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      A real-world drug safety surveillance study from the FAERS database of hepatocellular carcinoma patients receiving pembrolizumab alone and plus lenvatinib

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          Abstract

          Pembrolizumab plus Lenvatinib is regarded as a significant treatment option for advanced unresectable hepatocellular carcinoma (HCC). This study aims to meticulously monitor and identify adverse events (AEs) related to this combined therapy, enhance patient safety, and offer evidence-based recommendations for the appropriate use of these drugs. We gathered adverse drug reactions (ADRs)-related data from the FAERS database for HCC patients who received Pembrolizumab, both alone and in combination with Lenvatinib from the first quarter of 2014 to the fourth quarter of 2023. ADRs signal detection was performed using the ROR, PRR, BCPNN, MHRA, and MGPS methods. We gathered data on 459 and 358 AEs from patients with HCC treated with pembrolizumab alone and in combination with lenvatinib, respectively. Using four signal quantification techniques, we identified 50 and 38 distinct AEs, which were classified into 15 different System organ class (SOC) categories. Notably, the most common AEs associated with pembrolizumab were gastrointestinal disorders and hepatobiliary disorders. In both patient groups, the most frequently reported AEs were hepatic encephalopathy, blood bilirubin increased and diarrhea. We also observed some unexpected significant AEs, such as dehydration, skin ulcers, and intestinal perforation. The countries reporting the highest number of AEs were the United States, followed by China, France, and Japan. The median onset time for AEs related to pembrolizumab alone and its combination with lenvatinib was 80.5 days (interquartile range 20.0–217.3 days) and 77.5 days (interquartile range 19.7–212.3 days), respectively. This study offers new insights into the monitoring and management of ADRs in HCC patients receiving pembrolizumab alone or in combination with lenvatinib. It is crucial to closely monitor the safety of this treatment regimen in HCC patients to avoid serious AEs.

          Supplementary Information

          The online version contains supplementary material available at 10.1038/s41598-025-85831-4.

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          Most cited references44

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          Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

          First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
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            Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

            Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.
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              Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma

              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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                Author and article information

                Contributors
                whx19930307@163.com
                docwan@163.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                9 January 2025
                9 January 2025
                2025
                : 15
                : 1425
                Affiliations
                [1 ]Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, ( https://ror.org/01dr2b756) Shiyan, 442000 Hubei China
                [2 ]Department of Emergency Department, The Third People’s Hospital of Fujian University of Traditional Chinese Medicine, ( https://ror.org/05n0qbd70) Fuzhou, 350108 Fujian China
                [3 ]Department of Hepatobiliary Medicine, 900 Hospital of the Joint Logistic Team, Fuzhou, 350025 Fujian China
                Article
                85831
                10.1038/s41598-025-85831-4
                11718235
                39789316
                bf9d5cb2-b75d-4cee-a5cc-8ed20ed505a1
                © The Author(s) 2025

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 14 November 2024
                : 6 January 2025
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                © Springer Nature Limited 2025

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                cancer,drug discovery
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                cancer, drug discovery

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