Assessment of the Efficacy of Lenvatinib Versus Sorafenib in the Management of Advanced Hepatocellular Carcinoma
Status:
Recruiting
Trial end date:
2023-06-30
Target enrollment:
Participant gender:
Summary
Hepatocellular carcinoma is the most common type of liver cancer, which is the 3rd leading
cause of cancer deaths worldwide. The incidence is expected to increase as a consequence of
chronic liver disease with its multiple risk factors, including chronic hepatitis B virus
(HBV) and hepatitis C virus (HCV) infections, excessive alcohol consumption, nonalcoholic
fatty liver disease, hemochromatosis, and aflatoxin B1.It is estimated that 70%-90% of
patients with HCC have chronic liver disease and cirrhosis, which limits the feasibility of
surgical procedures in advanced cases. There are limited treatment options for HCC patients
who are ineligible for surgical resection. Locoregional therapies, such as radiofrequency
ablation, transarterial chemoembolization (TACE), transarterial embolization (TAE), or
hepatic arterial infusion chemotherapy (HAIC), are primarily recommended, and if one of those
fail, then systemic therapy is considered. The 2013 Japan Society of Hepatology HCC
Guidelines outlined that the factors influencing treatment decisions should be based on the
degree of liver damage (Child-Pugh), presence or absence of extrahepatic spread and
macrovascular invasion, the number of tumors, and tumor diameter. Sorafenib has been the
standard of care since 2007, when the SHARP trial demonstrated that sorafenib improved median
overall survival (OS) compared to placebo in patients who had not received prior systemic
therapy (10.7 vs 7.9 months, HR =0.69, P<0.001). In patients from the Asia-Pacific region
taking sorafenib, the median improvement in overall survival compared with placebo was 2.3
months (6.5 months vs 4.2 months; HR 0.68; p=0.014). Drug development for hepatocellular
carcinoma in the past 10 years has been marked by four failed global phase 3 trials (of
sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not show
non-inferiority. Sorafenib, an oral multikinase inhibitor, has been the only systemic therapy
demonstrated to extend overall survibility as a firstline treatment, showing a median
improvement of 2.8 months compared with placebo (10.7 months vs. 7.9 months; hazard ratio
[HR] 0.69; p\0.001).6 Inpatients from the Asia-Pacific region taking sorafenib, the median OS
(mOS) improvement compared with placebo was 2.3 months (HR 0.68; p = 0.014). The use of other
molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority
to sorafenib; thus, until the appearance of lenvatinib, sorafenib has also been widely used
as the first-line treatment for uHCC patients in Japan. Recently, regorafenib and Nivolumab
were approved as a second-line systemic treatment for patients who do not respond to the
first-line treatments. Otherwise, best supportive care or participation in clinical trials is
recommended in the second-line setting by treatment guidelines. Chemotherapy in combination
with sorafenib (doxorubicin) and radioembolization with SIR Spheres Y-90 resin microspheres
failed to demonstrate a survival benefit or showed a worse safety profile compared to
sorafenib in the first-line setting. Eventually, the PhaseIII non-inferiority REFLECT trial
showed that lenvatinib was non-inferior compared to sorafenib.