ONCAlert | Upfront Therapy for mRCC

Resistance to Targeted-TKI Treatment in Patients With CML

Published Online:12:28 PM, Mon July 8, 2019

Harry Erba, MD, PhD: So you see the patient is not responding at milestones or losing response. You look at compliance. I look at drug-drug interactions, proton pump inhibitors for nilotinib and dasatinib. But let’s say you rule out all those things. What kind of resistance mechanisms, specifically mutations, do we see?

Jorge Cortes, MD: One thing that’s important for mutations is primary resistance and secondary resistance. Primary resistance would be that patient doesn’t meet the goals that you are aiming to get. Secondary resistance would be the patient responded but now is losing their response. Mutations are particularly common in the secondary resistance.

The patient who got a complete cytogenetic response, who is compliant, now you see that they lost the complete cytogenetic response and certainly the hematologic response. Up to 50% of those patients can have mutations. The patient who just doesn’t make it to the desired goals—not just to the optimal response but even to those suboptimal responses—you will find some mutations, but it’s more in the range of 10% to 15%. So the yield is very low. It’s worth checking, of course, because if you’re going to change therapy based on that, you want to know that you’re going to change to something that has a good chance of working. But it’s also important to recognize that most of the time, you don’t have such a guide because you won’t find a mutation. It is important to recognize that difference.

Harry Erba, MD, PhD: In primary resistance, what are some of the resistance mechanisms that have been implicated?

Jorge Cortes, MD: Well, we talked about the receptor. There’s been the discussion as to whether…the activity of OCT1 is less. It doesn’t affect all the drugs. It affects imatinib more than it affects, for example, nilotinib. Not all the drugs need that receptor. We talked about SRC, and that could be a mechanism of resistance. Obviously, as you mentioned, adherence and the drug-drug interactions and all these things.

There are growing data, evolving data that suggest that some of these patients may actually have additional molecular abnormalities that we previously didn’t recognize as present. Some of them have to do with these clonal hematopoiesis, and ASXL1 and DNMT3A mutations. Now, there are evolving data. We don’t know how much of a role they play. But it is interesting that these patients who don’t have resistance—and even more, the patients who have an early transformation. Even though clinically it appears that they have chronic phase, they seem to already have a molecularly more complex disease than it appears just by cytogenetics.

Harry Erba, MD, PhD: Yeah, I think that’s a really important point. If you go back, way back, to data from The University of Texas MD Anderson Cancer Center and other places with interferon and hydroxyurea, and you look at when progressions occur, even now in the ABL TKI [tyrosine kinase inhibitor] era, there are numerically more progressions on any of those studies in the first year. Then it kind of slows down, almost as if something has been developing in those patients that is making them have a more resistant disease.

Jorge Cortes, MD: That is more correct. For those patients, you say, “Gee, why do these patients progress so quickly when the blasts were low?” There’s evidently a more complex disease than we recognize just by the BCR-ABL protein.

Harry Erba, MD, PhD: Do you look for mutations at baseline to help guide therapy?

Jorge Cortes, MD: No, not in the chronic phase. In the chronic phase, there have not been any mutations described at baseline. Patients who have a blast phase at the time of diagnosis, you will find mutations in some of these patients. You even have patients with a T315I mutation, and it’s a little bit more common if it’s a lymphoblast phase. You could argue is that a Philadelphia chromosome–positive ALL [acute lymphoblastic leukemia] or a lymphoblast phase. Sometimes, it’s impossible to tell. But in that context, you could have mutations at baseline. But in chronic phase, no, so I don’t check.

Harry Erba, MD, PhD: OK. Let’s now focus on those patients with secondary resistance. Typically, 50% of them will have a mutation. Do those mutations help guide second-line therapies?

Jorge Cortes, MD: Absolutely. There is a panel of mutations for each of our options for second-generation drugs that are not as sensitive to each 1 of them. For example, dasatinib doesn’t work against the V299L mutation. The same applies for bosutinib, by the way. Whereas nilotinib doesn’t work against the F359V mutations. For each drug, there are 2, 3, or 4 mutations in which it doesn’t work. Certainly, universal to all them, except ponatinib, is the T315I, and they all have. Of course, for imatinib, the panel of mutations that are resistant is larger. For dasatinib, nilotinib, and bosutinib, it’s 3 or 4 maximum.

Of course, in many instances, you find mutations in which there are either no data or no difference between the sensitivity of 1 drug versus the other. If that is the case, then it’s not informative. Of course, if there are no mutations and you go by other factors—whether comorbidities can help you, depending on the possibilities of a given adverse event that you’re worried about; the schedule; and the familiarity—it’s important to manage the drugs that you’re more familiar with because it will help you manage your patient better. All these factors end up being important in dosing since this is where the mutations don’t help.

Harry Erba, MD, PhD: The T315I mutation is set apart because there’s only 1 ABL TKI that works there.

Jorge Cortes, MD: Right now, ponatinib is the only drug that works. If you have T315I mutation, you have to go straight to ponatinib no matter how many prior lines of therapy. It tends to happen; it happens after 1 TKI. If you go down more lines of therapy, the frequency starts going up.

Transcript edited for clarity.

Harry Erba, MD, PhD: So you see the patient is not responding at milestones or losing response. You look at compliance. I look at drug-drug interactions, proton pump inhibitors for nilotinib and dasatinib. But let’s say you rule out all those things. What kind of resistance mechanisms, specifically mutations, do we see?

Jorge Cortes, MD: One thing that’s important for mutations is primary resistance and secondary resistance. Primary resistance would be that patient doesn’t meet the goals that you are aiming to get. Secondary resistance would be the patient responded but now is losing their response. Mutations are particularly common in the secondary resistance.

The patient who got a complete cytogenetic response, who is compliant, now you see that they lost the complete cytogenetic response and certainly the hematologic response. Up to 50% of those patients can have mutations. The patient who just doesn’t make it to the desired goals—not just to the optimal response but even to those suboptimal responses—you will find some mutations, but it’s more in the range of 10% to 15%. So the yield is very low. It’s worth checking, of course, because if you’re going to change therapy based on that, you want to know that you’re going to change to something that has a good chance of working. But it’s also important to recognize that most of the time, you don’t have such a guide because you won’t find a mutation. It is important to recognize that difference.

Harry Erba, MD, PhD: In primary resistance, what are some of the resistance mechanisms that have been implicated?

Jorge Cortes, MD: Well, we talked about the receptor. There’s been the discussion as to whether…the activity of OCT1 is less. It doesn’t affect all the drugs. It affects imatinib more than it affects, for example, nilotinib. Not all the drugs need that receptor. We talked about SRC, and that could be a mechanism of resistance. Obviously, as you mentioned, adherence and the drug-drug interactions and all these things.

There are growing data, evolving data that suggest that some of these patients may actually have additional molecular abnormalities that we previously didn’t recognize as present. Some of them have to do with these clonal hematopoiesis, and ASXL1 and DNMT3A mutations. Now, there are evolving data. We don’t know how much of a role they play. But it is interesting that these patients who don’t have resistance—and even more, the patients who have an early transformation. Even though clinically it appears that they have chronic phase, they seem to already have a molecularly more complex disease than it appears just by cytogenetics.

Harry Erba, MD, PhD: Yeah, I think that’s a really important point. If you go back, way back, to data from The University of Texas MD Anderson Cancer Center and other places with interferon and hydroxyurea, and you look at when progressions occur, even now in the ABL TKI [tyrosine kinase inhibitor] era, there are numerically more progressions on any of those studies in the first year. Then it kind of slows down, almost as if something has been developing in those patients that is making them have a more resistant disease.

Jorge Cortes, MD: That is more correct. For those patients, you say, “Gee, why do these patients progress so quickly when the blasts were low?” There’s evidently a more complex disease than we recognize just by the BCR-ABL protein.

Harry Erba, MD, PhD: Do you look for mutations at baseline to help guide therapy?

Jorge Cortes, MD: No, not in the chronic phase. In the chronic phase, there have not been any mutations described at baseline. Patients who have a blast phase at the time of diagnosis, you will find mutations in some of these patients. You even have patients with a T315I mutation, and it’s a little bit more common if it’s a lymphoblast phase. You could argue is that a Philadelphia chromosome–positive ALL [acute lymphoblastic leukemia] or a lymphoblast phase. Sometimes, it’s impossible to tell. But in that context, you could have mutations at baseline. But in chronic phase, no, so I don’t check.

Harry Erba, MD, PhD: OK. Let’s now focus on those patients with secondary resistance. Typically, 50% of them will have a mutation. Do those mutations help guide second-line therapies?

Jorge Cortes, MD: Absolutely. There is a panel of mutations for each of our options for second-generation drugs that are not as sensitive to each 1 of them. For example, dasatinib doesn’t work against the V299L mutation. The same applies for bosutinib, by the way. Whereas nilotinib doesn’t work against the F359V mutations. For each drug, there are 2, 3, or 4 mutations in which it doesn’t work. Certainly, universal to all them, except ponatinib, is the T315I, and they all have. Of course, for imatinib, the panel of mutations that are resistant is larger. For dasatinib, nilotinib, and bosutinib, it’s 3 or 4 maximum.

Of course, in many instances, you find mutations in which there are either no data or no difference between the sensitivity of 1 drug versus the other. If that is the case, then it’s not informative. Of course, if there are no mutations and you go by other factors—whether comorbidities can help you, depending on the possibilities of a given adverse event that you’re worried about; the schedule; and the familiarity—it’s important to manage the drugs that you’re more familiar with because it will help you manage your patient better. All these factors end up being important in dosing since this is where the mutations don’t help.

Harry Erba, MD, PhD: The T315I mutation is set apart because there’s only 1 ABL TKI that works there.

Jorge Cortes, MD: Right now, ponatinib is the only drug that works. If you have T315I mutation, you have to go straight to ponatinib no matter how many prior lines of therapy. It tends to happen; it happens after 1 TKI. If you go down more lines of therapy, the frequency starts going up.

Transcript edited for clarity.
Copyright © TargetedOnc 2019 Intellisphere, LLC. All Rights Reserved.