Not All MET Biomarkers Are the Same: Matching the Right Test to the Right Target

In this video, Dr Jamie Chaft explains why “MET-positive” is not a single biological category and why clinicians should distinguish among MET exon 14 skipping mutations, MET amplification, c-Met protein overexpression, and MET gene fusions. She also discusses how NGS, IHC, and FISH answer different biomarker questions and may affect tissue use, turnaround time 

Transcript

Dr Chaft: Hi, I'm Dr Jamie Chaft, professor of Thoracic Oncology at Memorial Sloan Kettering Cancer Center. MET is one of the most complicated biomarkers in non-small cell lung cancer, similar to HER2, where we see activating MET alterations with various genomic or biologic alterations. So there are activating MET exon 14 splice variants leading to a dysregulated, constitutively active protein. We see point mutations that are also activating. MET can also be dysregulated by amplification or copy number gain and overexpressed. These are different biomarkers with different therapeutic implications.  

If MET is altered at a genomic level leading to constitutive activation, we treat our patients with MET tyrosine kinase inhibitors. Additionally, MET amplification can be targeted in the same way. And of course, important to mention that MET can be dysregulated in both non-squamous and squamous cell carcinoma of the lung. So MET mutation and MET amplification are targeted intracellularly with tyrosine kinase inhibitor. MET overexpression can be targeted in the second-line setting with an antibody drug conjugate. So understanding the difference between these drivers of lung cancer pathogenesis is essential.  

How we do this is generally NGS, inclusive of RNA-seq, for MET mutation and amplification. Amplification can also be tested by FISH, although that is uncommon. MET expression must be tested by immunohistochemistry, and that's a bit of a new workflow for pathology labs. So it's not always done in the front line. Initial diagnostic biopsy at the time of diagnosis, although the guidelines do recommend it, in my own practice, if that data is not available at the time of initial diagnosis and we're in need of next-line options, I order the IHC. You can see MET point mutations on NGS reports that are SNPs or not clinically relevant. So really referencing genomic databases to understand if the alteration you're seeing is both activating and sensitive to our available MET inhibitors is essential when reviewing a report.  

In terms of amplification, there are so many different ways to assess amplification. Looking at the genomic report and how they define “normal” to be sure what you're seeing is amplification is essential. And for me, whenever I see amplification, I make sure there's no other driver of lung cancer in that patient, as if there is, it could be a resistance mechanism. For example, in an EGFR mutant lung cancer, we can see MET amplification as a resistance, and therapeutically, you may address that patient differently.  

In terms of expression, you're really looking for the H score, but both the strength and distribution of expression, and the pathology report should define that clearly. If it doesn't on either of these levels, at the pathology report, IHC, or on the NGS report, if you're not sure, you can always ask the pathologist. 

Jamie Chaft, MD, is an attending physician at Memorial Sloan Kettering Cancer Center, where she serves as the director of early-stage lung cancer research. She designs and leads clinical trials, striving to improve the cure rates in early-stage lung cancers. In such a capacity, she serves as study chair for the National Clinical Trials Network (NCTN) trial of adjuvant nivolumab within the ALCHEMIST program and co-lead of the Lung Cancer Research Foundation (LCRF) LEADER study bringing personalized neoadjuvant therapies to patients with resectable lung cancer. Dr Chaft's career is committed to moving drugs shown to have promise in more advanced lung cancers into the early-stage setting.