- Liver cancer is a common cause of cancer death worldwide. Hepatocellular
carcinomas comprise most of the liver cancers.
- Hepatitis B and C, liver cirrhosis, and other liver abnormalities are the most common
risk factors for HCC.
- Several signaling pathways are overexpressed or activated in HCCs. Moreover, gene
signatures associated with poor prognosis are observed in advanced-stage HCC with
higher levels of alpha-feta protein (AFP).
- Sorafenib is the first-line of treatment in HCC, which inhibits multiple receptor
tyrosine kinases like VEGFR1–3, PDGFR, KIT, and RET.
- As most HCCs are diagnosed at a late stage, there is a need for newer therapeutics
following sorafenib. The changing treatment landscape has introduced more systemic
therapies like Cabozantinib.
- Cabozantinib is a multiple receptor tyrosine kinases (RTKs) inhibitor.
- The review discusses the use of Cabozantinib in advanced HCCs previously treated
- Cabozantinib inhibits several RTKs like hepatocyte growth factor receptor MET,
VEGFR-1, -2 and -3, AXL, FLT-3, KIT, MER, RET, ROS1, TIE-2, TRKB, and
TYRO3, which have a role in angiogenesis, oncogenesis, tumor growth, and
- It has anti-angiogenetic and anti-proliferative properties and promotes apoptosis.
- Cabozantinib had high efficacy in HCCs with MET phosphorylation.
- Sorafenib targets VEGFR but not MET and increases the metastatic burden. On the
contrary, Cabozantinib targets both VEGFR and MET and inhibits lung and liver
metastasis, indicating the role of upregulated MET in metastasis.
- The drug exposure increased dose-proportionally. A capsule dose is recommended
without food to increase the exposure to the drug.
- It was observed that a mild hepatic impairment did not affect the exposure to the drug.
On the other hand, moderate hepatic impairment requires dose adjustment. Similarly,
patients with severe renal or hepatic damage are not recommended Cabozantinib.
- Cabozantinib being a substrate of CYP3A4 is not combined with drugs inducing or
inhibiting the activity of CYP3A4. Similarly, Cabozantinib is a substrate of MRP2,
indicating caution for drugs that induce this transporter.
Efficacy Of Cabozantinib:
- The review discusses the results of the phase III CELESTIAL trial, which assessed
the efficacy of Cabozantinib.
- The trial enrolled patients with disease progression and advanced HCC who had
received at least 1 prior systemic therapy, sorafenib.
- Cabozantinib significantly improved the OS and the PFS as compared to the placebo.
- The objective response rate in the Cabozantinib was better than in the placebo group.
- The disease control rate of Cabozantinib was twice that of placebo.
Cabozantinib-associated side effects
- Although a greater number of patients receiving Cabozantinib discontinued treatment
because of the associated side-effects, the toxicity of Cabozantinib was manageable
with dose reductions and supportive care.
- Diarrhea, decreased appetite, palmar-plantar erythrodysesthesia (PPE), fatigue,
nausea, hypertension, vomiting, increased AST level and asthenia were common in
the Cabozantinib group.
- Grade 5 AEs were seen in 1.3% of the Cabozantinib patients. These side effects were
mostly bronchoesophageal fistula, upper gastrointestinal (GI) hemorrhage, hepatic
failure, portal-vein thrombosis, pulmonary embolism, and hepatorenal syndrome.
- The trial suggested close monitoring of patients receiving Cabozantinib.
- The recommended dose of Cabozantinib after sorafenib is 60 mg once daily without
- Although sorafenib remains to be the most common therapy in advanced HCC
patients, new treatments have paved their way in its clinical management.
- Most drugs including second-line regorafenib, Cabozantinib, nivolumab,
pembrolizumab are RTK inhibitors. Cabozantinib is the most recently approved drug
in the treatment of advanced HCC.
- Cabozantinib has shown clinical activity against RTKs (MET and AXL) which are
associated with poor prognosis.
- Based on the results of the trials, it is now integrated as a second-line of treatment in
patients with advanced HCC.
- Regorafenib is also approved for patients with disease progression and prior sorafenib
- Comparison between the efficacy and safety of Cabozantinib and regorafenib can be
undertaken in the future. Furthermore, Cabozantinib can be assessed in patients with
- The cost-effectiveness of Cabozantinib is unclear. However, it has emerged as an
effective therapeutic in HCC patients with sorafenib treatment.