Targeted Therapy for MET-Dependent Lung Cancers

Benjamin Levy, MD, Associate Professor at Johns Hopkins School of Medicine, reviews his talk on targeted therapies for patients with MET-dependent lung cancers, which was presented at the virtual 2022 Great Debates & Updates in Lung Cancers conference.

In his presentation, titled, “Targeted Therapy for MET-Dependent Lung Cancers,” Dr Levy discussed MET exon 14 skipping mutations, MET amplification, and MET overexpression in non-small-cell lung cancer (NSCLC).

He also covered new treatments, such as capmatinib and tepotinib, and highlighted the potential that amivantamab—which is already FDA-approved for the treatment of NSCLC with EFGR exon 20 insertion mutations—has shown in early clinical trials.

Transcript:

Hi, I'm Dr. Benjamin Levy. I'm an associate professor at Johns Hopkins School of Medicine. I recently had the privilege to discuss MET alterations in non-small-cell lung cancer (NSCLC) at the great debates meeting. During this conference, and during my talk, I was able to make, I think, some very salient points regarding MET alterations in NSCLC. The first thing that is important to note is that not all MET alterations are the same. When we talk about MET alterations we're obviously not just talking about MET exon 14 skipping mutations, but we're also talking about MET amplification and MET overexpression. So I think that's an important point and perhaps more important is that these don't overlap. When you have a MET alteration in terms of MET exon 14 skipping mutations, you don't necessarily have C-MET overexpression by IHC or C-MET amplification.

So it's really important to remember that currently the only targeted therapies we have are for MET exon 14 skipping mutations. The other point when we talk about MET exon 14 skipping mutations is that these mutations and alterations are important. They make up about 3% of NSCLC adenocarcinoma. So it's critical that we test, we can't give the drugs unless we do comprehensive genomic profiling, which includes both tissue and liquid. When you look at historically the journey of MET exon 14 skipping alteration-targeted therapies, clearly the first drug was crizotinib and that demonstrated an objective response rate to 32%. But we've moved forward with 2 studies, the GEOM3TRY study evaluating capmatinib and the VISION study evaluating tepotinib. The bottom line in these studies was that capmatinib elicited a response rate of roughly 65% in the treatment naive setting for patients who had MET exon 14 skipping mutations and tepotinib also elicited meaningful responses, objective response rate, a little bit lower in the treatment naive setting, roughly 40 to 50%.

But if you look at the waterfall plots between these 2 drugs, they look fairly similar, both efficacious in MET exon 14 skipping mutations. Importantly, both of these drugs have the ability to cross the blood-brain barrier. I would make the recommendation and I did in my talk that these drugs should be used first. Identifying MET skipping alterations are important, and if identifying them, you should deliver targeted therapy. I also discuss new data coming out with amivantamab that was presented at ASCO, looking at amivantamab, a drug that's already approved for EGFR exon 20, but this bispecific EGFR MET antibody is active in MET exon 14 skipping mutation populations as well. That data showed in the second line in any line, an objective response rate of 57% and for treatment naive patients and in all patients, regardless of what line of therapy, an objective response rate of 33%.

So amivantamab meaningful activity in MET exon 14 skipping mutations. I think importantly, that MET exon 14 skipping mutations are not the whole story with MET alterations. We now are looking at other important biomarkers, including MET amplification. Remember MET amplification is a different biomarker than MET exon 14 skipping mutations. We've evaluated MET amplification in EGFR positive patients who develop resistance on osimertinib, MET amplification is important, and we've had some data looking at once again, amivantamab in combination with lazertinib in that resistance setting, showing that if you did have MET amplification as a mechanism of resistance, this combination elicited response rates of 47%. We also have data again with, excuse me capmatinib and tepotinib. These 2 drugs that are approved for MET exon 14, but also in these studies looked at MET amplification and show that there were meaningful responses, not as high as we saw in MET exon 14 skipping mutations, but still some meaningful responses and response rates anywhere from 40 to 50%.

The last thing I want to talk about, and what I talked about in my talk is, yes, you have MET exon 14 skipping mutations, [and] yes, you have MET amplifications, but you also have MET overexpression, which occurs in anywhere based on the data from 15 to 70% of all NSCLC and their new antibody drug conjugates looking at MET overexpression tumors. One of the antibody drug conjugates that I talk about, that's not yet approved is telisotuzumab vedotin. This is an antibody drug conjugate of course, made up of a monoclonal antibody, a linker, and then a payload that inhibits microtubule polymerization. The bottom line with telisotuzumab is that it does have activity specifically in MET-amplified NSCLC, either in the first line or second line. There's more data to come out of this. It's very early on, but clearly this drug is one to be looked at and watched because with further data, I think we may see an approval in the next 2 to 3 years with this drug.

Finally, not to get too much into the weeds, but we have identified mechanisms of resistance for MET skipping, excuse me, C-MET alterations, including MET exon 14 skipping mutations, patients who've been treated even with crizotinib first or capmatinib or tepotinib. We have identified mechanisms of resistance that may be able to be drugged with additional therapies. So it's an exciting time. Remember MET exon 14 skipping alterations are actionable alterations. You need to do testing. Capmatinib and tepotinib are FDA approved therapies. Amivantamab a drug that should be watched demonstrating promising activity specifically for MET exon 14 skipping mutations. Remember that it's not just about the skipping mutations, about MET overexpression and MET amplification, and we may have drugs approved for those alterations. Finally, test don't guess. We can't deliver these drugs unless we do the testing.

Source:

Levy, B. Targeted Therapy for MET-Dependent Lung Cancers. Presented at: Great Debates & Updates in Lung Cancers. Aug 24-26, 2022. Virtual.