Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma

  • Richard S. Finn
    David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, CA
  • Masafumi Ikeda
    Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
  • Andrew X. Zhu
    Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
  • Max W. Sung
    Tisch Cancer Institute at Mount Sinai, New York, NY
  • Ari D. Baron
    Sutter Health/California Pacific Medical Center Research Institute, San Francisco, CA
  • Masatoshi Kudo
    Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
  • Takuji Okusaka
    Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
  • Masahiro Kobayashi
    Department of Hepatology, Toranomon Hospital, Tokyo, Japan
  • Hiromitsu Kumada
    Department of Hepatology, Toranomon Hospital, Tokyo, Japan
  • Shuichi Kaneko
    Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
  • Marc Pracht
    Centre Eugène Marquis, Rennes, France
  • Konstantin Mamontov
    Altay Regional Oncological Hospital, Barnaul, Russian Federation
  • Tim Meyer
    Royal Free London National Health Service Foundation Trust, London, United Kingdom
  • Tomoki Kubota
    Eisai, Tokyo, Japan
  • Corina E. Dutcus
    Eisai, Woodcliff Lake, NJ
  • Kenichi Saito
    Eisai, Woodcliff Lake, NJ
  • Abby B. Siegel
    Merck, Kenilworth, NJ
  • Leonid Dubrovsky
    Merck, Kenilworth, NJ
  • Kalgi Mody
    Eisai, Woodcliff Lake, NJ
  • Josep M. Llovet
    Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

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<jats:sec><jats:title>PURPOSE</jats:title><jats:p> The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti–PD-1 antibody) in unresectable HCC (uHCC). </jats:p></jats:sec><jats:sec><jats:title>PATIENTS AND METHODS</jats:title><jats:p> In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals. </jats:p></jats:sec>

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