{
  "abstract": "Background T-cell engagers (TCE) have transformed the treatment of relapsed/refractory B-cell and plasma cell malignancies. In solid tumors (ST), progress has been limited by low efficacy, on-target/off-tumor toxicity, and high immunogenicity, but multiple ST TCE are now marketed or in advanced development. NM32-2668 is a novel trispecific, scFv-based MATCH3 TCE directed against the tumor antigen ROR1, CD3e, and human serum albumin, which has shown efficacy at picomolar concentrations in preclinical models. Here we present final results from the dose escalation of the NM32-2668-101 study.Methods NM32-2668-101 was a phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary antitumor activity of NM32-2668 monotherapy administered every two weeks to patients with ROR1-expressing solid tumors. In the first cycle, three weekly step doses were used to reach the target dose level. Trial eligibility included tumor cell ROR1 expression at any level (assessed by in-situ hybridization). Dose escalation followed a BOIN design, starting with single patient cohorts (Part 1), followed by multiple patient cohorts (Part 2) after reaching a pharmacologically active dose level.Results 11 patients with mesothelioma (4), esophageal cancer (2), lipo-/leiomyosarcoma (2) and endometrial, ovarian, renal cancer (1 each), were treated. Pharmacological activity was observed in the first patient (esophageal cancer, treated at 60-120-300ug), which exhibited a non-confirmed partial response (non-target lesion PD at subsequent scan). Three more patients were treated at this dose level, and another seven patients at dose level 2 (100-200-400ug). No tumor size reductions occurred beyond the initial patient.ROR1 expression in enrolled patients was between 4% and 83% of tumor cells (median 16%), the responding patient showed 63% ROR1-positive tumor cells.No DLTs were observed. Cytokine release syndrome was the predominant toxicity, occurring between C1D1 and C2D1 in 8/11 patients. The majority of events were Gr1, with five CRS Gr2 events recorded in three patients, and no Gr≥3 events. There was no evidence of on-target/off-tumor toxicity.Four patients developed ADA-mediated loss of exposure during Cycle 2.Conclusions NM32-2668 is a tumor-selective T-cell engager able to specifically activate tumor-infiltrating lymphocytes. In line with previous therapies targeting ROR1 in solid tumors, limited efficacy was observed, potentially due to ROR1 expression that was more heterogeneous than for targets where T-cell engagers have had clinical success.Trial Registration Clinicaltrials.gov NCT06299163Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: WCG1340057 (Carolina BioOncology, Gabrail Cancer Center, University of Wisconsin Carbone Cancer Center, Samuel Oschin Cancer Center/Cedars-Sinai Medical Center, Winship Cancer Institute/Emory University, Northwest Medical Specialties/Tacoma Medical Oncology), Advarra MCC# 22112 (Moffitt Cancer Center), BRANY 22-06-326-01 (Albert Einstein Cancer Center), IRB00349569 (Johns Hopkins University School of Medicine), 2022-0761 (The University of Texas MD Anderson Cancer Center), UHIRB STUDY20221273 (UH Cleveland Medical center, Seidman Cancer Center).",
  "authors": [
    {
      "affiliations": [
        "Legorreta Cancer Center at Brown University, Providence, RI, USA"
      ],
      "name": "Benedito A Carneiro"
    },
    {
      "affiliations": [
        "Cleveland Clinic Cancer Center, Cleveland, OH, USA"
      ],
      "name": "Dale Shepard"
    },
    {
      "affiliations": [
        "University of Alabama at Birmingham, Birmingham, AL, USA"
      ],
      "name": "Aakash Desai"
    },
    {
      "affiliations": [
        "Numab Therapeutics AG, Horgen, Switzerland"
      ],
      "name": "Josephine Adams"
    },
    {
      "affiliations": [
        "Numab Therapeutics AG, Horgen, Switzerland"
      ],
      "name": "Daniel Snell"
    },
    {
      "affiliations": [
        "Numab Therapeutics AG, Horgen, Switzerland"
      ],
      "name": "Nathalie Steinhoff"
    },
    {
      "affiliations": [
        "Affivant Sciences, Basel, Switzerland"
      ],
      "name": "Martin Stern"
    },
    {
      "affiliations": [
        "Numab Therapeutics AG, Horgen, Switzerland"
      ],
      "name": "David Urech"
    },
    {
      "affiliations": [
        "Strand Therapeutics, Pittsburgh, PA, USA"
      ],
      "name": "Jason J Luke"
    }
  ],
  "title": "517 A phase 1 trial of NM32–2668, a ROR1-CD3-HSA trispecific T-cell engager in patients with ROR1-expressing solid tumors",
  "uid": "0229e6b7-cdc6-529b-ae78-4e8646f449d1"
}