tolerability profiles are critical considerations in the development of any anticancer agent, particularly in populations often burdened by multiple prior therapies and associated comorbidities. BMS-986504 demonstrated a favorable safety profile, with the majority of treatment-related adverse events (TRAEs) confined to mild or moderate gradations (grades 1 and 2). Though 14% of solid tumor patients experienced more severe (grade ≥3) TRAEs, hematologic toxicities were reportedly manageable, with treatment-related anemia, neutropenia, and thrombocytopenia occurring in manageable frequencies. No new or unexpected safety signals emerged across tumor types included in the study, which encompassed not only NSCLC but also mesothelioma, pancreatic ductal adenocarcinoma, and cholangiocarcinoma.
From a biochemical and pharmacological standpoint, the selectivity of BMS-986504 arises from its ability to distinguish the PRMT5 enzyme depending on its biochemical milieu. In normal cells, where MTAP and consequently MTA levels are intact and low, PRMT5 functions unimpeded and remains uninhibited by the drug. Conversely, in MTAP-deleted cancer cells, the buildup of MTA forms an aberrant complex with PRMT5, which the drug targets effectively. This selectivity reduces off-target effects and enhances the therapeutic window, a hallmark feature of precision medicine paradigms. Such targeted approaches are crucial for improving efficacy while reducing toxicity inherent in more generalized cytotoxic therapies.
The encouraging activity and safety results from this phase 1 trial have naturally propelled BMS-986504 into further clinical investigation. Two pivotal studies are currently underway assessing its utility in advanced NSCLC patients with MTAP deletions. One study evaluates the safety and efficacy of BMS-986504 as monotherapy in patients who have already exhausted prior lines of treatment. Another randomized controlled trial explores its integration into first-line therapy, combining it with the immune checkpoint inhibitor pembrolizumab and chemotherapy, compared against standard regimens. These trials will be instrumental in establishing not only the drug’s clinical efficacy in larger populations but also its optimal use in combination strategies aimed at maximizing patient benefit.
The underlying biology of PRMT5’s role in cancer underscores the broader significance of this therapeutic approach. PRMT5-mediated methylation regulates diverse cellular processes including transcriptional repression, RNA splicing, and cell cycle progression—all pathways frequently dysregulated in oncogenesis. By disrupting this enzymatic function within a metabolically compromised environment characterized by MTA accumulation, BMS-986504 interferes with tumor-promoting activities at a fundamental level. This represents a potent example of rational drug design informed by molecular oncology and metabolomics.
Moreover, MTAP deletion has emerged as an actionable biomarker with implications beyond lung cancer, with deletions detected in varied malignancies such as mesothelioma and pancreatic cancer. The concept of targeting vulnerabilities associated with loss-of-function mutations or deletions expands the therapeutic landscape, providing hope for patients with historically intractable cancers. The progress of BMS-986504 sets a precedent for future agents designed to exploit cancer-specific metabolic and enzymatic alterations.
Collectively, these exciting clinical findings and scientific insights mark a significant milestone in lung cancer research. They exemplify the promise of precision oncology, marrying detailed genetic and metabolic tumor profiling with the development of highly selective, mechanism-based pharmacologic interventions. The field awaits the continued maturation of data from ongoing trials with great anticipation, hopeful that BMS-986504 will establish a new standard of care for patients afflicted with MTAP-deleted NSCLC and potentially other solid tumors harboring similar vulnerabilities.
Subject of Research: BMS-986504, a PRMT5-MTA targeting agent in MTAP-deleted non-small cell lung cancer
Article Title: Promising Antitumor Activity of BMS-986504 in MTAP-Deleted Non-Small Cell Lung Cancer: Insights from the IASLC 2025 World Conference on Lung Cancer
News Publication Date: September 8, 2025
Web References:
– ClinicalTrials.gov identifiers NCT06855771 and NCT07063745
– International Association for the Study of Lung Cancer: www.iaslc.org
Keywords: Lung cancer, non-small cell lung cancer, MTAP deletion, PRMT5 inhibitor, targeted therapy, precision oncology, methylthioadenosine, BMS-986504, oncology clinical trials, EGFR mutations, ALK rearrangements, phase 1 clinical trial
Tags: antitumor activity in advanced NSCLCBMS-986504cancer cell metabolic vulnerabilitiesEGFR and ALK-positive tumorsIASLC World Conference 2025methylthioadenosine accumulationMTAP gene deletion therapynon-small cell lung cancer treatmentnovel cancer therapiesprecision oncology advancementsPRMT5 enzyme inhibitiontargeted therapy for NSCLC
