{
  "abstract": "Background Ubamatamab, a mucin 16 × cluster of differentiation 3 (MUC16×CD3) bispecific antibody, bridges MUC16-positive tumor cells and MHC-independent T cells, promoting cytotoxicity. In a Phase 1/2 study, ubamatamab activity was observed in patients with recurrent advanced OC. CRS is a common adverse event during initial ubamatamab doses. Sarilumab, an anti-interleukin-6 (IL-6) receptor α-subunit monoclonal antibody, has pharmacodynamic effects including neutrophil margination. Here, we assessed sarilumab prophylaxis as a mitigation strategy for ubamatamab-induced CRS ( NCT03564340).Methods Patients received a single dose of sarilumab 350 mg intravenously before ubamatamab (sarilumab/ubamatamab), or ubamatamab alone without sarilumab. Ubamatamab step-up dosing: 1 mg Day (D)1, and 10 mg D8 and D9, followed by full dose in Week 3 (administered every three weeks), 800 mg (patients with OC) or 250 mg (patient with EC). CRS was graded using Lee Criteria. Serum sarilumab pharmacokinetics were analyzed over 6 weeks. Pharmacodynamic effects on cytokines, chemokines, and C-reactive protein (CRP) were evaluated.Results Overall, 32 patients received sarilumab/ubamatamab (OC: n=31; EC: n=1); 207 received ubamatamab alone. CRS was observed in 15.6% (sarilumab/ubamatamab: Grade [G]1, 12.5%; G2, 3.1%) and 84.5% (ubamatamab alone: G2, 38.2%; G3, 1.0%) of patients ( figure 1). Fewer incidences of infusion-related reactions (6.3% vs 18.4%) and Grade 3 anemia (6.3% vs 21.7%) occurred in patients treated with sarilumab/ubamatamab versus ubamatamab alone, respectively. No sarilumab/ubamatamab-treated patients experienced immune effector cell-associated neurotoxicity syndrome, while 3.4% of those receiving ubamatamab alone did. Neutropenia was observed in 31.3% and 5.8% of patients treated with sarilumab/ubamatamab and ubamatamab alone, respectively. No neutropenic fever cases were observed, and infection rates were similar between cohorts (sarilumab/ubamatamab: 43.8%; ubamatamab alone: 44.0%).Serum sarilumab concentration maintained active levels through Week 3. After sarilumab infusion, median peripheral IL-6 increased compared with baseline (20.7 vs 3.2 pg/mL, respectively) and continued to increase during ubamatamab step-up dosing compared with patients who received ubamatamab alone (median peak IL-6: >1166.0 vs 187.9 pg/mL, respectively) (figure 2A). Median peak CRP levels were lower in patients treated with sarilumab/ubamatamab versus ubamatamab alone (88.7 vs >186.0 mg/L, respectively) (figure 2B). In sarilumab/ubamatamab-treated patients, interferon-gamma, IL-8, tumor necrosis factor alpha, eotaxin, and monocyte chemoattractant protein-4 increased at Week 1; macrophage-derived, and thymus and activation-regulated chemokines increased at Week 4.Conclusions A single sarilumab dose before ubamatamab reduced CRS incidence and severity. Pharmacokinetic and pharmacodynamic findings demonstrated sarilumab activity throughout ubamatamab step-up dosing. Evaluation of sarilumab prophylaxis for ubamatamab-induced CRS is ongoing.Acknowledgements This study was supported by Regeneron Pharmaceuticals, Inc. Medical writing assistance was provided by Joe Bolton, of Oberon, a division of OPEN Health Communications, funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).Trial Registration NCT03564340Ethics Approval The study was conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice guidelines, and all applicable regulatory requirements. The research protocol was approved by the relevant institutional review boards or ethics committees at each site. All patients provided written informed consent.Abstract 546 Figure 1Sunburst plot of the incidence of CRS by grade over the first 4 weeks of ubamatamab administration in patients treated A) with sarilumab prophylaxis and B) without sarilumab prophylaxisAbstract 546 Figure 2Median IL-6 (A) and CRP (B) levels in patients treated with and without sarilumab prophylaxis",
  "authors": [
    {
      "affiliations": [
        "O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA"
      ],
      "name": "Rebecca C Arend"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Institut Català d´Oncologia (ICO), IDIBGI-CERCA, Girona, Spain"
      ],
      "name": "Maria Pilar Barretina-Ginesta"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands"
      ],
      "name": "Ingrid A Boere"
    },
    {
      "affiliations": [
        "Dipartimento Medicina e Chirurgia, Università Milano-Bicocca, Istituto Europeo Oncologia, IRCCS, Milan, Italy"
      ],
      "name": "Nicoletta Colombo"
    },
    {
      "affiliations": [
        "Yonsei Cancer Center and Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"
      ],
      "name": "Jung Yun Lee"
    },
    {
      "affiliations": [
        "Seoul National University College of Medicine, Seoul, Republic of Korea"
      ],
      "name": "Hee Seung Kim"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Hospital Clínico San Carlos, Department of Medicine, School of Medicine, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria (IdISSC), EURACAN Referral Centre, Madrid, Spain"
      ],
      "name": "Gloria Marquina"
    },
    {
      "affiliations": [
        "Clinical Research Early Phase Trials Unit, START Madrid-Fundación Jiménez Díaz (FJD), Hospital FJD, Madrid, Spain"
      ],
      "name": "Victor Moreno"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA"
      ],
      "name": "Róisín E O’Cearbhaill"
    },
    {
      "affiliations": [
        "Division of Gynecologic Oncology in Obstetrics and Gynecology, The Ohio State University and the James Comprehensive Cancer Center, Columbus, OH, USA"
      ],
      "name": "David O’Malley"
    },
    {
      "affiliations": [
        "Radboud University Medical Center, Nijmegen, Netherlands"
      ],
      "name": "Petronella B Ottevanger"
    },
    {
      "affiliations": [
        "Division of Oncology, Rambam Health Care Campus, Haifa, Israel"
      ],
      "name": "Ruth Perets"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands"
      ],
      "name": "Anna KL Reyners"
    },
    {
      "affiliations": [
        "Department of Woman, Child and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"
      ],
      "name": "Vanda Salutari"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Gloria S Huang"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Suk-Young Yoo"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Bin Wang"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Jingxiao Chen"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Jenn Visch"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Israel Lowy"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Elizabeth Miller"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Jurriaan Brouwer-Visser"
    },
    {
      "affiliations": [
        "Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA"
      ],
      "name": "Thomas S Uldrick"
    }
  ],
  "title": "546 Sarilumab as a potential mitigator of ubamatamab (MUC16×CD3)-induced cytokine release syndrome (CRS) in patients with advanced ovarian cancer (OC) or endometrial cancer (EC)",
  "uid": "f3af1b24-954a-52da-9eb8-ff4a5f3bb578"
}