Connecting the Dots: How MET Fits Into Comprehensive Molecular Profiling

Dr Jamie Chaft reviews the biological and clinical differences among MET biomarkers in NSCLC, emphasizing the importance of matching the specific biomarker question to the appropriate assay. The discussion covers NGS, IHC, and FISH, as well as specimen availability, prior therapy exposure, and the evolving clinical context. 

Transcript

Kelly Conger: Hello and welcome to the Oncology Learning Network. I’m Kelly Conger, and on today’s episode, we’ll take a deep dive into biomarker testing in non-small cell lung cancer, discussing MET alterations and more. Our guest today is Dr Jamie Chaft.   

Dr Chaft: Hi, I'm Dr Jamie Chaft, professor of thoracic oncology at Memorial Sloan Kettering Cancer Center. 

Kelly Conger: Thank you so much for joining us today, Dr Chaft. To get us started, could you give us a high-level overview of MET as a biomarker in non-small cell lung cancer? Are there different types of MET alterations and how are they targeted therapeutically?  

Dr Chaft: 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 constituently 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. 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 inhibitors. And MET overexpression can be targeted in the second-line setting with an antibody drug conjugate.  

Kelly Conger: Can you tell us more about the genomic MET alterations? How are they assessed and what are their implications clinically?  

Dr Chaft: 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.  

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 as amplification is essential. And for me, whenever I see amplification, I make sure there's no other driver of lung cancer in that patient. And 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. 

Kelly Conger: Now, if we look at just the changes in MET protein expression from a practical standpoint, what does the workflow look like for identifying cell surface protein expression?  

Dr Chaft: 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.  

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.  

Kelly Conger: Dr Chaft, thank you so much for speaking with us today. We have covered MET biomarkers, the various types of alterations and how to test for them, as well as clinical implications for treatment in non-small cell lung cancer. Thank you again for listening to this segment of the Oncology Learning Network.