Global Outlook on Advanced Nonsquamous NSCLC - Episode 13

NSCLC: Promising Molecular Targets


Suresh S. Ramalingam, MD: We talked a lot about some of the proven targeted therapies for subsets of patients. There are some additional subsets, like HER2 mutations, and more recently a lot of excitement about the detection of MET exon 14 mutations. I want to quickly get your thoughts on how you approach HER2 mutations first, and then MET mutations. Perhaps I’ll start with you, Marina, about HER2 mutations.

Marina Garassino, MD: For a HER2 mutation, we put patients into a clinical trial. We know that HER2 is not the HER2 of breast cancer. We have the mutation, but the HER2 mutation is not the HER2 amplification by FISH, where the results are scanty and not very clear. For a HER2 mutation, we have a clinical trial and we include patients in the clinical trial. I think that the HER2 mutation is just a bit different from the other driver mutations, and the study is quite complicated.

The study of MET seems clearer, and it is also important to underline that maybe in this case we have a phenotype because MET 14 is present in adenosquamous and in sarcomatoid tumors. If you have this phenotype and you search for it, you can find it. The clinical trials show MET inhibitors, and also crizotinib, are really active in this kind of mutation. The progression-free survival is long. It’s about 10 months. We know also that these kinds of driver mutations are not the best candidates for immunotherapy, because the results with them are quite poor. So, I think we can target them. The study of HER2 is less clear than MET. In the studies, MET is evolving very rapidly and we have the phenotype to search for it.

Suresh S. Ramalingam, MD: There were 2 studies reported at ASCO looking at specific HER2 inhibitors. The activity was relatively modest, as I recall. Benjamin, what are your thoughts on that?

Benjamin Besse, MD, PhD: I agree. MET is really like the other target. It’s a good target, with good drugs, and it’s 10 months PFS. It’s homogeneous. But the HER2 story is more complicated. It’s clear that the tyrosine kinase inhibitors in HER2-mutated NSCLC are poorly active, and it’s probably the antibodies against HER2 that are more active. T-DM1 [trastuzumab emtansine] is not that active, but there are next-generation antibody drug conjugates against HER2, and we should see the results with these drugs. The trastuzumab/pertuzumab combination that is used in HER2-positive breast cancer could be tested. We feel that adding a HER2 antibody to chemotherapy brings something to these patients. There are retrospective data that strongly suggest that, but we would need prospective data in this population.

Suresh S. Ramalingam, MD: Giorgio, what is your experience with the MET inhibitors that you’ve seen evolving?

Giorgio Scagliotti, MD, PhD: I truly believe that the only area in which the MET inhibitors reasonably would be active is in the field of c-MET amplification. Again, MET is a target. MET is an important target. There are preclinical data showing that MET inhibition is relevant when you have a c-MET amplification in the cell line. It’s also true in the initial clinical evidence that we have across several MET inhibitors, at least in the early phases of clinical development. It’s a matter of fact that there is a converging line of research across several institutions, pharmaceutical companies that are looking specifically to c-MET— amplified tumors. The very preliminary data that we have are talking about, even in the context of the second line, about 25%, 27% response rates. Obviously, we don’t have any data on PFS. But that is at least grounds on which you can explore, because I do not believe that the c-MET inhibition is the kind of inhibition that should be investigated in all-comers.

Suresh S. Ramalingam, MD: At this point, it’s fair to say that HER2, MET—the targeted options—are still evolving. Patients should still get platinum-based chemotherapy for sure as first-line therapy, and subsequently, if there’s a proper clinical trial to test these inhibitors, we would highly encourage those patients to participate in that clinical trial.

Giorgio Scagliotti, MD, PhD: Absolutely, yes.

Transcript Edited for Clarity