{
  "abstract": "Background RNA modifications profoundly impact RNA fate and have emerged as key post-transcriptional regulators in cancer. N6-Methyladenosine (m6A), the most prevalent internal mRNA modification, is installed by the RNA methyltransferase METTL3. METTL3 drives oncogenesis, tumor persistence, and tumor immune evasion by downregulating tumor suppressor pathways, including immune checkpoints. Conversely, METTL3 inhibition has been shown to enhance antitumor immunity by upregulating PD-L1 expression on tumor cells, promoting CD8+ T and NK cell tumor infiltration, reducing immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and coordinating immuno-stimulatory changes in the tumor microenvironment. Targeting METTL3 offers a promising strategy to induce anti-tumor responses and overcome immune resistance.STC-15 is a potent, first-in-class small molecule inhibitor of METTL3. Initial Phase 1 trial data demonstrated that STC-15 monotherapy induced durable, well-tolerated clinical responses in patients with advanced solid tumors. Preclinical findings demonstrate that STC-15 sensitizes the tumor microenvironment to checkpoint blockade, suggesting that combination therapy of STC-15 and toripalimab, an anti-PD-1 antibody, will provide a synergistic therapeutic benefit to enhance clinical activity.Methods This is an open-label, non-randomized, multi-cohort, multicenter Phase 1b/2 dose-escalation and expansion study to investigate the efficacy, safety, tolerability, and pharmacokinetics/pharmacodynamics (PK/PD) of STC-15 in combination with toripalimab in patients with advanced solid tumors. A fixed dose of toripalimab will be administered via intravenous (IV) infusion on Day 1 of each 21-day cycle. Up to 18 participants with unresectable, locally advanced, or metastatic cancers will be enrolled in the dose-escalation cohorts and administered STC-15 orally thrice weekly (TIW) at 3 escalating dose levels in combination with toripalimab, following a modified Fibonacci 3+3 design to evaluate dose-limiting toxicities (DLTs) during Cycle 1 and determine the recommended Phase 2 dose (RP2D). A parallel study will explore STC-15 administered once daily (QD) in combination with toripalimab in one or more cohorts. The Phase 2 dose-expansion will use a Simon 2 Stage design to evaluate the combination of STC-15 at RP2D TIW or QD with toripalimab in 164 participants (up to 41 per cohort) with recurrent or metastatic non-small cell lung cancer (NSCLC), melanoma, endometrial cancers, or head and neck squamous cell carcinoma (HNSCC) that have progressed following anti-PD-1/L1 therapy. Whole blood will be collected to analyze PD via m6A quantification and ctDNA. Plasma, serum, and optional skin/tumor biopsies will be collected to determine treatment PK, transcriptional changes, and profile immune activation. As of 06/13/2025, 3 patients are enrolled. Dose escalation is ongoing.Trial Registration NCT06975293Ethics Approval This study was approved by site IRBs. Protocol STC15-24202.",
  "authors": [
    {
      "affiliations": [
        "NEXT Oncology, Fairfax, VA, USA"
      ],
      "name": "Mohamad A Salkeni"
    },
    {
      "affiliations": [
        "START Cancer Center, San Antonio, TX, USA"
      ],
      "name": "Kyriakos P Papadopoulos"
    },
    {
      "affiliations": [
        "Northwell Health, New York, NY, USA"
      ],
      "name": "Nicholas J Hornstein"
    },
    {
      "affiliations": [
        "Honor Health, Scottsdale, AZ, USA"
      ],
      "name": "Frank Tsai"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Melinda Snyder"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Gerald McMahon"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Marguerite Hutchinson"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Eric S Martin"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Yaara Ofir-Rosenfeld"
    },
    {
      "affiliations": [
        "STORM Therapeutics Ltd., Cambridge, UK"
      ],
      "name": "Atif Abbas"
    }
  ],
  "title": "587 Phase 1b/2 dose escalation and expansion study of STC-15, a METTL3 inhibitor, in combination with toripalimab, an anti-PD-1 antibody, in patients with advanced solid tumors",
  "uid": "4671f335-772c-5e53-906a-95cf7cc13061"
}