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

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          Abstract

          PURPOSE

          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).

          PATIENTS AND METHODS

          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).

          RESULTS

          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.

          CONCLUSION

          Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)
          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Sorafenib in advanced hepatocellular carcinoma.

            Josep Llovet, Sergio Ricci, Vincenzo Mazzaferro … (2008)
            No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society
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              Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

              Min Ren, Silvija Kraljevic, Kenichi Saito … (2018)
              In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
              Article 0 comments Cited 1632 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Oncol
                Journal ID (iso-abbrev): J. Clin. Oncol
                Journal ID (hwp): jco
                Journal ID (pmc): jco
                Journal ID (publisher-id): JCO
                Title: Journal of Clinical Oncology
                Publisher: American Society of Clinical Oncology
                ISSN (Print): 0732-183X
                ISSN (Electronic): 1527-7755
                Publication date (Print): 10 September 2020
                Publication date (Electronic): 27 July 2020
                Publication date PMC-release: 10 September 2021
                Volume: 38
                Issue: 26
                Pages: 2960-2970
                Affiliations
                [ 1 ]David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, CA
                [ 2 ]Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
                [ 3 ]Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
                [ 4 ]Jiahui International Cancer Center, Jiahui Health, Shanghai, China
                [ 5 ]Tisch Cancer Institute at Mount Sinai, New York, NY
                [ 6 ]Sutter Health/California Pacific Medical Center Research Institute, San Francisco, CA
                [ 7 ]Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
                [ 8 ]Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
                [ 9 ]Department of Hepatology, Toranomon Hospital, Tokyo, Japan
                [ 10 ]Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
                [ 11 ]Centre Eugène Marquis, Rennes, France
                [ 12 ]Altay Regional Oncological Hospital, Barnaul, Russian Federation
                [ 13 ]Royal Free London National Health Service Foundation Trust, London, United Kingdom
                [ 14 ]Eisai, Tokyo, Japan
                [ 15 ]Eisai, Woodcliff Lake, NJ
                [ 16 ]Merck, Kenilworth, NJ
                [ 17 ]Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
                [ 18 ]Liver Cancer Translational Group, Liver Unit, August Pi i Sunyer Biomedical Research Institute Hospital Clinic, University of Barcelona, Catalonia, Spain
                Author notes
                Josep M. Llovet, MD, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 1123, Room 11F-70, New York, NY 10029; e-mail: josep.llovet@ 123456mssm.edu .
                Article
                Publisher ID: 2000808
                DOI: 10.1200/JCO.20.00808
                PMC ID: 7479760
                PubMed ID: 32716739
                SO-VID: 7eda4cfc-769b-4114-be95-cb625448cfed
                Copyright © © 2020 by American Society of Clinical Oncology
                License:

                Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Date accepted : 8 June 2020
                Page count
                Figures: 7, Tables: 7, Equations: 0, References: 36, Pages: 20
                Categories
                Compound subject: GIC54, Targeted Therapy
                Subject: RAPID COMMUNICATIONS
                Subject: Gastrointestinal Cancer
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