{
  "abstract": "Purpose IMC-C103C is an ImmTAC bispecific (MAGE-A4×CD3) T cell engager targeting a peptide from the cancer-testis antigen MAGE-A4 presented by HLA-A*02:01. This phase 1/2 study in advanced solid tumors (IMC-C103C-101; NCT03973333) investigated the safety and preliminary anti-tumor activity of IMC-C103C.Methods HLA-A*02:01 + patients with previously treated advanced solid tumors received IMC-C103C by weekly intravenous infusion, with step-up dosing introduced at higher dose levels. Dose-escalation decisions were guided by the mTPI-2 method. Key objectives included evaluating safety and preliminary anti-tumor activity; pharmacokinetics, pharmacodynamics, and biomarkers were also assessed.Results 68 patients were enrolled in 10 dose-escalation cohorts (n=56; 64% ovarian carcinoma (OC)) and one OC expansion cohort (n=12). In dose escalation, patients received doses ranging from 0.5 to 240 µg. The dose-limiting toxicity rate at the two highest dose levels (1/6 and 2/10) did not exceed the maximum tolerated dose. A lower-dose regimen of 15–45-140 µg, with clinical activity, and a more favorable tolerability profile, was selected as the expansion dose. There were no treatment-related discontinuations or deaths. The most common treatment-related adverse events were cytokine-mediated, including grade 1/2 cytokine release syndrome and associated symptoms. While MAGE-A4 expression was observed in most patient’s tumors (71% positive), the level of expression was low (median H-score=16). Initial clinical and pharmacodynamic activity was observed at doses of 15 µg, with more consistent activity observed at doses ≥90 µg. At doses ≥90 µg, patients with MAGE-A4 + OC had deeper reductions in tumor size and circulating tumor DNA and trended to have longer overall survival than patients with MAGE-A4– OC.Conclusions IMC-C103C was well tolerated at doses up to 140 µg, induced dose-dependent pharmacodynamic changes, and demonstrated clinical activity in multiple patients with MAGE-A4 + solid tumors. Clinical activity was dependent on MAGE-A4 expression; however, expression was especially low in the higher dosing cohorts, limiting adequate efficacy assessment.Trial registration number NCT03973333.",
  "authors": [
    {
      "affiliations": [
        "The University of Chicago, Chicago, Illinois, USA"
      ],
      "name": "Randy F Sweis"
    },
    {
      "affiliations": [
        "Clinica Universidad Navarra, CIMA and CIBERONC, Pamplona, Spain"
      ],
      "name": "Ignacio Melero"
    },
    {
      "affiliations": [
        "UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"
      ],
      "name": "Diwakar Davar"
    },
    {
      "affiliations": [
        "Hospital Universitario Vall d’Hebron, Vall d’Hebron Institute of oncology (VHIO), Barcelona, Spain"
      ],
      "name": "Elena Garralda"
    },
    {
      "affiliations": [
        "The Angeles Clinical and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, California, USA"
      ],
      "name": "Omid Hamid"
    },
    {
      "affiliations": [
        "University of California Davis Comprehensive Cancer Center, Sacramento, California, USA"
      ],
      "name": "Hui Amy Chen"
    },
    {
      "affiliations": [
        "Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK"
      ],
      "name": "Thomas R Jeffry Evans"
    },
    {
      "affiliations": [
        "The University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, USA"
      ],
      "name": "Kathleen N Moore"
    },
    {
      "affiliations": [
        "Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK",
        "University of Liverpool, Liverpool, UK"
      ],
      "name": "Joseph J Sacco"
    },
    {
      "affiliations": [
        "The Christie NHS Foundation Trust and University of Manchester, Manchester, UK"
      ],
      "name": "Fiona Thistlethwaite"
    },
    {
      "affiliations": [
        "Sarah Cannon Research Institute, London, UK"
      ],
      "name": "Anja Williams"
    },
    {
      "affiliations": [
        "Department of Thoracic and Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "George R Blumenschein"
    },
    {
      "affiliations": [
        "University of Connecticut School of Medicine, Farmington, Connecticut, USA"
      ],
      "name": "Margaret K Callahan"
    },
    {
      "affiliations": [
        "Sarah Cannon Research Institute at Tennessee Oncology, Nashville, Tennessee, USA"
      ],
      "name": "Melissa L Johnson"
    },
    {
      "affiliations": [
        "University of Colorado Anschutz Medical Center, Aurora, Colorado, USA"
      ],
      "name": "Erin L Schenk"
    },
    {
      "affiliations": [
        "Translational Medicine, Immunocore, Radnor, Pennsylvania, USA"
      ],
      "name": "Jason Wustner"
    },
    {
      "affiliations": [
        "Translational Medicine, Immunocore, Abingdon, UK"
      ],
      "name": "Sarah Stanhope"
    },
    {
      "affiliations": [
        "Biometrics, Immunocore, Gaithersburg, Maryland, USA"
      ],
      "name": "Kaixiang Tao"
    },
    {
      "affiliations": [
        "Clinical Development, Immunocore, Gaithersburg, Maryland, USA"
      ],
      "name": "Shannon Marshall"
    },
    {
      "affiliations": [
        "Drug Development Unit, Institute of Cancer Research and the Royal Marsden Hospital, London, UK"
      ],
      "name": "Juanita Lopez"
    }
  ],
  "title": "Phase 1/2 study of IMC-C103C, a T cell receptor bispecific (MAGE-A4×CD3) ImmTAC targeting MAGE-A4-expressing malignancies",
  "uid": "583ada7b-540d-5959-a145-a1eea2ef9a29"
}