Targeted Therapy for METex14-Mutated NSCLC

Transcript: Alexander Spira, MD, PhD, FACP: Both capmatinib and tepotinib are undergoing rapid evaluation for FDA approval based on breakthrough therapy. They both appear to be very active drugs. They’re both very similar in mechanism of action, from what we see. Tepotinib appears to have fewer adverse effects. If you look at the 2 studies, there appears to be slightly more grade 4 adverse events, resulting in treatment discontinuation. But both appear to be active drugs.

Both capmatinib and tepotinib are undergoing evaluation with a breakthrough designation in the second-line setting—so after chemotherapy failure. A lot needs to be learned about when these drugs might be used in the future—for first line, etc. But for now, that’s what the breakthrough designation is for, and we’re all excited to have that option.

Edward B. Garon, MD: As far as the breakthrough therapy, I must admit that as somebody who plays a role in academics rather than sort of drug development and industry, it’s always been a bit hard for me to know exactly what the breakthrough designation means, outside the idea that there’d be more frequent interactions with the FDA and that it is indicative of a quicker path. The exact implications of it are a little hard for me, in my position, to understand. What I think is easier for me to address is the clinical data that have been generated to date.

The GEOMETRY study is actually a multiple cohort study looking at capmatinib in patients with MET alterations and, I guess in some cases, patients without MET alterations. There are cohorts that were looked at based on amplification, and there were different subsets. There were some patients who had a gene copy number less than 4. Some patients had a gene copy number from 4 to 6, some from 6 to 10, and some greater than 10. Regarding the greater than 10 scenario, we’re still awaiting data from that. But the study looked at the role of capmatinib in patients with varying copy numbers of MET. Of course, a high copy number being what you would be referring to when we describe amplification.

In addition, there were cohorts looking at patients who have MET exon 14 skipping mutations. This is broadly broken down into cohorts for patients who are treatment-naïve, meaning that they have not received any therapy for advanced non—small cell lung cancer, and ones that are looking at patients who have received prior therapy for their cancer but no MET-directed therapy. For instance, they would have received cytotoxic chemotherapy, perhaps, but not a MET inhibitor.

In patients who had received prior therapy, the response rate exceeded 40%. In patients who were treatment-naïve, the response rate exceeded 60%. The duration of response data is still evolving, but it was certainly in the several months’ range. Not years, but several months. I would say it is encouraging that the patients who did have a response did have some durability of that response.

In terms of adverse events, the most common thing that we’ve seen has been edema—most frequently lower extremity edema. That’s something that we’ve commonly seen with this agent. Other things, somewhat nonspecific issues: Certainly some fatigue, some GI [gastrointestinal] issues, rare cases of liver abnormalities. But in general, the tolerability has been pretty good. I would say that some of these things have looked as if they may be class effects, meaning that there are similarities between the toxicity profiles of capmatinib and similar drugs that are targeting MET.

I think that approval in the frontline would be something that would basically take another group of patients and direct them to targeted therapies as their initial therapy. I think that in many respects, though, it is still early in terms of this target. There is a discrepancy between the response rate, for instance, in the treatment-naïve and the previously-treated patients on the GEOMETRY study. However, the numbers are still small. I think it will be important for us to see, over time, whether those differences hold up.

In general, we have found that in patients who have a driver mutation, they respond whether it’s frontline or second line. For EGFR mutations, that’s what we have generally seen. That is not necessarily going to be the case here. And again, with the preliminary data that we have from the GEOMETRY study, there is at least a suggestion of better outcomes in those who were receiving frontline therapy. But I think we need to wait and have a broader data set to know whether or not there is a true difference between the response rate in frontline versus previously treated patients.

Transcript Edited for Clarity