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TIDEL-II: Switching From Imatinib to Nilotinib in CML

Panelists: Harry P. Erba, MD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Michael Mauro, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Aug 16, 2018


Transcript: 

Harry P. Erba, MD: OK, so let’s move on. Let’s come back then to the TIDEL-II trial, where patients started on imatinib 600 mg and then certain things caused them to switch. And what showed up from that trial? Why would they switch, and what did we learn?

Michael Mauro, MD: I think the key points from the TIDEL studies were that you start with imatinib, or even an escalated dose of imatinib, and then optimize by looking at some things that are a bit novel, looking at the plasma levels, which isn’t routinely done but I think is probably provocative and useful. But then talking about milestones. The things we’ve learned are really molecular response or later milestones. Should you start with imatinib or higher-dose imatinib or intermediate-dose imatinib? In the end, with the 5-year data, you’re going to wind up switching at least one-third of patients.

I think the data showed that the patients who missed early milestones did not do very well. So, based on our conversations so far, we know that we probably can relax a little bit once a patient gets into early response and has good early reduction and be a little bit less demanding when it comes to how quickly they get a major molecular mission, as long as it hopefully occurs. And then more important, what is the role of a deep molecular remission, although there’s clearly a role?

But the ability to switch and optimize patients was good but a little bit more limited in the early failures and a little bit better in the later failures. But I think in the end, it showed us that that’s another path forward, that you can start with imatinib and optimize and have similar, probably better, success. But again, with all the trappings and having very meticulous follow-up and very careful optimization at key time points.

Jorge E. Cortes, MD: I’ll make a comment because when you look at the cumulative incidence of MR4.5 in the TIDEL-II, it is remarkably similar to the cumulative incidence of MR4.5 at 5 years from dasatinib or nilotinib. Very, very similar. However, let’s not forget that this was imatinib 600 mg. It’s not imatinib 400 mg. And when you put the cumulative incidence of MR4.5 with imatinib 400 mg and imatinib 600 mg, it’s not the same. We’ve done these studies. We used imatinib 800 mg, and without the early intervention and all of that, it looks remarkably similar to TIDEL-II. And when you look at the German study, the CML4, and then look at the imatinib 800 mg, it looks remarkably similar to TIDEL-II. So, there is a question mark there. Was this the early intervention, or was that the higher doses of imatinib? And we don’t have the answer.

But it also raised the question of whether that applies to imatinib 400 mg in early intervention. So, we don’t know those answers because the study is the only one that has been showing results in this early intervention of imatinib 600 mg with an early switch to nilotinib. Their first goal was first increased to 800 mg and whatever. So, that’s a question mark that we need to be aware of, that this is early intervention but starting with imatinib 600 mg.

Michael Mauro, MD: Back to your point, though. A lot of people around the world use imatinib. So, it’s enough evidence that’s significant to me to use intermediate-dose imatinib, even in the United States, as an initial treatment option. It’s not label, and it’s not for everybody, but I think it’s an option. And it might be a good option around the world, although clearly the second-generation inhibitors…

Jorge E. Cortes, MD: I don’t think I have to tell you that that’s what I use.

Harry P. Erba, MD: OK, but let me tell you what my concern remains about that approach of starting with imatinib and then moving based on a poor response at 3 months or 6 months to a second-generation drug. And my concern is that in every single trial of an ABL, of interferon—we’ll start with interferon—and then the ABL TKIs, the highest rates of progression occur in the first 6 to 12 months. They occur early on. My feeling is that, especially for the higher-risk patients, in CML, start with your best drug because, again, my goal is to prevent progression. So, one of my concerns about TIDEL-II when I tried to weed through the data and what happened to all the patients, there was a small number of patients who actually progressed during that first 3- to 6-month period. And it’s never going to be statistically significant, but when it happens to one of our patients, it’s going to be devastating.

Jorge E. Cortes, MD: Well, the rate of transformation is pretty low when you start, when you use the higher doses of imatinib. So, if we’re going to use the higher doses of imatinib, I have not such a concern. To me, the concern is more that we know that unfortunately the monitoring is not appropriate. There’s a series that has shown that, in the United States, at least, at any of the recommended given time points for monitoring, only about 30% of patients are monitored. So, if you’re so highly dependent on those outcomes to decide on a switch and whatever, well, you’re going to miss them. You’re going to miss opportunities, and we don’t know what they represent, but Mike emphasized the fact that this was in a highly controlled setting and all these patients were monitored and whatever. If you do it that way, at least you have that level of protection, if you’re going to miss them.

Transcript Edited for Clarity 

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Transcript: 

Harry P. Erba, MD: OK, so let’s move on. Let’s come back then to the TIDEL-II trial, where patients started on imatinib 600 mg and then certain things caused them to switch. And what showed up from that trial? Why would they switch, and what did we learn?

Michael Mauro, MD: I think the key points from the TIDEL studies were that you start with imatinib, or even an escalated dose of imatinib, and then optimize by looking at some things that are a bit novel, looking at the plasma levels, which isn’t routinely done but I think is probably provocative and useful. But then talking about milestones. The things we’ve learned are really molecular response or later milestones. Should you start with imatinib or higher-dose imatinib or intermediate-dose imatinib? In the end, with the 5-year data, you’re going to wind up switching at least one-third of patients.

I think the data showed that the patients who missed early milestones did not do very well. So, based on our conversations so far, we know that we probably can relax a little bit once a patient gets into early response and has good early reduction and be a little bit less demanding when it comes to how quickly they get a major molecular mission, as long as it hopefully occurs. And then more important, what is the role of a deep molecular remission, although there’s clearly a role?

But the ability to switch and optimize patients was good but a little bit more limited in the early failures and a little bit better in the later failures. But I think in the end, it showed us that that’s another path forward, that you can start with imatinib and optimize and have similar, probably better, success. But again, with all the trappings and having very meticulous follow-up and very careful optimization at key time points.

Jorge E. Cortes, MD: I’ll make a comment because when you look at the cumulative incidence of MR4.5 in the TIDEL-II, it is remarkably similar to the cumulative incidence of MR4.5 at 5 years from dasatinib or nilotinib. Very, very similar. However, let’s not forget that this was imatinib 600 mg. It’s not imatinib 400 mg. And when you put the cumulative incidence of MR4.5 with imatinib 400 mg and imatinib 600 mg, it’s not the same. We’ve done these studies. We used imatinib 800 mg, and without the early intervention and all of that, it looks remarkably similar to TIDEL-II. And when you look at the German study, the CML4, and then look at the imatinib 800 mg, it looks remarkably similar to TIDEL-II. So, there is a question mark there. Was this the early intervention, or was that the higher doses of imatinib? And we don’t have the answer.

But it also raised the question of whether that applies to imatinib 400 mg in early intervention. So, we don’t know those answers because the study is the only one that has been showing results in this early intervention of imatinib 600 mg with an early switch to nilotinib. Their first goal was first increased to 800 mg and whatever. So, that’s a question mark that we need to be aware of, that this is early intervention but starting with imatinib 600 mg.

Michael Mauro, MD: Back to your point, though. A lot of people around the world use imatinib. So, it’s enough evidence that’s significant to me to use intermediate-dose imatinib, even in the United States, as an initial treatment option. It’s not label, and it’s not for everybody, but I think it’s an option. And it might be a good option around the world, although clearly the second-generation inhibitors…

Jorge E. Cortes, MD: I don’t think I have to tell you that that’s what I use.

Harry P. Erba, MD: OK, but let me tell you what my concern remains about that approach of starting with imatinib and then moving based on a poor response at 3 months or 6 months to a second-generation drug. And my concern is that in every single trial of an ABL, of interferon—we’ll start with interferon—and then the ABL TKIs, the highest rates of progression occur in the first 6 to 12 months. They occur early on. My feeling is that, especially for the higher-risk patients, in CML, start with your best drug because, again, my goal is to prevent progression. So, one of my concerns about TIDEL-II when I tried to weed through the data and what happened to all the patients, there was a small number of patients who actually progressed during that first 3- to 6-month period. And it’s never going to be statistically significant, but when it happens to one of our patients, it’s going to be devastating.

Jorge E. Cortes, MD: Well, the rate of transformation is pretty low when you start, when you use the higher doses of imatinib. So, if we’re going to use the higher doses of imatinib, I have not such a concern. To me, the concern is more that we know that unfortunately the monitoring is not appropriate. There’s a series that has shown that, in the United States, at least, at any of the recommended given time points for monitoring, only about 30% of patients are monitored. So, if you’re so highly dependent on those outcomes to decide on a switch and whatever, well, you’re going to miss them. You’re going to miss opportunities, and we don’t know what they represent, but Mike emphasized the fact that this was in a highly controlled setting and all these patients were monitored and whatever. If you do it that way, at least you have that level of protection, if you’re going to miss them.

Transcript Edited for Clarity 
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