{
  "abstract": "Background Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC.Methods Patients with treatment-naïve or pretreated clear cell and/or sarcomatoid mRCC were eligible. Dose escalation explored FAP-IL2v every 2 weeks (Q2W) with atezolizumab Q2W (doublet, arm A), and with atezolizumab and bevacizumab Q2W (triplet, arm B) in patients treated with up to one prior systemic therapy. Dose extension explored in untreated patients the recommended FAP-IL2v dose administered Q2W (doublet, arm A; and triplet, arm B) or 3-weekly (doublet, arm C; and triplet, arm D). Primary objectives were the recommended FAP-IL2v dose and antitumor activity. Secondary objectives included safety, pharmacodynamics, and exploratory biomarkers in peripheral blood and paired biopsies.Results By the data cut-off date (31 August, 2021), 66 patients were enrolled. The median duration of treatment was 11.0 months. Objective response rates (ORRs) were 25% for the doublet and 47% for the triplet, and median progression-free survival was 6.3 and 18.3 months, respectively. Safety profiles were consistent with the individual drugs, including expected interleukin-2 (IL-2) class-specific adverse events (AEs). Two deaths were recorded caused by AEs related to study treatment (acute kidney injury, n=1; pancytopenia, n=1). Expansion and activation of NK and T cells, but not regulatory T cells, was observed in peripheral blood, leading to increased tumor infiltration and inflammation in paired biopsies. The addition of bevacizumab led to a reduced angiogenesis signature score and reduced vessel density.Conclusion The combination of FAP-IL2v plus atezolizumab with or without bevacizumab was consistent with the known safety profile of the individual drugs. The maximum tolerated dose was not reached, with a recommended FAP-IL2v dose of 10 mg. ORR was higher among patients receiving the triplet therapy compared with the doublet. Pharmacodynamic results were consistent with the mechanism of action of IL-2, supporting further research in this field.",
  "authors": [
    {
      "affiliations": [
        "Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain"
      ],
      "name": "Jose Luis Perez-Gracia"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain",
        "Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain",
        "Department of Medicine, University of Barcelona, Barcelona, Spain"
      ],
      "name": "Begoña Mellado"
    },
    {
      "affiliations": [
        "Division of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada",
        "Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia"
      ],
      "name": "Aaron Richard Hansen"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain"
      ],
      "name": "Teresa Alonso-Gordoa"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France"
      ],
      "name": "Carlos Gomez-Roca"
    },
    {
      "affiliations": [
        "Department of Oncology, Copenhagen University Hospital Rigshospitalet, Herlev, Denmark"
      ],
      "name": "Rikke Løvendahl Eefsen"
    },
    {
      "affiliations": [
        "Centre Léon Bérard, University of Lyon, Lyon, France"
      ],
      "name": "Sylvie Negrier"
    },
    {
      "affiliations": [
        "Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Barcelona, Spain"
      ],
      "name": "Cristina Suárez"
    },
    {
      "affiliations": [
        "Department of Oncology and Internal Medicine, Asan Medical Center, Songpa-gu, Korea (the Republic of)",
        "Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Songpa-gu, Korea (the Republic of)"
      ],
      "name": "Jae-Lyun Lee"
    },
    {
      "affiliations": [
        "University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA"
      ],
      "name": "Arif Hussain"
    },
    {
      "affiliations": [
        "Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy",
        "Department of Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy"
      ],
      "name": "Paolo Pedrazzoli"
    },
    {
      "affiliations": [
        "START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain"
      ],
      "name": "Victor Moreno"
    },
    {
      "affiliations": [
        "CIBERONC, Hospital del Mar, Barcelona, Spain"
      ],
      "name": "Alejo Rodriguez-Vida"
    },
    {
      "affiliations": [
        "Department of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA"
      ],
      "name": "Jeffrey Alan Sosman"
    },
    {
      "affiliations": [
        "Gastro-Oesophageal and Renal Unit, The Christie Hospital NHS Trust, Manchester, UK"
      ],
      "name": "Tom Waddell"
    },
    {
      "affiliations": [
        "Department of Urology, University Hospital Tübingen, Tübingen, Germany",
        "Department of Urology & Transplantation Surgery, Klinikum Stuttgart, Stuttgart, Germany"
      ],
      "name": "Jens Bedke"
    },
    {
      "affiliations": [
        "Samsung Medical Center, Sungkyunkwan University, Jongno-gu, Korea (the Republic of)"
      ],
      "name": "Se Hoon Park"
    },
    {
      "affiliations": [
        "Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Mario Sznol"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Lukasz Spychaj"
    },
    {
      "affiliations": [
        "EMEA-LATAM Region, Roche Diagnostics AS, Solna, Sweden"
      ],
      "name": "Emilia Andersson"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Alice Julien-Laferriere"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, New York, USA"
      ],
      "name": "Wei-Yi Cheng"
    },
    {
      "affiliations": [
        "A4P Consulting Ltd, Sandwich, UK"
      ],
      "name": "Carl Watson"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Ana Patricia Silva"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Christian Heichinger"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Nicolas Staedler"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Nassim Sleiman"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "David Dejardin"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Christophe Boetsch"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Stefan Evers"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Taner Vardar"
    },
    {
      "affiliations": [
        "F Hoffmann-La Roche AG, Welwyn Garden City, UK"
      ],
      "name": "Caroline Ardeshir-Tandon"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Jorge Dorado Pérez"
    },
    {
      "affiliations": [
        "Roche Innovation Center Zurich, Zurich, Switzerland"
      ],
      "name": "Jehad Charo"
    },
    {
      "affiliations": [
        "Roche Innovation Center Zurich, Zurich, Switzerland"
      ],
      "name": "Nino Keshelava"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Anton Kraxner"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Volker Teichgräber"
    },
    {
      "affiliations": [
        "Barts Health NHS Trust ECMC, Barts Cancer Institute, Queen Mary University of London, London, UK"
      ],
      "name": "Thomas Powles"
    }
  ],
  "title": "Simlukafusp alfa (FAP-IL2v) plus atezolizumab with or without bevacizumab in unresectable, metastatic renal cell carcinoma: a randomized, open-label phase Ib study",
  "uid": "e83c8ef8-b07c-5f4c-a104-22b4bf30e567"
}