Lung cancer is not a single, homogeneous disease. Lung tumors can form in different types of cells in the lung, which drives how they grow and divide. Furthermore, some tumors have very specific molecular changes (mutations) that cause cancer cells to grow, divide and spread. Targeted therapies effectively treat some of these mutations in patients with advanced lung cancer.
The two primary types of non-small cell lung cancers (the majority of lung cancers) are adenocarcinomas and squamous cell carcinomas. Although smoking is a significant risk factor for both types – and about 85 percent of all lung cancers occur in people with a current or prior history of smoking – individuals who’ve never smoked tend to develop adenocarcinomas. Targeted therapies treat advanced adenocarcinomas in these never-smokers who have one of several identified mutations.
Targeted therapies are now a huge part of treatment for NSCLCs, especially if you include immunotherapy, says Dr. Nathan A. Pennell, director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Center. “About half of [qualifying] patients are now getting targeted therapy instead of chemotherapy,” he says. “This a revolutionary change in treatment.”
As part of the diagnosis and staging process for new lung cancer patients, pathologists test a sample of their tumor to see if it has any of these identified biomarkers and to determine if one of the targeted therapies is likely to work or not, Pennell says.
So far, the U.S. Food and Drug Administration has approved targeted therapies for three mutations – EGFR, ALK and ROS1– in advanced-stage adenocarcinomas, says Dr. Cardinale Smith, an associate professor at Mount Sinai Health System who specializes in hematology and medical oncology, among other topics.
According to the National Cancer Institute, about 10 to 15 percent of NSCLCs are associated with mutations in the epidermal growth factor receptor gene. There are eight or more mutations in the EGFR gene in lung cancers, and they usually occur in adenocarcinomas in people who’ve never smoked. EGFR promotes cell growth; however, a class of drugs called EGFR inhibitors target these mutations. Another 5 percent or so of NSCLCs have changes in the ALK or ROS1 genes.
Targeted therapies do well for one thing: targeting a specific gene or mutation in patients with stage 4 (metastatic) lung cancers. They’ve extended life for patients with cancers that were previously untreatable. The current approved targeted therapies are already about 20 percent more effective than chemotherapy, Pennell says. However, they only work in people with these specific mutations.
As Smith says: “Chemotherapy kills all cells that are growing fast, including some healthy cells. The advantage of targeted therapies is that they are specific, so the side effects tend to be less.”
That said, targeted therapies still do have side effects. For EGFR inhibitors, most of the side effects occur in cells that have receptors for the EGF protein, which tend to be on the skin and gastrointestinal tract (epidermal means skin). For example, patients taking EGFR inhibitors may develop a rash on their face.
The bigger problem with targeted therapies is that patients’ tumors develop resistance to them so they no longer work, Smith says. “Cancers tend to respond to targeted therapy for about one year before they start to grow again.” Once you become resistant to a certain targeted therapy, your doctor will try another, newer medication. Sequentially offering the latest generation of medications can significantly extend the life of patients with advanced disease.
“People who are qualifying for targeted therapies can expect to live several years instead of one year or less,” Pennell says. He has patients with advanced lung cancer who have lived more than six years by participating in clinical trials for new targeted therapies. Many of these experimental drugs go on to be approved by the FDA. “For people who have incurable cancer, we can turn it into a chronic disease,” he says. “[Patients] live the rest of their natural life with cancer.”
Testing patients’ tumors is critically important, Pennell says. “Targeted therapies only work if you have a target. Everyone should be tested [for genetic mutations]. If you’re just getting chemotherapy, you may be missing out on lifesaving treatment.”
While these targeted therapies are helping a subset of patients with advanced lung cancer, there are clinical trials that are evaluating whether targeted therapy will also help patients with early stage lung cancers. The ALCHEMIST trial, for example, is studying whether targeted therapies will help prevent tumors from returning in people with early stage cancers who’ve had surgery to remove their tumors. According to the National Cancer Institute, even after successful treatment, people with early stage lung cancers have a 50 percent likelihood their cancer will come back.
If you have lung cancer, ask your doctor if you qualify for any clinical trials.
