Part 3: Addressing Toxicities in MET Inhibitors for NSCLC

Martin Dietrich, MD, PhD (Moderator)

DISCUSSION QUESTIONS

• How do you counsel patients receiving a MET inhibitor for NSCLC harboring a MET exon 14 skipping mutation?
• How do you monitor, mitigate, and manage toxicities associated with these agents?

TIM NGUYEN, MD: The most difficult toxicity would be the edema, which you said was difficult to treat, which is not responsive to furosemide [Lasix]. I acknowledge it can be manageable.

MARTIN DIETRICH, MD, PhD: Is anybody using the nausea prophylaxis? Do you have any tips and tricks on management of edema? How do you approach a patient that has fluid accumulation?

LUIS RAEZ, MD: I have more issues with nausea and vomiting. I have a patient who was nauseous the whole time on capmatinib [Tabrecta] for 5 or 6 months. It may be a matter of luck. I have another patient that has never had nausea and vomiting, while the first patient was throwing up for 6 months. We even did an esophagogastroduodenoscopy to be sure there was no ulcer. I prefer to tell them to take nausea medication before. If the patient gets edema, then I don’t know. We’re oncologists, sometimes we are more excited about the results than the adverse events [AEs]. If you tell the patient all of these things from the beginning, it makes things easier. Tell them, “You are not going to be on chemotherapy, but you may get edema in the legs.” And then they can buy some compression stockings, and do things like that, and that helps to prepare.

DIETRICH: I have a similar approach. I think the management is not going to be a straight line. I feel like those patients have peaks and valleys of fluid accumulation. I don’t have that much luck with compression stockings. I feel like what I create is almost like a mushroom of fluid that eventually overlaps. It’s sometimes challenging to do. But, obviously, with the expected lack of efficacy for chemoimmunotherapy here, and the AE profile of chemotherapy, I think this might be the better set of AEs.

ROBERT KOCH, MD: What is the current thinking about the etiology or pathophysiology of the edema in these patients?

DIETRICH: I think it’s a direct on-target effect of MET [inhibitors] that regulates vascular integrity. By inhibiting MET, there is a similar kind of fenestration as we would see in a VEGF overexpressive setting, where we have leakage of fluid through the fenestration of the vascular wall, and eventually have fluid deposition in the third space. I think it’s an on-target effect, and I don’t know that you can prevent it. We have an unaltered tyrosine kinase ATP pocket that is similar, whether it is amplified and overexpressed by MET exon 14 skipping mutation, or in the wild-type setting. There is no relative specificity. I think it’s an on-target effect on MET. I think that’s why it is so difficult to prevent. It is responsive to dose adjustment, but I don’t think it’s preventable, for the most part.