MET Targeted Therapy for NSCLC - Episode 3

FDA Priority Review of Capmatinib for METex14-Mutated NSCLC

March 23, 2020

Edward B. Garon, MD:There is a study, that is really the main study that we have data from, looking at capmatinib. It is a study that initially looked at patients who had amplification of theMETgene, and then subsequently looked at patients who hadMETexon 14 skipping. Those studies showed that the drug was generally well tolerated. I think the most common unique toxicity is some swelling that has seen generally lower extremity and has generally been seen in class in patients receiving MET inhibitors.

The study to date shows a response rate that’s around 40% in patients who have received prior therapy and a response rate that is much higher than that in patients who have not received prior therapy for metastatic non—small cell lung cancer.

Those are the data that were presented at ASCO [the American Society of Clinical Oncology Annual Meeting] in 2019. This did lead to breakthrough designation for capmatinib, and more recently capmatinib has been granted a priority review by the FDA.

Capmatinib is an oral small molecule inhibitor that is extremely potent againstMET. It is quite specific forMETwithout tremendous activity against other tyrosine kinase inhibitors, which in general is something that is looked at as important for limiting the toxicity associated with a therapy. In general it is a potent oral therapy directed quite specifically againstMET.

The GEOMETRY monotherapy study was the basis of the recent FDA priority review for capmatinib in the prior breakthrough status. This is in some ways a bit of a complicated study because there are many different cohorts. First, there were cohorts that were looking at the role of gene amplification. There was, for instance, a cohort that had a gene copy number between 2 and 4, which would not be highly amplified. You know, 1 that looked at 4 to 6, and then 1 that looked at higher numbers that actually split into 2 groups, gene copy number 6 to 10 versus 10 to whatever the top number would be.

That was a major part of the study. But then there were a few cohorts that were specific for patients withMETexon 14 skipping. Those cohorts were broken down into cohorts that are looking at patients who have received prior therapy, generally chemotherapy, directed against their metastatic disease. Whereas there was a smaller group that has looked at patients who have not received prior therapy.

In total, it was nearly 100 patients that were treated with capmatinib. The toxicity profile was generally favorable with the most common sort of unique toxicity being edema, which generally has been a class effect of MET inhibitors. And the response rate was around 40% for patients who had received prior therapy and considerably higher in the two-thirds range for patients who had not received prior therapy for their metastatic disease.

The duration of response data that we have to date are encouraging but immature. They differ a little based on the previously treated versus the untreated, but it is approaching a year.

There are very limited data on comparator drugs to capmatinib. The 1 published data set that we have is a data set looking at crizotinib that was recently published inNature Medicinein which the investigators looked at crizotinib in a group of patients who hadMETexon 14 skipping non—small cell lung cancer. The response rate there was around 30%. These are small numbers in small studies. I would caution people against cross-trial comparison; it did appear to be clearly an active drug.

Similarly, there’s no manuscript that I’m aware of to date on tepotinib, which is a similar drug to capmatinib. That data have also been presented at ASCO in 2019, and it is a little hard beyond just the typical caution against cross-trial comparison. It’s a little hard to compare that because they looked at patients who were diagnosed by tissue and then separately looked at patients who were diagnosed by circulating tumor DNA. But I would also say that data looked like quite impressive, that the drug is clearly active against this target ofMETexon 14 skipping.

The approval of capmatinib for non—small cell lung cancer would be exciting. It would lead to really the sixth different genomic alteration that is basically a target for targeted therapy. One other unique issue aboutMETexon 14 as compared with some of the other targets that have recently been approved or that people are looking at,METexon 14 skipping is not particularly rare. It is probably in the ballpark of 3% to 4% of non—small cell lung cancer; very similar in number to what we see forALKgene rearrangement. Although that also may sound small in terms of a percentage, people have to remember that there are approximately 200,000 new cases of lung cancer a year in the United States alone. And so when we’re talking about 3% to 4% of that, we’re talking about a significant number of patients if they can be identified.

I think that when one looks at the data for capmatinib, 1 of the concerns that always comes up—which I think is appropriate—is that although we have limited data, we don’t have a full and complete understanding of what the anticipated response rates are. For instance, in the second line to docetaxel-based therapy, or in the first line compared with what now has become the standard, which has typically been chemotherapy plus immunotherapy. For many practitioners like myself, what has been seen with the duration of response gives us full confidence that even outside a direct comparison—compared with docetaxel-based therapy when 1 looks at the efficacy and the toxicity profile—this would be a preferable approach.

In the frontline setting, when we don’t have as much data, particularly on chemoimmunotherapy, individual practitioners will make the decision as to whether they want to be looking at chemoimmunotherapy, for instance, as their frontline approach in these patients versus capmatinib, should there be an approval for capmatinib in previously untreated patients withMETexon 14 skipping non—small cell lung cancer.

Transcript edited for clarity.