How are targeted therapies used in lung cancer treatment?

Lung cancer is the third-most common type of cancer and the most common cause of cancer-related deaths in the United States, according to the National Cancer Institute. With numerous treatment advances in the last two decades, however, the outlook for patients with lung cancer has begun to look more hopeful.

May 2024 marked the twentieth anniversary of the discovery of the first lung cancer target for targeted therapy: epidermal growth factor receptor, or EGFR. “That opened the door to many landmark discoveries,” says thoracic/head and neck medical oncologist Lauren Byers, M.D. “Now, the first thing we do when we see patients who have been newly diagnosed with lung cancer is testing to determine what type of lung cancer it is and how we can personalize their treatment.”

Targeted therapies based on lung cancer type

There are two main categories of lung cancer:

• non-small cell lung cancer (NSCLC)
• small cell lung cancer (SCLC)

About 85% of patients diagnosed with lung cancer have NSCLC, while the other 15% have SCLC.

In non-small cell lung cancer, patients have alterations to their DNA, such as mutations or fusions, that affect specific genes. Therapies for NSCLC take advantage of this by targeting these problem genes, turning them off at the DNA level and stopping the growth of the cancer cells.

Patients with small cell lung cancer still have changes to their DNA, but the changes can’t be targeted in the same way as those in non-small cell disease. Still, that’s not to say that this type of cancer can’t be treated. “For small-cell lung cancer, it’s more about which genes are turned on and which ones are turned off,” says Byers. “For the genes that are turned on, we now have targets for those patients that are proteins on the surfaces of cancer cells.”

Non-small cell lung cancer targeted therapy options

For patients with newly diagnosed NSCLC, doctors will run tests to see what biomarkers they have. About 40% to 50% of patients with NSCLC have biomarkers that indicate they are candidates for targeted therapy. The biomarkers include alterations in these genes:

• ALK
• BRAF
• EGFR
• HER2
• KRAS
• MET
• NTRK
• PDL1
• RET
• ROS1

KRAS and EGFR are the most common types of mutations seen in patients with non-small cell lung cancer. Together, these mutations make up around 40% of all the alterations seen.

The frequency of other mutations varies, and certain mutations are more common in certain populations. “For example, EGFR lung cancers are more common in Asian patients, in never smokers and in females, whereas KRAS and BRAF are more common in people with a smoking history,” explains Byers.

Side effects of NSCLC targeted therapies

Doctors use different targeted therapy drugs to treat patients with different gene mutations. Because of this variety of drugs used, side effects can vary. The most common side effects are:

• skin rash or dryness
• changes to the nails
• irritation or inflammation
• mild diarrhea

All of these are very manageable, according to Byers.

As researchers develop newer versions of these drugs, the drugs become more specific. This means the drugs get better at affecting only cancer cells, not healthy cells. This means fewer side effects for patients receiving these drugs. For example, osimertinib, a newer EGFR inhibitor, has significantly fewer side effects than the original EGFR inhibitors developed 20 years ago.

Drug dosages can also be changed, notes Byers: “Just like we personalize the treatment, we can also adjust the dose for the individual patient to navigate that balance of having the best benefit but also managing their side effects.”

SCLC targeted therapy options

Historically, advances in treatment options for small cell lung cancer have lagged compared to non-small cell treatments, but recent breakthroughs are promising. “We think that targeting the surfaceome, which is the proteins that are on the surface of the cancer cell, will be a new way that we can develop more effective targeted treatments for patients with SCLC,” Byers says.

Researchers are using a different type of targeted therapy, antibody drug conjugates, to target the surfaceome. Antibody drug conjugates have two parts: a piece that finds and attaches to the proteins on the cancer cell surface and a chemotherapy drug. This allows chemotherapy drugs to be delivered directly to the cancer cells.

One ongoing clinical trial is testing an antibody drug conjugate that targets SEZ6, a cell surface protein found to be common in SCLC, and ABBV-706, an investigational drug. While results are very preliminary, Byers notes, “The number of patients who have had shrinkage of their SCLC tumors and the durability of the response so far have been unlike anything we’ve seen before.”

Lung cancer targeted therapy research is advancing

Lung cancer targeted therapy research is progressing in three significant ways.

First, researchers are tackling treating lung cancer at earlier stages. “These drugs were initially developed and approved primarily for patients with metastatic lung cancers, meaning advanced cancers that had already spread to other areas,” explains Byers. However, several recent clinical trials for patients with locally advanced, earlier-stage lung cancers are promising. “Adding targeted therapy to the traditional treatment of surgery or surgery and chemotherapy is providing a huge additional benefit for these patients.”

Second, scientists are developing next-generation versions of existing targeted therapies. “These next-generation drugs can expand the number of patients with lung cancer who may be able to benefit, and they can also provide a more durable benefit,” Byers notes. “They work even better, and because they’re so personalized to the cancer itself, they tend to have fewer side effects compared to either older drugs or more traditional treatments like chemotherapy.”

Lastly, breakthroughs in new treatment targets or in new types of drugs continue to expand patients’ choices. “Patients who currently have lung cancer or have been recently diagnosed with lung cancer will have more and more options over the course of their treatment,” says Byers.

For example, the first KRAS inhibitors were specific to one particular mutation in the KRAS gene: KRAS G12C. “Until now, there have been many patients with lung cancers that have a mutation in the KRAS gene but not the specific KRAS mutation that the first drugs were developed to target,” Byers says. Research into targeting other KRAS mutations will expand the number of patients who can benefit from targeted therapy.

The future of targeted therapies for lung cancer

“Progress is moving so quickly in terms of new discoveries and therapeutics,” Byers observes. “I’m taking care of patients today who often are benefiting from a drug that wasn’t even part of what we could offer at the time they were diagnosed.”

When she is in the clinic, Byers notes, “One of my favorite things is to hear from patients about what they’re looking forward to in terms of trips with their family or special celebrations that are coming up. It’s been really meaningful to see that the treatments are allowing them to get back to the things that matter.”

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