BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 2

BCR-ABL1-Targeted TKIs in Treatment of CML

June 24, 2019

Harry Erba, MD, PhD:CML [chronic myelocytic leukemia] appears to be driven by theBCR-ABLfusion protein. Tell us about these inhibitors ofBCR-ABL. How many are there? What are the differences?

Jorge Cortes, MD:The pioneer, the 1 that started all this, is imatinib. It’s a drug that we first got to know as STI-571, and this was a drug that started this revolution. It’s what we call the first-generation tyrosine kinase inhibitor. Then we have available today clinically what we call second-generation tyrosine kinase inhibitors: dasatinib, nilotinib, and bosutinib. These all have been investigated for the treatment of patients who had developed resistance or intolerance to imatinib, and they work effectively. They’re more potent than imatinib. They cover most of the mutations that confer resistance to patients that have failure with imatinib. They’re all approved. These 4—imatinib and the 3 second-generation tyrosine kinase inhibitors—are all approved also for initial therapy.

Then we have our third-generation tyrosine kinase inhibitor. One of the things that we recognized was that some patients develop mutations that are insensitive to all these tyrosine kinase inhibitors, notably theseT315Imutations. That led to the development of ponatinib, which is perhaps the most potent of the tyrosine kinase inhibitors, and it covers all the mutations that we know that can develop on patients with resistance to tyrosine kinase inhibitors. That’s our 1 third-generation tyrosine kinase inhibitor. Ponatinib is approved only for patients who have resistance or failure with other tyrosine kinase inhibitors. It’s not approved or indicated at the moment for frontline therapy. But it is a very good option for patients who need subsequent lines of therapy or who have that mutation.

Harry Erba, MD, PhD:Are they all equally selective forBCR-ABLor are there differences?

Jorge Cortes, MD:There are differences. For example, dasatinib and bosutinib are also SRC inhibitors, as well as ponatinib has some activity against SRC. All these drugs except for bosutinib inhibits… PDGF receptor. That’s why, for example, they work in GIST [gastrointestinal stromal tumors] and in other entities that have PDGF receptor rearrangements, like some of the hypereosinophilic syndromes. Bosutinib wouldn’t cover those. Then there are other targets. For example, ponatinib inhibits the VEGF receptor. That doesn’t seem to have any value in terms of that because it may correlate with some of the adverse events that we see, like hypertension with ponatinib. There is a variability in terms of their profile of kinases that are inhibited.

Harry Erba, MD, PhD:If these drugs are able to block the activity ofBCR-ABL, why would it be possible for the disease to progress then?

Jorge Cortes, MD:Well, there are different mechanisms that have been identified. The 1 that we recognize best—and that’s probably the most common, or at least the 1 that we find more frequently—is the development of these mutations. What happens with these mutations is that there are changes, usually 1 amino acid change, and most of the time what they do is they prevent binding of the inhibitor or maintain the activity of the kinase, even in the presence of a tyrosine kinase inhibitor. Therefore, the drug is there, but it’s no longer able to inhibit the kinase activity. If you change to a different tyrosine kinase inhibitor that is able to overcome that, that does bind or that does inhibit in the presence of that mutation, then you can regain sensitivity. In that instance, …the kinase regains activity because the drug is no longer inhibiting.

With theT315Ithat we mentioned, for example, this is a very bulky residue of isoleucine instead of the threonine at these 315 residues. That prevents the binding of all these inhibitors. And for ponatinib, the biochemical configuration is such that it allows to bind even in the presence of that bulky residue. That’s how some of these work. We know other mechanisms of resistance much less well characterized. Some of them you cannot identify in the clinic. There’s no good test for them. We know that there’s some description ofSRCactivation in some patients. The transporter that brings the drugs into the cell, something that’s called OCT1, seems to play a role into that. But those have been mostly research questions. There’s no really good clinical test to tell you that. So really, right now, mutations is 1, and that’s how we’d work.

Transcript edited for clarity.