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Lung Cancer

Targeted Therapies: Finding the Key to Managing Non–Small-Cell Lung Cancer

Targeted therapies for lung cancer are newer therapies designed to target specific types of genetic mutations found in some patients, and improve the response to treatment.
May 2018 – Cancer Biomarkers and Molecular Testing
Bruce Gershenhorn, DO
Medical Oncologist and Medical Director of the Lung Center, Midwestern Regional Medical Center, Cancer Treatment Centers of America (CTCA), Chicago, IL

Targeted therapies are a part of a new era in cancer treatment. These drugs are designed to block the growth or spread of cancer, either by preventing cancer cells from dividing and multiplying, or by destroying them altogether. To be able to manage cancer with a targeted therapy, we first need to understand what is driving the cancer (making it grow) at the molecular level.

With today’s advancements in cancer care, we are becoming smarter about how to identify this key driver in cancer development, and we’re finding more targeted therapies that may enhance a patient’s quality and length of life.

Before an oncologist can determine if a targeted therapy is appropriate for the specific type of cancer the patient has, we need to perform what is called “molecular profiling,” or a genomic tumor assessment. Typically obtained through a biopsy, molecular testing looks at the genes involved in the patient’s tumor to determine what is driving the cancer.

The Cancer Genome

Think of the cancer genome as an engine. You must understand the engine before you can identify the appropriate key to shut it off.

That is the goal of a genomic tumor assessment—to determine which treatment options, in this case targeted therapies, can shut down the cancer cells, by directly targeting the mutations (changes) involved in the cancer.

Genomic profiling does not relate to the patient’s hereditary genes or mutations, but rather it looks at mutations that occur within the patient’s cancer cell DNA. This understanding contradicts the theory that all lung cancer is the same and should be treated in the same way. Instead, it has demonstrated that (unlike inherited genetic changes) each patient has a specific mutation or mutations (also referred to as “biomarkers”) that are driving the growth of his or her individual cancer.

Targeted therapies may be administered intravenously or taken orally as pills. What makes targeted therapies so appealing is that unlike chemotherapy, which attacks all dividing cells (healthy and cancerous cells), these therapies are designed to stop the growth of cancer cells or eradicate them entirely without attacking the healthy cells. This also means targeted therapies tend to have less severe side effects than chemotherapy.

However, some patients do have side effects (rashes and dry skin, diarrhea, nail changes, blood clotting, or high blood pressure). Any side effects should be discussed with the patient’s medical oncologist; some supportive therapies may help to reduce their intensity.

Targeted Therapies for Non–Small-Cell Lung Cancer

Targeted therapies changed the face of non–small-cell lung cancer (NSCLC) care beginning in 2004, when the EGFR mutation was discovered. An EGFR mutation is present in nearly 10% to 15% of patients with NSCLC. At that time, the FDA approved the first targeted therapy Tarceva (erlotinib) for patients whose cancer METastasized (spread) to other parts of the body, and had failed at least one chemotherapy regimen.

Since then, we have learned that there is a specific population of patients for whom Tarceva worked extremely well (those with EGFR mutations), and other populations in which it did not work well. This means we are zoning in on the patients who would best benefit from the drug.

Fast forward to today, we now have 4 targeted therapies approved for EGFR mutations in NSCLC, including Tarceva, Gilotrif (afatinib), Iressa (gefitinib), and most recently, Tagrisso (osimertinib), which is the first therapy that targets the specific type of EGFR mutation known as T790.

Research has shown that cancer control rates have dramatically increased with these drugs. And today, these can be used as a first-line treatment, meaning patients don’t need to try chemotherapy first if they have an EGFR mutation.1

Throughout the years, researchers have continued to identify other genetic mutations in patients with NSCLC, such as ALK and ROS1 mutations, which may benefit from specific targeted therapies approved for those mutations, such as Xalkori (crizotinib). Several drugs have now been approved for NSCLC with ALK mutations, including Zykadia (ceritinib) and the 2 drugs that were approved in 2017—Alunbrig (brigatinib) and Alecensa (alectinib).

Furthermore, new targeted drugs were recently identified for NSCLC with BRAF or MET exon 14 skipping mutations. In January 2017, a study found that patients with NSCLC and a MET exon 14 mutation, which accounts for roughly 5% of all NSCLC cases, would potentially benefit from MET-inhibiting drugs.2 In this study, patients with NSCLC and the MET exon 14 mutation received Xalkori, which is currently approved for NSCLC with ALK mutations. Patients with the MET mutation responded favorably to Xalkori.2

In addition, in June 2017, the FDA approved the combination of Tafinlar (daBRAFenib) and Mekinist (traMETinib) for use together for patients with NSCLC who carry the BRAF V600E mutation, which was initially only identified with melanoma. This was the first type of combination therapy approved for patients with NSCLC and a BRAF mutation, which accounts for 1% to 2% of patients with NSCLC.3

Other targeted therapies available for patients with NSCLC are angiogenesis inhibitors, which block the cancer from growing or spreading through the blood vessels. The 2 angiogenesis inhibitors for NSCLC are Avastin (bevacizumab) and Cyramza (ramucirumab), and each is often used in combination with chemotherapy to achieve the best results.

What Does This Mean For You?

If you are a patient with NSCLC, you may be wondering what all this means for you. It means that every day, we are making progress in the battle against cancer, finding more treatments that may target your specific cancer. Based on the advancements made since 2004 alone, treatments have been identified for patients with NSCLC associated with a specific mutation that accounts for 10% to 15% of NSCLC cases. We are cutting into a larger slice of the pie as our understanding of targets rapidly expands.

This means that more patients are becoming eligible to use targeted therapies. In addition, as more targeted therapies are discovered, we are able to better control the cancer for longer periods without it progressing. These drugs are now often used as the first treatment, and they are improving patients’ quality of life thanks to their potentially reduced side effects.

For now, targeted therapies tend to work only for a certain period before the cancer is no longer stable (or not responding to treatment). In addition, currently, targeted therapies for lung cancer are only benefiting those diagnosed with NSCLC.

Research is ongoing in the search for biomarkers that could benefit from targeted therapies for patients with small-cell lung cancer. But again, as more advancements are made, and new clinical trials are conducted, more targeted therapies are being discovered to help us outsmart cancer.

We are also learning that some targeted therapies work best in combination with each other, or with other cancer therapies.

Genomic Testing

If you are diagnosed with NSCLC, tALK to your medical oncologist about genomic tumor profiling to identify any targeted therapies that may target your cancer’s specific DNA. The number of genes reviewed through a genomic test may vary from hospital to hospital.

At a minimum, I recommend testing all patients diagnosed with NSCLC for the EGFR, ALK, ROS1, BRAF, and MET mutations.

If you do not qualify for a targeted therapy currently approved by the FDA, also consider joining a clinical trial, which can often provide the medication for free during the study.

Keep in mind that if you don’t have one of these genomic mutations, you will not benefit from targeted therapies. Empower yourself with knowledge on your specific cancer type and the treatment options available to you.

The Power of Cancer Research

Targeted therapies have already changed the landscape of cancer treatment. For now, there is a strong focus on these cancer-causing DNA rearrangements (or biomarkers), and on determining how we can shut them down.

As we continue to get better at understanding the body’s immune system, we will likely be able to use these treatments to empower the body’s own immune system to target and kill cancer.

It is my hope that one day we will find the perfect key to manage every patient’s specific cancer as a chronic disease, through continued advancements, treatments, and new discoveries.

References

1. National Cancer Institute. FDA approval for erlotinib hydrochloride. 2013. www.cancer.gov/about-cancer/treatment/drugs/fda-erlotinib-hydrochloride.
2. Meetinglibrary.asco.org. Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC). 2017. https://meetinglibrary.asco.org/record/145462/abstract.
3. National Cancer Institute. FDA approves drugs for lung cancers with BRAF mutations. 2017. www.cancer.gov/news-events/cancer-currents-blog/2017/fda-trametinib-dabrafenib-lung-cancer.
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Last modified: June 26, 2018

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