Multikinase TKI Toxicity Profile


Jessica Bauman, MD: The problem with cabozantinib and vandetanib, which have up until now the most data in terms of responses for patients who have RET fusion mutations, is, unfortunately, that they have significant toxicity profiles. Because they are multi-targeted, unfortunately what that means is there are multiple pathways in cells that are affected. And that leads to increased toxicities. In particular, we see toxicities like GI [gastrointestinal] toxicities, such as nausea, vomiting, diarrhea. We also see very significant rashes.

And then the hardest part of the toxicities is the VEGF inhibition, which is part of the multikinase inhibitors, which can lead to hypertension, which could also lead to proteinuria, sometimes issues with bleeding and clotting. So all of the multikinase inhibitors have led to multiple dose reductions and dose interruptions when you try to use those for patients with RET fusion mutations because although, yes, they are targeting RET to a certain extent, they're also targeting all of these other pathways, which increase the toxicities.

The other issue with vandetanib and cabozantinib is neither of them have significant responses or duration of responses in terms of the data that we have so far. So not only do they have increased toxicity, but we also only see progression-free survival somewhere between 5 and 7 months for patients with these with these mutations and on these drugs. Because of that, we certainly need better treatments.

When I compare these to patients who have EGFR and ALK mutations, we know that the first-line targeted therapies that we have for that population now have very significant progression-free survival, upward of 18 months for osimertinib for patients with EGFR mutations. And alectinib for patients with ALK mutations has over a 24-month progression-free survival.

So we know that when we target these very specific mutations for certainly some other parallel populations, we can get significant responses, duration of responses, and better overall toxicity profiles.

Robert Doebele, MD, PhD: One of the really important developments over the last couple of years for RET inhibition is the development of selective RET inhibitors, rather than multikinase inhibitors. Over the past 5 or so years, many multikinase inhibitors that have some RET inhibitory activity have been developed. Unfortunately, both the response rate and the duration of those responses have been less than what we had hoped.

Typically response rates are in the 20% range in progression-free survival, and duration of response only in the range of a few months. The way that we think about this is because those were multikinase inhibitors, you cannot achieve full dosing to maximally inhibit RET in patients because you are getting off-target toxicity. So because they were multikinase inhibitors that inhibited other things, probably one of the predominant off-target effectors here is the VEGF receptor.

By also having activity against that, you were dose limited in the ability to achieve maximal RET inhibition because you were running into adverse effects like high blood pressure and other vascular events that are associated with inhibition of the vascular endothelial growth factor receptor. And so this is critical in developing selective RET inhibitors that don't hit those other targets, causing toxicity that limits the activity of these drugs.

The recent guidelines suggest in lung cancer that we should be broadly testing our patients. I think there are very clear recommendations in the NCCN [National Comprehensive Cancer Network] guidelines and others that at a minimum, we should be testing for EGFR, ALK, ROS1, and BRAF. If those are all negative, then we should also be testing for NTRK fusions. But I think also within these guidelines is the realization that there are many targets for which new drugs are emerging.

Those include RET gene fusions, MET exon 14, and perhaps now even KRAS mutations. I think lung cancer is now perhaps the clearest example of where broad next-generation sequencing panels make the most sense because there are so many targets with so many approved drugs in this disease that every patient should be getting next-generation sequencing that is comprehensive and can test for a variety of alterations all at once.

Transcript Edited for Clarity

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