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Cabozantinib Therapy In Hepatocellular Carcinoma

Cabozantinib Therapy In Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a predominant form of liver cancer, accounting for approximately 90% of cases. Unfortunately, it carries a grim prognosis, with a median survival rate ranging from 6 to 18 months. Historically, sorafenib had been the established first-line therapy for HCC. However, in recent times, alternatives such as lenvatinib, atezolizumab, and bevacizumab have emerged as potential treatment options. Despite these advancements, many HCC patients ultimately require second-line treatments due to the aggressive nature of the disease.

The progression of HCC and its resistance to treatment are often associated with abnormal signaling of receptor tyrosine kinases (RTKs), with the MET receptor being a particularly relevant player in this context.

Cabozantinib, a multi-RTK inhibitor designed to target MET and other relevant pathways, has displayed considerable promise in clinical trials, notably in the CELESTIAL study. In this study, cabozantinib demonstrated its effectiveness by reducing the risk of death by 24% when compared to a placebo. This is a significant breakthrough in the treatment of HCC.

Furthermore, the serum ALBI score, which serves as a more accurate indicator of liver function compared to the traditional Child–Pugh grade, has been instrumental in highlighting cabozantinib’s efficacy. Remarkably, cabozantinib’s benefits extend across different ALBI grades, indicating its potential to benefit a wide range of HCC patients, regardless of their liver function status.

In summary, HCC, as a prevalent and aggressive form of liver cancer, presents a significant challenge in terms of treatment. While sorafenib was once the primary option, new therapies like cabozantinib, with its multi-RTK inhibition targeting MET and other pathways, have shown remarkable promise. These advancements offer hope for improved outcomes and extended survival for HCC patients, marking a critical step forward in the battle against this formidable disease.

A Japanese phase II study affirmed cabozantinib’s benefits in patients previously treated with systemic therapies, including sorafenib. It exhibited a favorable benefit-risk profile, even in patients with prior therapies. Cabozantinib is now approved in over 50 countries, including the US, Europe, and Japan.

This analysis extended data to March 2021 and included investigator assessments of radiographic response and disease progression, augmenting the previous report that relied solely on the Independent Review Committee’s assessments. It also examined changes in patients’ ALBI grades over time.

HCC poses a significant health challenge, with limited treatment options. Cabozantinib, a multi-RTK inhibitor, has shown promise in extending survival for patients, especially those who previously received systemic therapies. This analysis reinforces its efficacy and safety, making it an approved treatment in various countries. Further research into its potential as a first-line therapy and its long-term effects on ALBI grades is warranted to improve HCC patient outcomes.

Study Methods

Study Overview:

This analysis summarizes data from a Japanese phase II study of cabozantinib (NCT03586973) up to March 2021. The study enrolled Japanese patients with hepatocellular carcinoma (HCC), who met specific criteria, including prior systemic anticancer therapy and differentiating between those who had or hadn’t used sorafenib.

Participant Criteria:

The study focused on Japanese patients aged 20 and above diagnosed with hepatocellular carcinoma (HCC), a type of liver cancer, through histological or cytological confirmation. To be eligible, participants needed good liver function (Child–Pugh class A) and a favorable performance status, indicating their overall health. They must have previously undergone one or two systemic anticancer therapies for advanced HCC, followed by radiographic progression, signifying that their cancer had continued to worsen despite prior treatments.

Two distinct groups of patients were included in the study: the prior-sorafenib cohort, comprising individuals who had previously received sorafenib treatment, and the sorafenib-naïve cohort, consisting of patients who had not undergone sorafenib treatment before.

All participants received a daily oral dose of 60 mg of cabozantinib, with the possibility of dose adjustments if needed. This standardized treatment aimed to evaluate the safety and effectiveness of cabozantinib in Japanese HCC patients, considering their treatment history and overall health.

By conducting this study, researchers sought to understand how cabozantinib, a multi-receptor tyrosine kinase inhibitor, would impact patients with advanced HCC who had already undergone previous treatments. The goal was to assess the drug’s potential benefits and its suitability for this specific patient population.

Assessment of Efficacy and Safety:

Efficacy and safety evaluations included progression-free survival and tumor response rates based on RECIST version 1.1 criteria. Progression-free survival measured the time from cabozantinib initiation to disease progression or death, with the primary endpoint being the 24-week progression-free survival rate. Objective tumor response rate and disease control rate assessed treatment efficacy. Safety was monitored using CTCAE version 4.03.

Statistical Analysis:

The analysis covered data until March 2021, encompassing all patients who received at least one cabozantinib dose. Progression-free survival and overall survival were analyzed using the Kaplan–Meier methodology. Tumor response rates, with 95% confidence intervals, were assessed. ALBI scores, calculated using serum albumin and bilirubin, helped evaluate liver function over time.


In this study, a total of 34 patients diagnosed with advanced hepatocellular carcinoma (HCC) were recruited from 17 clinical centers in Japan. All 34 patients participated in the study and were included in both the full analysis set and the safety analysis set. The baseline demographic and clinical characteristics of these patients were previously published. It’s worth noting that all patients had Child–Pugh class A disease, which aligns with the study’s inclusion criteria.

Regarding their prior medical history, 20 patients had undergone previous treatment with sorafenib (referred to as the prior-sorafenib cohort), while 14 patients had not received sorafenib treatment before (sorafenib-naïve cohort). Additionally, within these groups, some patients had prior experience with lenvatinib or immune checkpoint inhibitors.

The study commenced in August 2018 and concluded in December 2020. As of the primary analysis cutoff date in July 2019, six patients were still undergoing treatment with cabozantinib, with two in the prior-sorafenib cohort and four in the sorafenib-naïve cohort. However, all six patients eventually discontinued the study treatment. Among the prior-sorafenib cohort, both patients discontinued cabozantinib due to disease progression. In the sorafenib-naïve cohort, reasons for discontinuation included disease progression for two patients, study termination by the sponsor for one patient, and a physician’s decision for one patient.

The median duration of exposure to cabozantinib at the final database lock was 5.6 months, with a range of 0.8 to 23.0 months. Additionally, the median dose intensity was 35.9%, ranging from 13.1% to 74.8%.


The latest comprehensive examination of data from a phase II study involving Japanese patients with advanced hepatocellular carcinoma (HCC) has confirmed the effectiveness of cabozantinib therapy for this specific group of patients. Importantly, there were no new safety issues identified. When considered alongside the primary analysis, these findings collectively demonstrate the efficacy and manageable safety profile of cabozantinib for Japanese patients with advanced HCC, corroborating the results obtained from the CELESTIAL study in this patient population

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