Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: A case report

The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies.

Liu et al BMC Cancer (2019) 19:1062 https://doi.org/10.1186/s12885-019-6287-8 CASE REPORT Open Access Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report Zhaonan Liu1†, Xingjie Li1†, Xuequn He2†, Yingchun Xu1* and Xi Wang2* Abstract Background: The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies Case presentation: We report a rare case of HCC from a patient who had a complete response (CR) with the use of combination of Lenvatinib and Pembrolizumab A 63-year-old man presented at the hospital with serious abdominal pain and was found to have a mass with heterogeneous enhancement and with hemorrhage in segment III of the liver after the examination of abdominal computerized tomography (CT) scan The patient’s history of viral hepatitis B infection, liver cirrhosis and the ɑ-fetoprotein (AFP) level of 14,429.3 ng/ml supported the clinical diagnosis of HCC and laboratory results demonstrated liver function damage status (Child-Pugh class B, Score 8) The patient first received hepatic arterial embolization treatment on 28th November 2017 At this stage supportive care was recommended for poor liver function In February 2018, combined immunotherapy of Pembrolizumab (2 mg/kg, q3w) and Lenvatinib (8 mg–4 mg, qd) were performed Nine months following the treatment he had a CR and now, 22 months since the initial treatment, there is no clinical evidence of disease progression The current overall survival is 22 months Conclusions: HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases Keywords: Hepatocellular carcinoma, Immunotherapy, Lenvatinib, Pembrolizumab Background Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer death in the United States with a 5-year survival rate of 18% for all stages [1] and its incidence rate is rising faster than that of any other cancer in both men and women [2] Rates of both incidence (18.3 per 100,000) and mortality (17.1 per 100,000) are to times higher in China than those estimated in most other world regions [1] The major risk factors of HCC vary from region to region The key determinants in China are chronic hepatitis B virus (HBV) infection and * Correspondence: xiaoxu2384@163.com; d.wangxi@hotmail.com † Zhaonan Liu, Xingjie Li and Xue-Qun He are co-first author Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, People’s Republic of China Department of Oncology, the 903rd Hospital of PLA, 14 Lingyin Road, Hangzhou 310013, China aflatoxin exposure, therefore most cases of HCC in China are at younger ages and with cirrhosis Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited Furthermore, with the wide range of local regional therapies available to patients with unresectable HCC (uHCC), evidence for favorable systemic therapy for metastatic disease on overall survival (OS) is lacking Cytotoxic chemotherapies have reported to have low response rates Oral multi-kinase inhibitors that suppress tumor cell proliferation and angiogenesis in HCC have been approved Currently, the first line options for uHCC include Sorafenib and Lenvatinib, and second line options are formed by Regorafenib and Cabozantinib Clinical studies with Nivolumab (Checkmate 040 trial) or © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Liu et al BMC Cancer (2019) 19:1062 Pembrolizumab (KEYNOTE-224) also have promising data for patients with advanced HCC who progressed on or after Sorafenib The rationale for the combination of Lenvatinib and Pembrolizumab has been illustrated in preclinical studies Clinical studies of the combination treatment had not been published until June 2018 Preliminary data of the Phase Ib clinical trial of combination treatment (PEM plus LEN) in HCC patients have been published as Keynote-524 in 2019 in the journal of the American Association for Cancer Research (AACR) To evaluate clinical efficacy of the combination rationale including immune checkpoint inhibitors and multikinase inhibitors, we report a case of HCC with poor liver function in the setting of cirrhosis from HBV infection responding dramatically to the combination treatment of Pembrolizumab and Lenvatinib after initial hepatic arterial embolization (HAE) and we hope to explore further study for anti-PD-1 therapy and multikinase targeted therapy combination for HCC treatment in the future Case description Our patient, a 63-year-old male with a history of chronic HBV infection for 18 years, presented to the emergency department with severe abdominal pain and flatulence in November 2017 Enhanced abdominal CT showed a heterogeneous irregular mass with the largest measuring up to 5.0 * 3.8 cm in size in segment within the left lobe of liver(Fig 1a-c) Hepatocellular carcinoma (HCC) Page of with hemorrhage and peritoneal effusion should be considered first The CT scan also revealed liver cirrhosis, splenomegaly, portal hypertension with multiple collateral circulations (Fig 1d) and partial thrombosis of the left portal vein (Fig 1e, f) The laboratory test data revealed serum ɑ-fetoprotein (AFP) was 14,429.3 ng/ml and HBV DNA level of 2.37*10^3 IU/ml The patient was confirmed with the clinical diagnosis of Barcelona Clinic Liver Cancer (BCLC) C and Child-Pugh class B (Score 8) (Table 1) HCC with the background of cirrhosis secondary to viral B infection The patient first received HAE and then discharged with an HBV DNA level below 30 IU/ml after antiviral treatment with entecavir He had radiographic progression months later (Fig 2a) with poor liver function (Child-Pugh class B 7) (Table 1) For Sorafenib, 400 mg twice daily was only recommended for HCC with liver function of ChildPugh class A For lack of an available clinical trial, the patient was prescribed off-label immunotherapy based on the phase I/II data mentioned above (KEYNOTE224) He was recommended to take Pembrolizumab 100 mg (2 mg/kg, q3w) on Feb 8th 2018, which was well tolerated Baseline computed tomography (CT) showed one large liver lesion and extrahepatic hilar lymph node metastasis (Fig 2a) After one cycle of Pembrolizumab, his AFP increased to 55,107.82 ng/ml compared to 47, 739.14 ng/ml before Pembrolizumab was administered (Fig 2b) The patient was recommended to continue on Pembrolizumab due to the stable clinical status of the Fig CT of the abdomen showing the segment liver lesions at diagnosis a The characteristics of liver mass in plain scan; b Liver mass in arterial phase; c Liver mass in portal phase; d Multiple collateral circulations; e Partial thrombosis of the left portal vein in arterial phase; f Partial thrombosis of the left portal vein in portal phase Liu et al BMC Cancer (2019) 19:1062 Page of Table The Child-Pugh class level, HBV DNA level and full blood test analysis corresponding to pembrolizumab and lenvatinib combination therapy Date ALB(g/l) HE PT INR Ascites T-BIL Score HBV-DNA WBC(10^9/L) GR(10^9/L) HGB(g/L) PLT(10^9/L) 17.11.27 30.4 N 15.3 1.35 Y 16.4 2370 1.3 0.58 112 42 18.2.7 31.6 N 15.4 1.3 N 17.3