ONCAlert | Upfront Therapy for mRCC

Frontline Treatment for CML With BCR-ABL-Targeted TKIs

Published Online:12:35 PM, Wed July 10, 2019

Harry Erba, MD, PhD: Let’s now turn to that patient who you made the diagnosis for. We now have 4 drugs from which to choose: based on the IRIS trial, imatinib; ENESTnd led to a nilotinib approval; DASISION trial led to dasatinib approval; and most recently the BFORE trial, which you published in JCO [Journal of Clinical Oncology] recently, led to the approval of bosutinib. So we have 4 drugs. How do you choose among these? And I’m not going to let you say, “Whichever the insurance company tells you, you can prescribe.”

Jorge Cortes, MD: Well, unfortunately, sometimes that’s the answer, but I’m not going to answer that way. The first question that I want to answer is, do I want imatinib or do I want a second-generation TKI [tyrosine kinase inhibitor]? All these studies you mentioned have shown us that with the second-generation tyrosine kinase inhibitors, you get deeper responses, faster responses, you actually get more responses, and you get a lower rate of transformation. The proportions vary. But in general, that is the case. Second-generation TKIs have those benefits against imatinib. They don’t give you a survival advantage, or at least they haven’t so far, and they don’t give you a progression-free survival, an event-free survival. But that’s probably not that unrealistic, considering that with imatinib, you do get a high cytogenetic response rate and with that, the survival already goes pretty close to the normal life expectancy.

But there are all these other benefits, including lower risk of transformation. That’s my first decision. In general, I prefer to go with the second-generation tyrosine kinase inhibitors because I value those benefits for the patient, not only for the immediate benefit that it confers but for the long term. We’re going to talk more about that. Then we will discuss which 1 of the 3. I have dasatinib, nilotinib, and bosutinib. Perhaps the next important aspect that I take in consideration for the selection is the expected toxicities, the comorbidities, and how each 1 of these may play for that particular patient. There’s no direct comparison among these 3 drugs. If you put the 3 studies side by side, the data look very comparable. You can look at small differences, but considering you’re comparing different studies, it’s very hard to make too much out of those small differences.

I think that the next issue is about the comorbidities and the risk of a given toxicity based on the patient. You have to discuss them with the patients. Sometimes for a patient’s lifestyle, giving adverse event, diarrhea, or fluid retention may be more meaningful than some others. Even some things that may not be a form of contraindication. I don’t think a patient with diabetes shouldn’t take nilotinib. You can perfectly well treat a patient with diabetes. But if you have options, and there is a patient who has had problems with control of the diabetes, well, maybe you can select something else. If somebody has pulmonary issues and whatever, again, I have treated patients with dasatinib. But if you have that option, well, maybe I would stay away from that initially and go with something that has less risk of pleural effusions and things like that. For somebody who has already problems with their bowels, such as irritable bowel syndrome, diarrhea may be more of a problem. So those things can help you make those decisions.

Harry Erba, MD, PhD: I like how you walked through those, but let me put you on the spot for 1 that a lot of us are concerned about. To me, I think the data show that the second-generation ABL TKIs do have more cardiovascular risk in terms of arterial occlusive events than imatinib. Do you think there’s a significant difference between the 3 second-generation drugs? Do you use cardiovascular risk as a reason to choose between the second-generation drugs, or would you use imatinib in a patient with cardiovascular disease?

Jorge Cortes, MD: I think that that’s something that took us awhile to learn. We didn’t recognize that early on, but now we do, and it is very clear that there is an increased risk of arterial thrombotic events, arterial occlusive events, with these drugs. I think that it’s a common thing. Certainly with ponatinib, and nilotinib, and dasatinib, you see higher risks compared with imatinib in these randomized studies. With bosutinib, there appears to be less of a risk. I still think that imatinib probably has the lowest risk, but of the second-generation inhibitors, it appears that bosutinib has the lowest of the 3. I think that that’s an important consideration.

Just like this Framingham Heart Study risk score, a number of risk factors put a patient at risk of having heart attacks and things like that. If it is a patient who already has a lot of risk factors—has hypercholesterolemia, and is hypertensive or diabetic, smokes, and so forth—imatinib gives you the lowest risk of all these drugs. That’s why we still use imatinib in some patients. That may be the safest thing. Do you lose something in terms of efficacy? You lose something, but we shouldn’t forget that it is an effective drug. What you gain in terms of safety may be justified.

If it is a patient who has very few risk factors or maybe only 1, and certainly if you can control, let’s say, the hypertension, maybe you have a little bit more flexibility. If it’s a patient for whom I really want to use a second-generation inhibitor, but I’m a little concerned, I may go with bosutinib in that patient, although it still needs attention, and we need to be careful on managing all these comorbidities to minimize your risk.

Harry Erba, MD, PhD: Yeah, I practice the exact same way. If I have a patient, especially older patients with significant cardiovascular risk factors and actual prior events, I’m going to go with imatinib as first-line therapy. Let’s say I go with imatinib as first line, and they’re not meeting their milestones. Are you a believer in going up on the dose, or do you switch?

Jorge Cortes, MD: Oh, I am a believer in going up in the dose in a given scenario. Certainly, switching is better. There was this old study with dasatinib that was a randomized study: the START-R, where it would be these patients who were not responding well. The criteria for switching were different from the ones we use nowadays—the criteria for failure and all that. But still, the point is that the patients were randomized to either switch to dasatinib or increase the dose of imatinib, and switching was better. But I do think that for a given patient for whom the risks are very high with the switch, increasing the dose can help some patients. That could be a consideration for a patient like the 1 you described.

Transcript edited for clarity.

Harry Erba, MD, PhD: Let’s now turn to that patient who you made the diagnosis for. We now have 4 drugs from which to choose: based on the IRIS trial, imatinib; ENESTnd led to a nilotinib approval; DASISION trial led to dasatinib approval; and most recently the BFORE trial, which you published in JCO [Journal of Clinical Oncology] recently, led to the approval of bosutinib. So we have 4 drugs. How do you choose among these? And I’m not going to let you say, “Whichever the insurance company tells you, you can prescribe.”

Jorge Cortes, MD: Well, unfortunately, sometimes that’s the answer, but I’m not going to answer that way. The first question that I want to answer is, do I want imatinib or do I want a second-generation TKI [tyrosine kinase inhibitor]? All these studies you mentioned have shown us that with the second-generation tyrosine kinase inhibitors, you get deeper responses, faster responses, you actually get more responses, and you get a lower rate of transformation. The proportions vary. But in general, that is the case. Second-generation TKIs have those benefits against imatinib. They don’t give you a survival advantage, or at least they haven’t so far, and they don’t give you a progression-free survival, an event-free survival. But that’s probably not that unrealistic, considering that with imatinib, you do get a high cytogenetic response rate and with that, the survival already goes pretty close to the normal life expectancy.

But there are all these other benefits, including lower risk of transformation. That’s my first decision. In general, I prefer to go with the second-generation tyrosine kinase inhibitors because I value those benefits for the patient, not only for the immediate benefit that it confers but for the long term. We’re going to talk more about that. Then we will discuss which 1 of the 3. I have dasatinib, nilotinib, and bosutinib. Perhaps the next important aspect that I take in consideration for the selection is the expected toxicities, the comorbidities, and how each 1 of these may play for that particular patient. There’s no direct comparison among these 3 drugs. If you put the 3 studies side by side, the data look very comparable. You can look at small differences, but considering you’re comparing different studies, it’s very hard to make too much out of those small differences.

I think that the next issue is about the comorbidities and the risk of a given toxicity based on the patient. You have to discuss them with the patients. Sometimes for a patient’s lifestyle, giving adverse event, diarrhea, or fluid retention may be more meaningful than some others. Even some things that may not be a form of contraindication. I don’t think a patient with diabetes shouldn’t take nilotinib. You can perfectly well treat a patient with diabetes. But if you have options, and there is a patient who has had problems with control of the diabetes, well, maybe you can select something else. If somebody has pulmonary issues and whatever, again, I have treated patients with dasatinib. But if you have that option, well, maybe I would stay away from that initially and go with something that has less risk of pleural effusions and things like that. For somebody who has already problems with their bowels, such as irritable bowel syndrome, diarrhea may be more of a problem. So those things can help you make those decisions.

Harry Erba, MD, PhD: I like how you walked through those, but let me put you on the spot for 1 that a lot of us are concerned about. To me, I think the data show that the second-generation ABL TKIs do have more cardiovascular risk in terms of arterial occlusive events than imatinib. Do you think there’s a significant difference between the 3 second-generation drugs? Do you use cardiovascular risk as a reason to choose between the second-generation drugs, or would you use imatinib in a patient with cardiovascular disease?

Jorge Cortes, MD: I think that that’s something that took us awhile to learn. We didn’t recognize that early on, but now we do, and it is very clear that there is an increased risk of arterial thrombotic events, arterial occlusive events, with these drugs. I think that it’s a common thing. Certainly with ponatinib, and nilotinib, and dasatinib, you see higher risks compared with imatinib in these randomized studies. With bosutinib, there appears to be less of a risk. I still think that imatinib probably has the lowest risk, but of the second-generation inhibitors, it appears that bosutinib has the lowest of the 3. I think that that’s an important consideration.

Just like this Framingham Heart Study risk score, a number of risk factors put a patient at risk of having heart attacks and things like that. If it is a patient who already has a lot of risk factors—has hypercholesterolemia, and is hypertensive or diabetic, smokes, and so forth—imatinib gives you the lowest risk of all these drugs. That’s why we still use imatinib in some patients. That may be the safest thing. Do you lose something in terms of efficacy? You lose something, but we shouldn’t forget that it is an effective drug. What you gain in terms of safety may be justified.

If it is a patient who has very few risk factors or maybe only 1, and certainly if you can control, let’s say, the hypertension, maybe you have a little bit more flexibility. If it’s a patient for whom I really want to use a second-generation inhibitor, but I’m a little concerned, I may go with bosutinib in that patient, although it still needs attention, and we need to be careful on managing all these comorbidities to minimize your risk.

Harry Erba, MD, PhD: Yeah, I practice the exact same way. If I have a patient, especially older patients with significant cardiovascular risk factors and actual prior events, I’m going to go with imatinib as first-line therapy. Let’s say I go with imatinib as first line, and they’re not meeting their milestones. Are you a believer in going up on the dose, or do you switch?

Jorge Cortes, MD: Oh, I am a believer in going up in the dose in a given scenario. Certainly, switching is better. There was this old study with dasatinib that was a randomized study: the START-R, where it would be these patients who were not responding well. The criteria for switching were different from the ones we use nowadays—the criteria for failure and all that. But still, the point is that the patients were randomized to either switch to dasatinib or increase the dose of imatinib, and switching was better. But I do think that for a given patient for whom the risks are very high with the switch, increasing the dose can help some patients. That could be a consideration for a patient like the 1 you described.

Transcript edited for clarity.
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