Targeted Therapy for Liver Cancer Treatment

Targeted therapy for liver cancer treatment uses drugs specifically designed to identify and attack cancer cells while limiting damage to healthy cells. It is sometimes used together with traditional chemotherapy or immunotherapy to treat liver cancer.

Targeted therapy works by targeting the specific genes, proteins and tissue environments that are unique to cancer cells and play a vital role in their uncontrolled growth and survival. In this way, targeted therapy interferes with and stops the cancer’s growth and spread within the body.

Specifically for bile duct cancer (cholangiocarcinoma), your doctors might run some laboratory tests on your blood and tumor tissue samples to find out if targeted therapy is suitable for you. Known as biomarker testing, the purpose of this is to identify any genes, proteins or other characteristics of your cancer cells that can be specifically targeted by drugs used in this type of cancer treatment. In this way, you will be matched with the type of targeted therapy that is most effective for you.

Targeted therapy drugs are typically administered every two to three weeks as an infusion into your veins (intravenously) during outpatient visits to your hospital or cancer center, or can be administered orally (pills). When it comes to liver cancer, doctors are looking more towards targeted therapies as opposed to chemotherapy, which may not be very effective in people with liver cancer. On top of that, because targeted drugs are fine-tuned to attack cancer cells only, healthy tissue can be spared from damage.

There are various types of targeted therapy drugs used in the treatment of liver cancer. They include monoclonal antibodies and tyrosine kinase inhibitors.

Tyrosine kinase inhibitors

Tyrosine receptor kinase inhibitors (TKIs) are small-molecule drugs that target specific proteins called tyrosine receptor kinases (TRKs), which can be found inside or on the surface of cancer cells. These proteins are implicated in multiple cellular processes such as cell growth and tumor angiogenesis. In liver cancer, there may be an overexpression of TRKs or their activity is upregulated. This, in turn, leads to uncontrolled cell growth and ultimately cancer progression. Therefore, by targeting these kinases, TKIs can inhibit the cancer-promoting signals they send out and stop the cancer cells from dividing rapidly and forming new blood vessels.

Many of the targeted drugs used in liver cancer treatment are TRKIs, which include:

• Sorafenib: This drug is typically used for liver cancers that cannot be treated with surgery or have spread to other parts of the body. It is taken twice daily as a pill. Do take note that your liver must be functioning (Child-Pugh class A) to take sorafenib.
• Lenvatinib: Lenvatinib is used in a similar way to sorafenib, but apart from a functioning liver, you need to be well enough to carry out normal activities (performance status of 0 or 1).
• Regorafenib: This drug is used for advanced liver cancer, usually if other treatments are no longer effective. Similar to lenvatinib, your liver must be functioning normally (Child-Pugh class A), and you need to be well enough to carry out normal activities (performance status of 0 or 1). It is given as a pill that is taken once daily for three weeks, followed by a week off the pill.
• Cabozantinib: Similar to regorafenib, cabozantinib is used to treat advanced liver cancer that no longer responds to other treatments. It is also taken orally once a day.
• Pemigatinib and futibatinib: These TKIs are used specifically in the treatment of previously treated bile duct cancer that has spread or cannot be removed with surgery. It works by targeting a TRK called fibroblast growth factor receptor 2 (FGFR2), which should be found mutated in the tumor for these drugs to be effective. Pemigatinib is taken as a pill, once daily for 14 consecutive days, followed by a week off the pill, while futibatinib is taken continuously.
• Ivosidenib: This inhibitor is used specifically in the treatment of previously treated bile duct cancer that has spread or cannot be removed with surgery. It works by targeting the gene called IDH1, which should be found mutated in the tumor for ivosidenib to be effective.
• Larotrectinib and entrectinib: Some TRK proteins are produced by a group of genes known as neurotrophic tyrosine receptor kinase (NTRK) genes. Rearrangements in the NTRK genes can lead to two genes fusing together and producing altered and abnormal TRKs that continuously send signals, resulting in uncontrolled cell growth and ultimately cancer progression. These two drugs target NTRK gene fusions, which are rare. Therefore, by targeting these kinases, NTRK inhibitors can inhibit the cancer-promoting signals they send out and stop the cancer cells from growing rapidly.

Monoclonal antibodies

Monoclonal antibodies are man-made versions of immune system proteins created in the laboratory. Those used in the treatment of liver cancer work by attaching to proteins found on or in cancer cells and interfering with tumor angiogenesis. Angiogenesis plays a critical role in cancer progression because, to grow and develop, tumors require a constant supply of oxygen and nutrients that are delivered by blood vessels. Therefore, by preventing the cancer from making new blood vessels, this treatment starves the tumor of the resources it needs to grow, which can stunt tumor growth and spread.

The monoclonal antibody drugs used in liver cancer treatment are:

• Bevacizumab: This monoclonal antibody drug targets a protein called vascular endothelial growth factor (VEGF), which binds to a different protein known as VEGF receptor 2 (VEGFR2) on the surface of cancer cells. This interaction signals the cancer cells to initiate angiogenesis and thus stimulates cancer growth. Bevacizumab works to inhibit the interaction between the two proteins for anti-angiogenesis. It is typically used in conjunction with the immunotherapeutic atezolizumab as a first-line treatment for liver cancer that cannot be treated with surgery or has spread to other bodily organs. It is administered as an infusion into your vein (intravenous), usually once every three weeks. For you to receive bevacizumab and atezolizumab, your liver must be functioning normally (Child-Pugh class A), and you need to be well enough to carry out normal activities (performance status of 0 or 1).
• Ramucirumab: This drug works similarly to bevacizumab in that it blocks the interaction between VEGF and VEGFR2, but instead of VEGF, it targets the VEGFR2 protein on the surface of cancer cells. It can be used for advanced liver cancer, usually after another type of treatment is no longer effective. Ramucirumab is administered via an infusion into your vein (intravenous), typically once every two weeks.
• Zanidatamab: This drug works by blocking the activation of the HER2 receptor. It could be used in cancer of the bile duct when this receptor is overexpressed or the gene amplified. Zanidatamab is administered via an infusion into your vein (intravenous), typically once every three weeks.

The side effects of targeted therapy for liver cancer vary greatly depending on the drugs. Some common side effects of targeted drug therapy are:

• Fatigue
• Loss of appetite
• Hand and foot syndrome
• High blood pressure
• Weight loss
• Diarrhea
• Abdominal pain
• Increased risk of infections (due to low white blood cell counts)
• Headaches
• Mouth sores

Rare but more severe side effects include:

• Problems with blood flow to the heart (e.g., blood clots)
• Severe bleeding
• Abnormal thyroid tests
• Perforations in the stomach or intestines
• Slow wound healing

Your doctor(s) will usually provide you with medication to manage some of the more common side effects. But if these problems grow more severe or if they do not resolve, do inform your healthcare providers.

Your doctors will take into account several factors when deciding whether you should receive targeted therapy as part of your treatment plan. These include the type of liver cancer you have, the cancer’s stage, analysis of your tumor and other factors, like your overall health. In general, targeted therapy is used to treat advanced liver cancer and/or liver cancer that cannot be treated with surgery (because the tumor is too large or too close to major blood vessels). While it may not be able to cure the cancer, targeted drugs can help control tumor growth, slow cancer progression and improve overall survival.

If you have any questions regarding targeted therapy and how it can help in the treatment of your liver cancer, please talk to your doctors and cancer care team.