Targeted Therapies for Stomach Cancer

If you have stomach (or gastric) cancer and are discussing treatment options with your cancer care team, you may have heard of targeted therapy. Your doctors may even recommend it as part of your treatment plan. While all this new information about targeted therapy can be overwhelming and difficult to digest, understanding how this type of treatment works is very useful. It will help you stay on top of medical discussions and prepare you for what to expect when receiving targeted therapy.

Targeted therapy is a type of cancer treatment that uses drugs specifically designed to identify and attack cancer cells while limiting damage to healthy cells. Targeted therapy is typically combined with systemic chemotherapy for the treatment of advanced gastric cancers such as stage 4 gastric cancer and cancers that come back after treatment (cancer recurrence).

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.

To find out if targeted therapy is suitable for you, your doctors will run some laboratory tests on your blood and tumor tissue samples. 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. Most of these drugs are monoclonal antibodies or small molecule drugs which are tiny enough to pass through the cell membrane and enter cancer cells.

There are various types of targeted therapy drugs used in the treatment of gastric adenocarcinomas, which are the most common type of gastric cancer. They include monoclonal antibodies, antibody-drug conjugates and multikinase inhibitors.

Monoclonal antibodies

Monoclonal antibodies are man-made versions of immune system proteins created in the laboratory. They work by attaching to proteins found on or in cancer cells which help the cells to grow. By interfering with these proteins, the monoclonal antibodies are then able to kill the cancer cells, slow down their growth or prevent them from spreading.

There are different types of monoclonal antibody drugs, including:

• Trastuzumab: Some gastric tumors produce excessive amounts of a protein called human epidermal growth factor receptor 2 (HER2) on the surface of their cells. These are called HER2-positive cancers, which are found in 10 to 15% of people with gastric cancer. HER2 proteins promote the growth of cancer cells by sending signals to these cells to grow and divide. Trastuzumab can attach to HER2 proteins and block its growth-stimulating effects.
  
• Ramucirumab: Ramucirumab is a monoclonal antibody drug used in anti-angiogenesis therapy. This type of cancer treatment is focused on inhibiting angiogenesis, which is the formation of new blood vessels. Angiogenesis plays a critical role in cancer progression because in order 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 can stunt your tumor’s growth and keep it from spreading.
  
  Gastric tumors release 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. While the full mechanism of VEGF inhibitors like ramucirumab remains debated, it is generally thought that these drugs work by inhibiting tumor angiogenesis and slowing the tumor’s growth.
  
• Zolbetuximab: Zolbetuximab is a monoclonal antibody drug that targets a protein called Claudin18.2. Claudin18.2 is a protein biomarker that is overexpressed in 14% to 87% of gastric cancers and can be found on the surface of malignant epithelial cells in the gastric mucosa. Zolbetuximab is able to bind to Claudin18.2 on the cancer cell surface of gastric epithelial cells and trigger cell death (apoptosis). The drug is currently being studied in multiple clinical trials, either as a monotherapy or in combination with other drugs, such as chemotherapeutic and immunotherapeutic agents. If approved, zolbetuximab would be the first Claudin18.2-targeted therapy available in America for patients with advanced or metastatic gastric or GEJ adenocarcinoma whose tumors are HER2-negative and Claudin18.2-positive. Find out more information about zolbetuximab here.

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are drugs formed when a monoclonal antibody is chemically linked to a chemotherapy drug. The antibody is responsible for delivering the chemotherapy agent to the cancer cells, which can then enter the cells to destroy them. As such, this form of cancer treatment works by combining the targeting properties of monoclonal antibodies with the potent cancer-killing capabilities of chemotherapy drugs.

Fam-trastuzumab deruxtecan is an ADC used to treat advanced HER2-positive gastric cancers for which initial trastuzumab treatment alone was not effective. This drug is made up of the monoclonal antibody trastuzumab linked to a chemotherapy agent called deruxtecan. When the antibody attaches to HER2 proteins on the surface of cancer cells, it delivers deruxtecan directly to these cells to carry out its cancer-killing function.

Tyrosine kinase inhibitors

Tyrosine receptor kinase (TRK) inhibitors 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 survival and angiogenesis.

The genes encoding these proteins belong to the neurotrophic tyrosine receptor kinase (NTRK) gene family, of which there are three members: NTRK1, NTRK2 and NTRK3. Rearrangements in the NTRK genes can lead to two genes fusing together and producing altered and abnormal TRKs that continuously send signals promoting those cellular processes. In this way, NTRK gene fusions can result in uncontrolled cell growth and ultimately cancer progression. Therefore, by targeting these kinases, NTRK inhibitors can inhibit the cancer-promoting signals they send out and stop the cancer cells from growing rapidly.

Two TRK inhibitors being studied in the treatment of gastrointestinal cancers are larotrectinib and entrectinib. These drugs target three TRKs that are encoded by the NTRK gene family. The NTRK inhibitors larotrectinib and entrectinib are currently only approved to target NTRK gene fusions, which are extremely rare.

The field of cancer research continues to look into specific molecular targets that could potentially be used in targeted therapies for gastric cancer. Different drugs — some of which are already used to treat other cancers and some which are new — are also being developed and tested in clinical trials to determine if they can be utilized in this type of cancer treatment. If you have any questions regarding targeted therapy and how it can help in the treatment of your gastric cancer, please talk to your doctors and cancer care team.