Preliminary efficacy results from an ongoing phase I/II trial of CTS2190, a PRMT1 inhibitor, in patients with advanced/metastatic solid tumors.

3082 Background: Epigenetic gene regulation, including arginine methylation holds significant promise in immunomodulation and long survival outcomes. It represents a potential clinical approach to address the highly unmet needs of patients (pts) with advanced solid tumors who failed PD-(L)1 immune checkpoint inhibitors (ICIs) or standard of cares（SoCs) therapies. CTS2190, the orally available, first-in-class small molecule, specifically inhibits arginine methyltransferase 1 (PRMT1) with significant reduction of intra-tumor asymmetric dimethylarginine (ADMA) level, DNA damage response (DDR), androgen receptor (AR) level, and oncogenic proliferation through epigenetic modulation in various solid tumors. Here we present clinical data from an ongoing Phase I/II study of CTS2190 (NCT06224387). Methods: Eligible pts in the dose-escalation stage received 60~300 mg of CTS2190 orally, while pts in the dose-expansion stage were treated with 180 or 240 mg until disease progression or intolerable toxicity. Efficacy, safety, PK, PD and biomarker profiles were evaluated. Results: As of January 24, 2025, 38 pts had received CTS2190 treatment, 32 of them were response-evaluable. In the PD-(L)1 primarily resistant group, the objective response rate (ORR) and disease control rate (DCR) were 18.2% (2/11) and 72.7% (8/11), respectively. In addition, in PD-(L)1 primarily resistant non-small cell lung cancer (NSCLC) subgroup, the ORR and DCR were 28.6% (2/7) and 71.4% (5/7), respectively, with significantly prolonged median progression-free survival (PFS) (summarized in the table below). Among 2 response-evaluable pts with metastatic castration-resistant prostate cancer (mCRPC), one achieved partial response (PR) while the other exhibited stable disease (SD) with tumor shrinkage. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable. The only TRAE ≥ grade 3 with an incident rate > 15% was platelet count decreased (31.6%). No TRAEs led to treatment discontinuation or death. CTS2190 exposure increased proportionally with escalating doses, and a PK-PD-efficacy model demonstrated a relationship between CTS2190 exposure, efficacy and PD marker changes. The correlation between clinical efficacy and intra-tumor PRMT1 expression, as detected by immunohistochemistry (IHC), is under investigation. Conclusions: CTS2190 demonstrated a favorable safety profile and promising efficacy in heavily pretreated pts with advanced solid tumors, particularly in immunologically cold mCRPC and PD-(L)1 primarily resistant NSCLC. These results position CTS2190 as a promising therapeutic option to fulfil unmet medical needs following ICIs therapies. Clinical trial information: NCT06224387 . PFS of pts with PD-(L)1 primary resistance. Patients, n ≥ 3 prior lines of therapy, n (%) Event Median PFS (weeks) All comers 11 7 (63.6%) 7 12.7 (95% CI: 8.0~35.3) NSCLC 7 4 (57.1%) 5 24.9 (95% CI: 8.0~35.3)