{
  "abstract": "Background The orally available toll-like receptor 7 (TLR7) agonist prodrug RO7119929 is converted to active drug predominantly in the liver, where it is hypothesized to reprogram the local immune microenvironment. We aimed to explore the safety, pharmacokinetics (PK), and preliminary antitumor activity and obtain the proof-of-mechanism for RO7119929 in patients with liver cancer.Methods RO7119929 was investigated in mouse tumors and liver tissue from cynomolgus monkeys. In the first-in-human, open-label, dose-escalation and expansion study, patients with histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement received RO7119929 weekly in 3-week cycles either on a flat-dose (FD) or step-up dose (SUD) schedule.Results Preclinical results demonstrated antitumor activity and the proinflammatory proof-of-mechanism in mouse liver tumors and cynomolgus monkey liver tissue. The subsequent first-in-human study enrolled 27 patients in five FD dose-escalation cohorts, 18 patients in a FD dose-expansion cohort, and 9 patients in two SUD dose-escalation cohorts. The most common primary tumor type at study entry was hepatocellular carcinoma (HCC) (31%). PK data showed fast conversion of RO7119929 to the active TLR7 agonist. Treatment-related adverse events (TRAEs) were observed in 50 (91%) patients across all treated patients; the most commonly reported TRAE was cytokine release syndrome (CRS) in 48 (81%) patients. CRS was also identified as a dose-limiting safety risk and had a dose-dependent incidence and severity. Grade 3 CRS occurred in six (13%) patients receiving FD RO7119929, while no grade 3 CRS was reported in SUD patients at comparable target dose levels. TLR7-related transient, dose-dependent gene expression and cytokine induction was observed both with FD and SUD treatment and corresponded with treatment-induced local inflammation of the tumor microenvironment induced by reprogramming of the myeloid cells. Among 17 patients with HCC, one durable complete response was observed, and 10 (59%) patients had stable disease.Conclusions SUD appears to reduce the risk of CRS while maintaining mode-of-action-relevant pharmacodynamic effects. The clinical activity of RO7119929 as a single agent was limited, suggesting that combination therapy with a checkpoint inhibitor may be needed to leverage the proinflammatory potential of RO7119929 and further increase antitumor activity.Trial registration number NCT04338685.",
  "authors": [
    {
      "affiliations": [
        "University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)"
      ],
      "name": "Changhoon Yoo"
    },
    {
      "affiliations": [
        "Vall d’Hebron University Hospital, Barcelona, Spain"
      ],
      "name": "Carles Fabregat-Franco"
    },
    {
      "affiliations": [
        "National Taiwan University Hospital, Taipei City, Taiwan"
      ],
      "name": "Chia-Chi Lin"
    },
    {
      "affiliations": [
        "Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Camilla Qvortrup"
    },
    {
      "affiliations": [
        "Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea (the Republic of)",
        "Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Jongno-gu, Korea (the Republic of)"
      ],
      "name": "Do-Youn Oh"
    },
    {
      "affiliations": [
        "Medicine, Queen Mary Hospital, Hong Kong, Hong Kong"
      ],
      "name": "Thomas Yau"
    },
    {
      "affiliations": [
        "University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)"
      ],
      "name": "Hyung-Don Kim"
    },
    {
      "affiliations": [
        "Vall d’Hebron University Hospital, Barcelona, Spain"
      ],
      "name": "Florian Castet"
    },
    {
      "affiliations": [
        "HPB Oncology Area, Cancer Center Clínica Universidad de Navarra and CIMA, Pamplona, Spain"
      ],
      "name": "Mariano Ponz Sarvise"
    },
    {
      "affiliations": [
        "National Taiwan University Hospital, Taipei City, Taiwan"
      ],
      "name": "Chiun Hsu"
    },
    {
      "affiliations": [
        "Department of Oncology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Kristoffer Staal Rohrberg"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Felix Sebastian Lichtenegger"
    },
    {
      "affiliations": [
        "Roche Diagnostics GmbH Penzberg, Penzberg, Germany"
      ],
      "name": "Izolda Franjkovic"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Nicole A Kratochwil"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Juliana Bessa"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Eva Rossmann"
    },
    {
      "affiliations": [
        "Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Petra C Schwalie"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Natascha Rieder"
    },
    {
      "affiliations": [
        "Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Thomas Pöschinger"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Christina Godfried Sie"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Steffen Dettling"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Ramona Schlenker"
    },
    {
      "affiliations": [
        "Roche Innovation Center Shanghai, Shanghai, China"
      ],
      "name": "Tianyi Jiang"
    },
    {
      "affiliations": [
        "Roche Innovation Center Shanghai, Shanghai, China"
      ],
      "name": "Congqi Dai"
    },
    {
      "affiliations": [
        "Roche Innovation Center Shanghai, Shanghai, China"
      ],
      "name": "Hongying Yun"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Elia Hall"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Audrey Yeo Te-Ying"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Sabine Hoves"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Michael A Cannarile"
    },
    {
      "affiliations": [
        "Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Christina Schiff"
    },
    {
      "affiliations": [
        "HPB Oncology Area, Cancer Center Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain"
      ],
      "name": "Bruno Sangro"
    }
  ],
  "title": "First-in-human phase 1 study of RO7119929, an oral TLR7 agonist prodrug, in patients with advanced primary or metastatic liver cancers",
  "uid": "b2074b89-6be2-5d60-928e-196b6ff70aa5"
}