Progress in Treatments for NSCLC Patients with METex14 Mutations

Juhi Kunde, MA, LUNGevity Science Writer

Abnormalities in the MET gene have been shown to be key drivers in the development and growth of non-small cell lung cancer (NSCLC). These MET abnormalities frequently occur as exon-14 skipping mutations, in which the MET transcript lacks exon 14.  These MET exon-14-skipping mutations (METex14) are found in approximately 3%-4 % of NSCLC patients. These mutations make the MET protein hyper-active.

LUNGevity spoke with Rebecca Heist, MD, MPH, associate professor of Medicine at Massachusetts General Hospital and recipient of a 2011 Targeted Therapeutics Award from LUNGevity, to learn more about the progress in the diagnosis and treatment of NSCLC patients who test positive for METex14 mutations.
 

LUNGevity Foundation: What is METex14? Why does it matter?

Dr. Rebecca Heist: The MET gene (mesenchymal epithelial transition factor receptor) is known to be involved in regulating many aspects of normal cell growth, including cell proliferation, apoptosis (programmed cell death), and cell survival. METex14 refers to one of many genomic changes that can lead to skipping exon 14 in the mRNA transcript.  This alternatively spliced MET drives the development of NSCLC. When the MET gene develops a mutation to splice out exon 14, the resulting MET receptor demonstrates sustained activation and signaling which can lead to cancer development.
 

Who should get tested for METex14 mutations?

All patients with NSCLC should be tested. We have seen that METex14 tends to occur in a slightly older population than other oncogenic drivers, and we have also seen it across all smoking histories, and across all histologies. So, it is important that all NSCLC patients be tested, but I don’t think this testing should be limited to MET.  I think it is best for patients to speak to their doctors and discuss broad-spectrum testing that includes MET, EGFR, ALK, RET, ROS, and many other biomarkers that can be targeted with therapies. 
 

What is capmatinib and why is it significant?

Capmatinib is a drug that was approved by the FDA in May 2020 for the treatment of patients with metastatic NSCLC who are also positive for METex14. In a key clinical trial, capmatinib showed a promising overall response rate among patients: 68%, when used as the initial treatment, and 41% when used in second- and third-line settings. In addition, capmatinib is relatively well tolerated by patients. Because NSCLC has been known to metastasize to the central nervous system, it is also important to note that capmatinib can penetrate into the central nervous system. Taken together, these results suggest that capmatinib could be a good treatment option to consider for NSCLC patients who are positive for METex14 mutations.
 

What type of treatments target METex14 mutations?

The MET protein has important tyrosine kinase activity, which leads to the downstream regulation of cell growth, cell death and proliferation. In the case of METex14 mutations, this balance is skewed toward unregulated cell growth. There is a class of drugs called TKIs (tyrosine kinase inhibitors) that inhibit the signaling activity of proteins with tyrosine kinase domains. Capmatinib is a TKI that was specifically designed to treat cancers with METex14 mutations by inhibiting the overactive signaling in the MET pathway that leads to cancer development. Other MET TKIs such as crizotinib, tepotinib, and savolitinib, may also be useful in treating NSCLC with METex14 mutations. There are also antibodies being developed and other classes of drugs being developed to target these mutations.
 

What are exciting areas of research in this field? 

A lot of great work is underway. In terms of therapies, a number of small molecule inhibitors are being studied, as well as antibodies and antibody-drug conjugates. Other researchers are studying the underlying biological mechanisms of NSCLC with METex14 mutations to learn how to prolong the effectiveness of treatments and overcome drug resistance.
 

How can we ensure that we continue to have progress in this space?

Well, I think continuing to support lung cancer research is an important way to keep the momentum going. I know LUNGevity has a huge track record of promoting lung cancer research, and they will have a future role in promoting research and fostering patient awareness and advocacy. We know much more than we used to about lung cancer, but there is still more to learn. This is just the beginning.

 

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Juhi KundeJuhi Kunde, MA, is a science writer for LUNGevity.

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