Targeted Therapy for Gastrointestinal Stromal Tumors (GISTs)

As part of your treatment plan for GIST, your doctors may recommend targeted therapy. It is important to learn about this treatment option before starting it, as it can help you better understand what to expect and communicate more effectively with your cancer care team. By doing so, you will be prepared for what lies ahead and can have a smoother journey towards recovery.

GISTs are a rare type of soft tissue sarcoma — a general term for cancers beginning in connective tissues surrounding and protecting organs of the body. While these tumors can occur anywhere along the gastrointestinal (GI) tract, most begin in the stomach and small intestine. GISTs originate from specialized cells called the interstitial cells of Cajal (ICCs) found in the muscularis propria layer of the GI wall. Known as the ‘pacemaker’ cells of the gut, ICCs are responsible for sending signals to trigger muscular contractions that move stomach food and liquid along the digestive tract (peristalsis).

GISTs are mostly indolent (slow-growing), and usually smaller than 2 cm. In these cases, they are quite unlikely to spread to other regions of the body and are typically not life-threatening. On the other hand, fast-growing and larger GISTs, especially those above 5 cm, are at a higher risk of growing into nearby tissues and spreading to other organs.

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. It targets the specific genes, proteins and tissue environments that are unique to GISTs and play a vital role in their uncontrolled growth and survival. By inhibiting these targets, drugs used in targeted therapy can interfere with and stop the cancer’s growth and spread within the body.

For GISTs, the targets of these drugs are usually proteins called tyrosine kinases, which are found inside or on the surface of tumor cells. Tyrosine kinases send signals that promote cellular processes such as cancer cell growth and survival, angiogenesis and tumor invasion and metastasis, which encourage cancer progression altogether.

Approximately 90% of GIST cases have mutations (changes or abnormalities) in either of two genes: c-KIT and platelet-derived growth factor receptor alpha (PDGFRA). These respective genes provide instructions for the production of KIT and PDGFRA proteins, both of which function as tyrosine kinase receptors involved in cell growth. These receptors have an outer part that interacts with substances outside the cell and an inner part that works inside the cell, helping to transmit signals to promote cell growth.

If the c-KIT or PDGFRA genes are mutated, this can cause the receptors to be active permanently, leading to uncontrolled cell growth that contributes to the development of cancer.

As abnormalities in the c-KIT and PDGFRA genes are associated with the growth of most GISTs, drugs used to treat this type of cancerous tumor work by targeting KIT, PDGFRA and/or other tyrosine kinases to block the cancer-stimulating signals they send out. This helps to slow or stop the GIST cells from growing and dividing uncontrollably. The targeted drugs used in the treatment of GISTs are therefore known as tyrosine kinase inhibitors (TKIs) and include imatinib, sunitinib, regorafenib, ripretinib and avapritinib.

Imatinib

More commonly known by its commercial name Glivec, imatinib targets both the KIT and PDGFRA tyrosine kinases (among other tyrosine kinases) and inhibits their ability to stimulate cancer growth and survival. Therefore, to determine if your tumor will respond to imatinib, your doctors are likely to test the tumor cells for mutations in the c-KIT and PDGFRA genes.

Imatinib is typically used as first-line treatment for advanced GISTs that have metastasized and cannot be surgically removed. While it may not cure the tumors, imatinib can help shrink or slow tumor growth for several years. If the drug no longer works and the tumor begins to grow again, increasing the dose of imatinib may help with controlling cancer growth, but this can result in further side effects

Imatinib can be used with surgery to treat resectable tumors under certain circumstances, which include:

• Neoadjuvant therapy: Imatinib can be given before surgery, with the aim of shrinking the GIST so that it is easier to remove during the procedure. This is called neoadjuvant therapy.
• Adjuvant therapy: Imatinib administered after surgery is known as adjuvant therapy. The aim of adjuvant therapy is to kill any remaining cancer cells that were not visible during the procedure and subsequently left behind. This can happen for larger GISTs that have grown into nearby tissues. Adjuvant therapy therefore reduces the likelihood of the tumor coming back, which is known as cancer recurrence. Imatinib is usually given for at least three years after a GIST has been completely removed by surgery. However, if there is a higher risk of your tumor returning, your doctors may recommend taking imatinib for at least three years post-surgery. The chances of cancer recurrence depend on the size of the GIST and how quickly it was growing.

Imatinib comes in the form of a pill that is taken orally once or twice a day. While it does cause some common side effects such as nausea, fatigue and diarrhea, these are often successfully managed with dose adjustments or other medications. There are more serious side effects associated with the use of imatinib, including high blood pressure and inflammation of the liver. However, these are relatively rare.

Sunitinib

Sunitinib is often used to shrink or slow the growth of metastatic GISTs that no longer respond to imatinib. You may also receive sunitinib if the side effects you are experiencing from imatinib are too severe and your doctors want to try another drug.

Apart from KIT and PDGFRA, this drug blocks the action of many other tyrosine kinases to effectively shrink the tumor or stop its growth and survival.

Similar to imatinib, sunitinib is taken orally once a day in the form of a pill. Common side effects include diarrhea, nausea and mouth irritation while some more serious side effects are swelling and high blood pressure.

Regorafenib

Regorafenib is a TKI typically used to treat advanced GISTs that no longer respond to imatinib and sunitinib and have progressed after treatment with these drugs. You may also receive regorafenib if the side effects you are experiencing from both imatinib and sunitinib are too severe and your doctors want to try another drug.

This drug inhibits multiple tyrosine kinases that play crucial roles in stimulating the growth and survival of GISTs, including KIT and PDGFRA. A notable tyrosine kinase targeted by regorafenib is vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 promotes tumor angiogenesis when bound to its partner protein, vascular endothelial growth factor (VEGF), which is released by most GIST cells. Therefore, by blocking the effect of VEGFR2, regorafenib is able to prevent tumor angiogenesis, which essentially “starves” the tumor and slows or stops its growth.

Similar to imatinib and sunitinib, regorafenib comes in the form of a pill that can be taken orally once a day. Common side effects of regorafenib include fatigue, diarrhea and abdominal pain while more severe side effects include bleeding, infections and high blood pressure.

Ripretinib

Ripretinib is a fourth-line treatment for advanced GISTs. It is used if other TKIs, like imatinib, sunitinib and regorafenib, are no longer working and have not stopped the growth and spread of the GIST. You may also receive regorafenib if the side effects you are experiencing from those three drugs are too severe and your doctors want to try another drug.

This drug targets multiple tyrosine kinases, including KIT and PDGFRA, to shrink GISTs or slow their growth.

Like other TKIs, ripretinib is administered in the form of a pill that is taken orally once a day. Common side effects of ripretinib include fatigue, nausea and diarrhea. Rarer but more severe side effects include heart problems and high blood pressure.

Avapritinib

If your doctors find out during laboratory tests that your tumor cells have a certain mutation in the PDGFRA gene known as an exon 18 D842V mutation, you will likely be recommended a TKI called avapritinib.

Avapritinib is primarily used to treat advanced GISTs whose cells have this specific gene mutation. These tumors typically do not respond well to traditional TKIs like imatinib, sunitinib, regorafenib and ripretinib and avapritinib is the only known drug that has exhibited clinical activity against this uncommon mutation.

Apart from targeting tumors with the PDGFRA exon 18 D842V gene mutation, avapritinib also blocks the action of other tyrosine kinases, such as KIT.

This drug is taken as a pill orally once a day. Common side effects of avapritinib include fatigue, nausea, diarrhea and fluid accumulation. Less common but more severe side effects include bleeding in the brain and problems with attention, memory or thinking. However, this can be managed with an adjustment of the treatment dosage as necessary.

Other tyrosine kinase inhibitors

If your tumors no longer respond to the targeted drugs mentioned above, your doctors may recommend other TKIs, such as sorafenib, nilotinib, dasatinib and pazopanib, that are currently being studied in clinical trials. While it is unclear how helpful these drugs are against GISTs, they may be good options to consider.

If you have any questions regarding targeted therapy and how it can help your treatment, please talk to your doctors and cancer care team. They may run some laboratory tests on your tumor tissue samples to find out if targeted therapy is suitable for you and if it is, which targeted therapy drug would be most effective in the treatment of your GIST.