EGFR. ALK. BRAF. MET. NTRK. RET. ROS1. This may seem like what you see when you dump a box of Scrabble tiles on a table, but these letter combinations are actually the names of genes that — when mutated — drive the formation, growth, and spread of lung cancer.
In aggregate, mutations in these seven genes cause about one-third of all non-small cell lung cancers. And each of them has at least one drug designed to counteract them that’s been approved by the US Food and Drug Administration. For patients who are matched with one of these drugs, treatment tends to be much more effective than it is with chemotherapy, which kills not just cancer but all fast-growing cells. Additionally, targeted drugs usually have fewer side effects than other forms of treatment.
“Our goal is always to find the best treatment for every patient,” says Memorial Sloan Kettering medical oncologist Helena Yu, who specializes in evaluating targeted therapies for lung cancer. “But you don’t know what the best treatment is until you look at all the options, and you won’t know all the options until you do molecular testing.”
A History of Developing Molecular Tests
Nearly two decades ago — when the first drugs for EGFR mutations were being evaluated — researchers at MSK recognized that targeted therapy would be an especially important approach for people with lung cancer. This was because the drugs worked extremely well in a subset of patients. Also, many people stood to benefit because lung cancer is so common. Targeted drugs work by zeroing in on the activities of mutated proteins in cancer cells and shutting down the cells’ growth, mostly sparing healthy cells.
MSK researchers also understood how vital it was to examine tumor tissue and determine whether it contained the mutations that were being targeted. Studies had shown that EGFR drugs were quite effective in people whose tumors had EGFR mutations. Those whose tumors had other mutations would not benefit. (What happened is not uncommon in cancer drug development — when the trials of drugs targeting EGFR began, investigators didn’t know who would most benefit from them.)
In 2004, MSK was one of the first hospitals in the world to begin regularly testing people with non-small cell lung cancer for EGFR mutations. The development of this clinical test was led by molecular pathologist Marc Ladanyi.
In the years after that test was created, Dr. Ladanyi and his team in MSK’s Molecular Diagnostics Service have continued to roll out new molecular tests, including MSK-IMPACTTM, which expanded the benefits of molecular testing to all solid tumors. Today, this test can detect alterations in 505 cancer-related genes while requiring only one small piece of tissue. MSK-IMPACT was cleared as a tumor genetic profiling assay by the FDA in 2017. In 2019, MSK began using MSK-ACCESS, a tool that can detect mutations in 129 genes by analyzing just a small amount of blood. MSK-IMPACT and MSK-ACCESS enable doctors to match patients with drugs designed to target their tumors and provide them with many other details about a tumor’s genetics as well.
“When a patient comes to me with newly diagnosed, metastatic lung cancer, the first thing I do is order an MSK-ACCESS test for them,” Dr. Yu says. “We get the results within two weeks, and if their cancer cells contain one of these mutations, we can start them on a targeted therapy right away.” Because MSK-IMPACT requires a tissue sample, it may not be available to patients who received their biopsy and diagnosis at another hospital. But if enough tissue is left over from earlier tests, MSK-IMPACT can be used to confirm the diagnosis and provide further detail. “MSK-IMPACT is still the gold standard for molecular testing,” she adds.
Clinical Trials Lead to New Therapies
As leader of MSK’s Early Drug Development Service, medical oncologist Alexander Drilon has been at the helm of several clinical trials for targeted therapies that are now used to treat lung and other cancers. Recently, he led the clinical trial that resulted in the FDA’s approval of selpercatinib (RetevmoTM), which treats lung and thyroid cancers driven by a mutation called a RET fusion. Studies showed that among patients who had stopped responding to other drugs, 64% had their tumors shrink when treated with selpercatinib. For those who had never received chemotherapy or another treatment, the response was even higher — 85%.
MSK-IMPACT can detect mutations and other types of alterations in 505 cancer-related genes. The test requires only a small piece of tumor tissue and a blood sample.
MSK-ACCESS can detect mutations in 129 genes. The test requires two vials of blood.
“As more targeted therapies are developed, tests like MSK-IMPACT that look for many mutations at the same time have become so important,” Dr. Drilon said. “If you run individual tests for each mutation separately, you’ll exhaust the amount of the patient’s tumor tissue that’s available for analysis.”
Selpercatinib and other targeted therapies were initially approved to treat stage IV disease that could not be operated on — cancers that had spread beyond the lungs to other parts of the body. Investigators at MSK are now conducting studies to determine whether they can help people with less-advanced cancers. The drugs may be given before surgery, to shrink tumors and make them easier to remove, or after surgery, to destroy any cancer that may be left behind.
Unfortunately, many people can develop resistance to these drugs, and MSK researchers are now focused on developing new drugs that can take over when one targeted therapy stops working. MSK-ACCESS plays an important role here, too: Doctors can use blood tests to monitor the cancer and determine whether it has acquired additional mutations without having to conduct a surgical or needle biopsy to get another tissue sample.
Advancing the Search for New Drugs and New Targets
MSK investigators are also leading the way in the search for drugs that target mutations in other genes. In September 2020, medical oncologists Bob Li and Piro Lito published results from the first-ever trial for sotorasib, a drug that targets a mutation called KRAS-G12C. This mutation is found in about 10% of non-small cell lung cancers, most often in former or current smokers.
Dr. Li and Dr. Drilon are also conducting a trial to determine whether the drug trastuzumab deruxtecan (Enhertu®), which was approved for breast cancer in December 2019, is effective in treating lung cancers driven by genetic changes in a gene called HER2.
“You need really good sequencing tests to find all these mutations,” Dr. Drilon says. “As testing becomes cheaper and more and more drugs become available, the medical community needs to move toward a paradigm where every person with lung cancer receives molecular testing.”