Expanding Targets in NSCLC - Episode 14

Adopting Newer MET Inhibitors Into Practice in NSCLC

Transcript: Edward B. Garon, MD: I think that the approval of a second-line MET inhibitor would certainly be a great advance. It would take this population that we now know has a targetable alteration and would allow them to have a standard therapy directed against it. My suspicion is that most patients in the United States, right now, who have MET exon 14 skipping don’t know about it. And of those who do, many of them probably don’t receive treatment because there are no approved therapies.

Now, the additional question is, what would be an advantage of a drug like capmatinib or tepotinib over the drugs that I mentioned that are approved in other settings, that do have activity against MET? Those would be crizotinib, for instance, or cabozantinib. I think 1 major advantage that you would see—at least it has been presented to date with capmatinib—is that there is penetration into the brain. Unfortunately, lung cancer is a disease that has a predilection to spread to the brain, and we know that patients with MET exon 14 skipping are not an exception to that. Certainly, brain metastases are common and can be a source of significant morbidity. These agents—at least as they say it has been demonstrated for capmatinib, to date—do have penetrations of the brain. I believe that of 13 patients on the GEOMETRY trial who did have brain metastases, all but 1 achieved disease control in the brain with capmatinib. The majority of them actually had an intracranial response.

Alexander Spira, MD, PhD, FACP: Once these drugs get approved, assuming that they do—we all anticipate that 1, if not both capmatinib and tepotinib, will be approved—we fully expect them to be used in the second-line setting, according to the label, which is what the breakthrough designation is for.

There’s going to be a lot to be learned as to whether or not these drugs can and should be used in the first-line setting. It’s very enticing to have a drug that you can give orally, that has a targeted mechanism that appears to have response rates in the 50% to 60% range, and to use that in the first-line setting. I’m sure many people will. I’m sure many patients would like to use that in that scenario as well. Clearly we’re going to need more data, and the studies that are ongoing will bear some of that data in terms of long-term outcomes as well.

Given the efficacy of chemotherapy with checkpoint inhibitors, it’s a very high bar to beat that. But there are certain things that are very enticing about these drugs to be used for MET translocations.

Edward B. Garon, MD: I think we need more data before we know whether the frontline or the second-line would be the appropriate place for MET inhibitors. No. 1, we need to have a better sense of what the potential difference is between frontline treatment and previously treated patients in terms of the response rate. And 2, the duration of response. Based on the fairly limited number of patients we have in the GEOMETRY study, I’m not sure we can have a great data set on that.

The 2 other important data pieces that I think we need to see are, No. 1, we need to have a better sense of what happens with patients who have MET exon 14 skipping mutations if they receive chemoimmunotherapy. So most patients with nonsquamous non—small cell lung cancer in the United States—and most of these cases are nonsquamous, so most cases now—are receiving chemoimmunotherapy. Because that is a fairly new approach, I think we don’t know what the response rate is or what the duration of response is in that population to those therapies. Obviously when you’re weighing 1 therapy against another, it’s important to have a sense, really robustly, of what both of them would do in the frontline; and also, the cost of delaying 1 to a later line of treatment.

There’s probably another important piece, at least in my mind, which is that some drugs have had substantial toxicity when given with immunotherapy in particular. I would like to see some additional data on MET inhibitors plus an immunotherapy. Even though we would be talking about giving a MET inhibitor after immunotherapy in this setting, the immunotherapies that are used to date are monoclonal antibodies that generally have a half-life that is on the order of weeks. And so there are still significant amounts of drugs that would be there.

I’m particularly cautious because we were involved in a study that combined crizotinib, which obviously, as I mentioned, does have MET inhibition along with nivolumab, which is a PD-1 [programmed cell death protein 1] inhibitor. The toxicity was prohibited there. And so that theoretically could be another rationale to give the MET inhibition as a frontline therapy—if there were concerns about toxicity, being that you would basically give the MET inhibitor and, only after that, expose people to an immunotherapy rather than having the risk of patients having both drugs onboard at the same time.

I think there are still a lot of things we need to learn before knowing whether this would be an appropriate therapy in the frontline setting. I think with the data we have available, it’s certainly encouraging that one would anticipate it would be a better option as opposed to alternate second-line approaches.

Transcript Edited for Clarity