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Study Identifies MET Amplification as a Driver for Some Non–Small Cell Lung Cancers


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A study published by D. Ross Camidge, MD, PhD, and colleagues in the Journal of Thoracic Oncology has helped to define MET amplification as a rare but potentially actionable driver for non–small cell lung cancer (NSCLC).

Dr. Camidge said many of the major developments in the treatment of NSCLC have come from defining molecularly specific subsets of the disease for which researchers have been able to develop targeted treatments. Until now, all these subsets have been based on either genetic mutations or gene rearrangements.

D. Ross Camidge, MD, PhD

D. Ross Camidge, MD, PhD

"What we've started to realize is that NSCLC isn't just one disease," said Dr. Camidge, Director of Thoracic Oncology at the University of Colorado School of Medicine and member of the CU Cancer Center. "Over the last 15 or so years, we've started to pull apart separate diseases within that umbrella. Now, there are at least eight different molecularly specific subtypes with an FDA-approved therapy."

Gene Amplification as Cancer Driver

The new report introduces a third means of defining NSCLC subsets that can be targeted with a specific drug. Rather than a mutation or a gene rearrangement, this third category represents oncogene activation through gene amplification. Gene amplification occurs when there is an increase in the usual number of copies of a particular gene, but the process can be difficult to identify.

"Unlike gene mutations or gene rearrangements—which are either there or not—gene amplification is a continuous variable," said Dr. Camidge. "How many extra copies do you need for it to make a difference? Is it an increase in just that one gene because it's so important to the cancer, or is it being dragged along for the ride by an increase in lots of other genes in the same part of the chromosome? Where do you put the cutpoint to say this level matters and this level does not? That's why identifying gene amplification as a definable driver of NSCLC has been challenging."

For this study, Dr. Camidge and colleagues focused specifically on MET amplification. MET is a gene that encodes a protein normally involved in cell growth. Although it is normally well controlled, it can become dysregulated and drive some cancers' behavior. This can sometimes occur as a result of genetic mutations or gene rearrangement, but it can also occur through gene amplification.

If MET amplification is a cancer driver in some patients, then it stood to reason that inhibiting MET could slow or stop the progression of NSCLC in those patients.

Efficacy of Crizotinib

To test that theory, the study required hospitals and cancer centers to screen tumor samples from patients with NSCLC for MET amplification using fluorescence in situ hybridization (FISH). During the study, a total of 88 patients with varying levels of MET amplification received crizotinib. Although crizotinib is currently licensed as an ALK and ROS1 inhibitor for the treatment of some other subtypes of NSCLC, it is also a MET inhibitor.

The results showed that patients with the highest levels of MET amplification responded to therapy with crizotinib at the highest rates, experiencing longer periods of progression-free survival, whereas patients with lower levels of MET amplification responded less favorably to the treatment.

The study, which started in 2006, is one of the largest efforts to define the relevant diagnostic test for meaningful levels of MET gene amplification and prove that MET inhibitors are effective for treating patients with NSCLC driven by MET amplification.

"It has been a long and difficult course for this rare subtype of lung cancer, but I think this is fairly good proof that there are some patients where MET amplification alone is driving their cancer," said Dr. Camidge says.

It's not your classic driver oncogene subtype. It tends to break most of the rules we normally associate with driver oncogenes.
— D. Ross Camidge, MD, PhD

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Making the Case for MET Amplification Testing and Therapies

Dr. Camidge said that MET amplification-driven NSCLC is unique for a number of reasons. First, it's extremely rare, accounting for less than 1% of all NSCLCs. Second, it tends to occur in patients who are not normally identified as having lung cancers with oncogenic drivers, including smokers and the elderly.

"It's not your classic driver oncogene subtype," he explained. "It tends to break most of the rules we normally associate with driver oncogenes, which is that they are normally found in younger people and people who have never smoked. So, even if you're a smoker, even if you're older, if your doctor hasn't found a driver oncogene and they haven't looked for MET amplification—they should think about it."

Because of this, Dr. Camidge says that patients with NSCLC without an identified driver oncogene should consider getting tested for MET amplification. He specifically recommends using the FISH testing method utilized in the study rather than relying solely on next-generation sequencing, a different type of genetic testing that can return false-negatives when it comes to identifying MET amplification.

"This is a truly actionable oncogene," he concluded. "It's rare, but it's real."

Disclosure: For full disclosures of the study authors, visit jto.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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