Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report
- 270 Downloads
The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies.
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.
HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.
KeywordsHepatocellular carcinoma Immunotherapy Lenvatinib Pembrolizumab
Barcelona Clinic Liver Cancer
circulating tumor DNA
Dose limited toxicity
mismatch repair deficient
Duration of response
Eastern Cooperative Oncology Group
Hepatic arterial embolization
Hepatitis B virus
international standard ratio
modified response evaluation criteria in solid tumors
Maximum tolerance dose
Objective response rate
Programmed death receptor-1
Programmed cell death ligand 1
Transcatheter arterial chemoembolization
Transforming growth factor-β
T cell immunoglobulin domain and mucin domain-3
Tumor mutation burden
unresectable hepatocellular carcinoma
White blood cell
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  and its incidence rate is rising faster than that of any other cancer in both men and women . Rates of both incidence (18.3 per 100,000) and mortality (17.1 per 100,000) are 2 to 3 times higher in China than those estimated in most other world regions . The major risk factors of HCC vary from region to region. The key determinants in China are chronic hepatitis B virus (HBV) infection and 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 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 multi-kinase 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 multi-kinase targeted therapy combination for HCC treatment in the future.
The Child-Pugh class level, HBV DNA level and full blood test analysis corresponding to pembrolizumab and lenvatinib combination therapy
ALB albumin, HE hepatic encephalopathy, PT prothrombin time, INR international standard ratio, T-BIL total bilirubin, WBC white blood cell, GR granulocyte, PLT platelet
ORR objective response rate, AE adverse event, DLT dose limited toxicity, LEN Lenvatinib, PEM Pembrolizumab, MTD maximum tolerance dose, DOR duration of response, dMMR mismatch repair deficient, PFS progression-free survival, OS overall survival, CR complete response, PD-L1 programmed cell death ligand 1, TMB tumor mutation burden
Discussion and conclusion
HCC is often diagnosed at advanced stages with limited curative therapy options, leading to a 5-year survival rate of 2% . Conventional systemic therapy with cytotoxic drugs such as doxorubicin and cisplatin achieve low objective response rates (typically < 10%), failing to improve the overall survival (OS) of these patients . FOLFOX4 was compared to doxorubicin in a phase III trial and the PFS was greater for FOLFOX4, but the primary OS endpoint was not met .
The launch of sorafenib, a molecular kinase inhibitor, was thought to be a breakthrough in treating uHCC given the results in two randomized-controlled trials (SHARP trial  and Asia-Pacific trial ) although only 3 months longer OS was found in sorafenib group. Remaining the only FDA-approved therapy for a decade, the benefits of Sorafenib was limited for lack of either therapeutic alternative or second-line treatment for those who are intolerant to Sorafenib . However, during the two-year period from 2017 through 2018, treatment for patients with advanced HCC is dramatically changed by novel multi-target inhibitors approved, Regorafenib, Lenvatinib, Cabozantinib, and single target Ramucirumab or immune checkpoint inhibitors-Nivolumab and Pembrolizumab.
The efficacy of lenvatinib, a multitarget inhibitor, was proved in a phase 3 open-label, multicenter non-inferiority trial, REFLECT study, and the results were published in the Lancet . Median overall survival for lenvatinib was 13.6 months, compared to Sorafenib at 12.3 months (hazard ratio 0.92, 95%CI 0.79–1.06), meeting the study primary criteria for non-inferiority. As a result, the FDA approved Lenvatinib in a first-line setting for patients with unresectable advanced HCC in August 2018 .
In recent years, immune checkpoint blockade has brought a paradigm shift in the treatment of a number of malignancies. Various immune checkpoint blocking agents are being tested for their efficacy in HCC. Furthermore, the immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of Pembrolizumab (KEYNOTE-224) and Nivolumab (Checkmate 040 trial). KEYNOTE-224 is a non-randomized, multicenter, open-label, phase 2 trial , 104 patients with advanced HCC who had progression on or intolerance to Sorafenib received Pembrolizumab 200 mg every 3 weeks. Objective Response rate in 18 patients (17, 95% CI 11–26%) and severe adverse events in 16 of the 104 patients indicate its tolerability and efficacy. Nivolumab, another anti-PD-1 antibody, was assessed in the Checkmate 040 trial for patients with advanced HCC. The objective response rate was about 20%, the disease control rate was 64% and the median duration of response is 17 months for Sorafenib-naïve patients and 19 months for patients who had been previously treated with Sorafenib . The FDA approved the use of Nivolumab in 2017 for patients with HCC who progressed on or after Sorafenib and the liver function is Child-Pugh A or B9. A phase III RCT, Checkmate 459, in which nivolumab is being compared to Sorafenib as first-line treatment in patients with advanced HCC is currently in progress (NCT02576509).
Ongoing clinical trials with immune checkpoint blockade pembrolizumab and lenvatinib in solid tumors
Number of patients
Line of therapy
Gene or protein detection
Advanced Gastric Cancer
Transitional Cell Carcinoma
Renal Cell Carcinoma
Clear Cell Renal Cell Carcinoma
active, not recruiting
Tumors involving non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, squamous cell carcinoma of the head and neck, or melanoma
1.MTD (phase 1b)
1.AE 2.DLT 3.ORR 4.DOR by Mrecist and RECIST 1.1 based on IIR analysis
Advanced Solid Tumors
Triple Negative Breast Cancer
Biliary Tract Cancers
dMMR for Colorectal Cancer
1.ORR 2.Percentage of AE 3.Percentage of Discontinue Study Treatment
not yet recruiting
not yet recruiting
Thyroid Gland Carcinoma
1.CR rate 2.Confirmed response rate
Non-small Cell Lung Cancer
PD-L1 ≥ 1%
not yet recruiting
correlative biomarker studies.
Nonsquamous Non-small Cell Lung Cancer
Part 1: DLT AE Part 2: PFS OS
not yet recruiting
Renal Cell Carcinoma
Advanced Non-Small Cell Lung Cancer
Gene expression profile and TMB
There are a few potential factors discussed to estimate prognosis, including emergent adverse AFP, PD-L1, requiring further evidence to verify their potency in this novel combination treatment. AFP (over 400 ng/mg) and PD-L1 (over 1%) are reviewed as potential biomarkers to estimate the prognosis in certain treatment regimen of HCC patients whereas neoantigen, tumor mutational burden, and interferon gamma need further investigation . Notably, our patient lacked diagnosis that was confirmed by pathology and without data of PD-L1 expression, we recommended the gene examination of peripheral blood ctDNA, but the patient refused to pay for this additional testing. Even without the benefit of PD-L1 expression data he still got a good response for this combination treatment, which raises questions about the value of PD-L1, dMMR, or TMB testing as a biomarker in HCC when immunotherapy is combined with other therapies. Whether this great success could be duplicated is still unknown. Exploration of the possible indicators for the combination and prognosis estimating factors are the foundation for a wider application.
Other anti-angiogenic/immunotherapy combinations are also currently popular subjects for research. An Atezolizumab (atezo) and Bevacizumab (bev) regimen was well-tolerated and had a manageable safety profile in patients with microsatellite-high (MSI-high) metastatic colorectal cancer (mCRC), according to results of a preliminary clinical evaluation presented at the 2017 Gastrointestinal Cancers Symposium. The overall response rate was 40% using the RECIST criteria and 30% via immune-related response criteria (irRC) . Another study of Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer (REGONIVO, EPOC1603) was published at ASCO 2019, the ORR and DCR was 40 and 88% respectively . Studies of Bevacizumab in combination with Atezolizumab in patients with untreated melanoma brain metastases (NCT03175432), NSCLC (NCT03836066), recurrent or metastatic squamous-cell carcinoma of the head and neck (NCT03818061) are ongoing.
In summary, what we could learn from this case is that the combination treatment of LEN and PEM with decreased dose and prolonged interval may be tolerable and effective among unresectable HCC patients with cirrhosis (those with hepatitis B infection) at a decompensated stage. While our case highlights some important aspects of the use of combination therapy, especially in HCC cases that lacked definitive expression of PD-L1 or dMMR, the potential side effects of the combination treatment should be highly concerned, and fully discussed with the patients in clinical practice. Lenvatinib plus Pembrolizumab may present a new potential treatment option for the sub-population. However, its efficacy and safety need further investigation in a randomized phase 3 study.
The authors would like to thank the patient’s family for giving consent and for providing the detail information of this case.
LZN and LXJ wrote the manuscript. XYC analyzed the data and provide guidance. HXQ took care of the patient. WX provided the data of this case. All authors have read and approved the manuscript.
This study was supported by the Zhejiang Provincial Natural Science Foundation of China (Grant No. LY14H160045) and the Hangzhou Science and Technology Commission (Grant No. 20140633B41).
Ethics approval and consent to participate
This study has been approved by Ethic Committee of the 903rd Hospital of PLA. The patient and his relations have signed an informed consent.
Consent for publication
The patient and his family were informed that the information published may potentially compromise anonymity. Publication was consented by the patient. Written informed consent was obtained from the case patient for publication of this report and any accompany images. A copy of the written consent is available for review by the Editor of this journal.
The authors declare that they have no competing interests.
- 4.Qin S, Cheng Y, Liang J, Shen L, Bai Y, Li J, Fan J, Liang L, Zhang Y, Wu G, Rau KM, Yang TS, Jian Z, Liang H, Sun Y. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study. Oncologist. 2014;19(11):1169–78.CrossRefGoogle Scholar
- 11.El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling THR, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.CrossRefGoogle Scholar
- 15.Kato Y , Bao X , Macgrath S, et al. Lenvatinib mesilate (LEN) enhanced antitumor activity of a PD-1 blockade agent by potentiating Th1 immune response. Annals of Oncology. 2016, 27(suppl_6).Google Scholar
- 16.Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, Schmidt EV, Guo M, Sachdev P, Shumaker R, Aghajanian C, Taylor M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019: S1470-2045(19)30020–8.Google Scholar
Open AccessThis 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.