Off-Label Crizotinib for the Treatment of METex14-Mutated NSCLC

Edward B. Garon, MD:Traditionally, in all honesty, we probably have not identified patients who hadMETexon 14 skipping. The tests that we had routinely used to identify mutations in lung cancer patients, at least historically, generally would not pick up these mutations. Most of these patients would have received chemotherapy, potentially immunotherapy. The data are at least suggestive to date that this is not a group that derives particular benefits from those other standard therapies.

There are no approved inhibitors ofMETexon 14 skipping at the time that we’re speaking, at least right now, about this. There are some drugs that are approved in other indications that people have used off-label to treatMETexon 14 skipping. The most common that ends up being used is crizotinib. When I started working with crizotinib in the laboratory, we actually called it Pfizer’s METinhibitor because it was originally being developed as a METinhibitor. And there is, of course, similarity between many of these kinases, and particularly similarly amongMET,ALK,andROS1. Crizotinib of course is approved forALKandROS1. NCCN [National Comprehensive Cancer Network] does note crizotinib as a potential option in this disease, and some patients do receive it. It can be effective as a METinhibitor and is sometimes used. The other drug that sometimes does get used is cabozantinib, which is also off-label but also does have activity againstMET. It is approved in other indications.

In terms of this resistance associated with crizotinib, which again is not an approved therapy forMETexon 14 skipping patients, it is really that it has very little penetration into the brain. Of course, as we know, in management of patients with lung cancer, brain metastases are a very significant problem. And the ability to affectively treat brain metastases is important. I don’t know that we have good data on what the effects of crizotinib are specifically inMETexon 14 skipping patients. But we do know is that the brain penetration that we’ve seen in the approved indications is generally quite limited.

In terms of acquired resistance, it’s an important question to address. But to date I would say we don’t have a tremendous amount of data on what are the drivers of acquired resistance. That’s something that at the time that we do have approved MET inhibitors, I think we would be hopeful to be able to do research in those very important questions. As you know, in other settings, particularly theEGFR[epidermal growth factor receptor] mutation setting, studies of acquired resistance over time were able to really move the field forward.

Transcript edited for clarity.