Targeted Therapies

Cancer cells are different from normal cells. Many cancer cells have mutations that cause them to grow and survive when normal cells would not. Uncontrolled cell growth is what leads to cancer.

Targeted therapies aim at the features that make cancer cells different. They offer a unique treatment option for certain skin cancers.

What is a cell?

Cells are the building blocks for your body.^1,2 They do your body’s work. They provide structure. They turn nutrients into energy. They perform specialized jobs.

A membrane (outer lining) surrounds the cell. Inside the cell are many different organelles (special structures) that do the cell’s work. The nucleus is the cell’s command center. The nucleus contains the DNA. DNA has the instructions (genes) for making different proteins.

Figure 1. Cell structure

How does normal cell signaling work?

There are receptors within the cell membrane. Part of the receptor may stick out of the cell (“extracellular domain”). Part of the receptor may stick into the cell (“intracellular domain”).

Receptors receive chemical signals from outside the cell. Examples of chemical signals are hormones, growth factors, or cytokines. The chemical signal binds with (plugs into) the receptor. Binding activates (turns on) the receptor. The activated receptor changes within the cell. Proteins may move toward the receptor and activate other proteins.

These proteins pass signals from one to the other, like a game of telephone. Eventually, the signal gets to the nucleus. In the nucleus, the instructions for building a protein are copied from the DNA. Other parts of the cell assemble the protein.

In normal cells, there are “on” and “off” switches for these chains of events. A pathway only becomes active as needed.

Cancer develops when there are harmful changes in DNA. These harmful changes are called mutations. For example, a mutation can lead to a receptor that stays active all the time, instead of turning “on” and “off” as appropriate.

Figure 2. Basic cell signaling

How is targeted therapy used to treat skin cancer?

Targeted therapies are available to treat some types of skin cancers. Specifically, targeted therapies treat:

• Advanced melanoma with BRAF mutation
• Advanced melanoma with c-KIT mutation
• Advanced basal cell carcinoma (BCC)

What targeted therapies treat advanced melanoma with BRAF mutation?

Targeted therapies have improved outcomes for people with advanced melanoma. Advanced melanoma may generally be defined as cancer that:

• Has spread to distant parts of the body (metastasized) or
• Cannot be treated with surgery (unresectable)

Approximately one-third of melanomas have mutations in the gene (instructions) for a protein called BRAF.³ BRAF is a protein in the MAPK (or ERK) pathway, which is involved in the cell's growth. BRAF mutations can cause cancer cells to grow uncontrollably. Today, there are several medications for advanced melanoma with BRAF mutation, including:

• Tafinlar® (dabrafenib)
• Zelboraf® (vemurafenib)
• Mekinist® (trametinib)
• Braftovi™ (encorafenib) (which is used in combination with Mektovi® (binimetinib)
• Dabrafenib and trametinib may also be used in combination (In addition to treating advanced melanoma, this combination may also be used as adjuvant (additional) treatment for certain forms of melanoma after the melanoma has been surgically removed in people with disease in the lymph nodes)
• Cotellic® (cobimetinib) - which is used in combination with Zelboraf® (vemurafenib)
• Cotellic® (cobimetinib) and Zelboraf® (vemurafenib) targeted therapies may be used in combination with Tecentriq® (atezolizumab) immunotherapy

These medications have slightly different uses. The BRAF and MEK inhibitors treat certain forms of melanoma with the BRAF V600E mutation.^4-6 V600E is the most common type of BRAF mutation in melanoma. Most of these medications may also be used to treat some forms of melanoma with the BRAF V600K mutation.⁵ Medications that target BRAF gene mutations in certain forms of melanoma improve response rates, progression-free survival, and overall survival.^6,7 They have somewhat different side effects.

MEK is a protein that is further along the MAPK pathway. Medications that target MEK include:

• Cotellic® (cobimetinib)
• Mekinist® (trametinib)
• Mektovi® (binimetinib)

Certain MEK inhibitors may be taken by themselves, but when taken this way, MEK inhibitors may not work for some patients.⁷ That is why these medications are often paired with a BRAF inhibitor:

• Tafinlar/Mekinist
• Zelboraf/Cotellic
• Braftovi/Mektovi

What targeted therapies treat advanced melanoma with c-KIT mutation?

National cancer guidelines suggest Gleevec® (imatinib) as one option for advanced melanoma with c-KIT mutation.⁷ This use of Gleevec is not approved by the Food and Drug Administration.⁸ Nevertheless, it may be an option when other treatments are not working.⁷

The c-KIT receptor kick starts several different signaling pathways. Up to 20% of acral or mucosal melanomas have c-KIT mutations.⁹ These are types of melanoma that are not related to sun exposure.

Another medication that targets c-KIT gene mutations is named Tasigna® (nilotinib). It is approved to treat certain forms of blood cancer but not melanoma, although it may be a treatment option in some cases of melanoma.

What targeted therapies treat advanced basal cell carcinoma?

Surgery is more effective than targeted therapy for BCC. Targeted therapies have serious risks and side effects. Therefore, medication is typically only used when surgery or radiation are no longer options.¹⁰

Two medications called SMO inhibitors treat certain forms of advanced BCC:

• Odomzo® (sonidegib)
• Erivedge® (vismodegib)

SMO is short for “Smoothened.” SMO is a receptor in a cellular signaling pathway called the Hedgehog pathway. About 40% of BCC have mutations that cause an overactive Hedgehog pathway.¹¹

The approved uses for these two medications are slightly different. Erivedge treats metastatic and locally advanced BCC.¹² Odomzo treats locally advanced BCC only.¹³

Both medications carry a serious risk of birth defects and stillbirth. Other common side effects of these medications include muscle spasms, hair loss, and taste changes. The label for Odomzo includes a warning about rare but serious muscle injury.¹³