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Small-Molecule Inhibitors: Ibrutinib in CLL

Panelists:Alessandra Ferrajoli, MD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, Weill Cornell Medical College; Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine, Susan M. O’Brien, MD, UC Irvine Health; William G. Wierda, MD, PhD, University of Texas MD Anderson Cancer Center
Published: Tuesday, Mar 22, 2016


Transcript:

William G. Wierda, MD, PhD:
Let's talk about the small molecule inhibitors. I think there's a lot of data that's being reported here at ASH 2015 with regard to the small molecule inhibitors. I think what we'd like to do is start with ibrutinib and have an idea from Susan how she thinks ibrutinib has changed the landscape in CLL.

Susan M. O’Brien, MD: Obviously, it's changed enormously. We touched on the fact that the biggest complication, and most frequent and most feared with chemoimmunotherapy, is myelosuppression and infection in a patient population who, for other reasons, tend to have infections already because of the immunosuppression associated with their disease, their dysfunctional T-cells, hypogammaglobulinemia, etc.

I think one of the biggest advantages of the B-cell receptor inhibitors, and this sometimes gets lost a little bit because the efficacy is so good that you focus on that, is that they're not myelosuppressive. And not only are they not myelosuppressive, but cytopenias actually improve. And that's really very interesting because we used to say that with chemotherapy, cytopenias will improve. But in the beginning they won't because you get myelosuppression and because you have to clear out the bone marrow, right?

Well, clearly, I don't know the exact mechanism of action here, but the cytopenias are improving even when the leukocyte count can be 100,000. So, it's a little more complicated than that. It's not the simplistic idea of clearing out the marrow. I think that's one of the hugest advantages of these new molecules, and that enables us to more easily give them to older patients, in particular where, again, if a 75-year-old gets pneumonia and they wind up in the hospital, they're going to be completely deconditioned by the time they get out.

So, obviously efficacy is good, durability is good, but I think one of the main advantages that changed the whole landscape is the lack of myelosuppression and some infections because of the nature of the population, not because we're myelosuppressing these people.

William G. Wierda, MD, PhD: Alessandra, you've done a lot of work at Anderson with the elderly population, and there's a trial that's being reported for the first time here at this ASH meeting referred to as the RESONATE-2 trial. I wonder if you could give us your opinion on the results of the RESONATE study. There hasn't been data necessarily yet reported—there was a press release—But perhaps you can comment on what your thoughts are on the RESONATE-2 trial.

Alessandra Ferrajoli, MD: Yes. The RESONATE-2 trial will be presented at this meeting, and it is a cooperative study to look at randomized ibrutinib versus chlorambucil. This was in elderly patients with indication for therapy. It's a trial where we already know the answer, and that is the results with ibrutinib are superior in terms of overall response rate, in terms of complete response rate. But there is also superiority in terms of survival, even if a crossover was allowed in this trial, although later and during the conduction of the trial.

I think what we are all surprised is how big of a difference we are seeing. Because the results show that the response rate is close to 90% with the ibrutinib and also the survival, and the difference in survival is quite marked with an 85% improvement in survival with that relative short follow-up, and therefore is going to be improved over time.

William G. Wierda, MD, PhD: Dr. Ma, I'm sure you've used quite a bit of ibrutinib. What are some of the things that you look for in patients who you're starting on ibrutinib? What are some of the side effects that you monitor for, and how do you mitigate those problems?

Shuo Ma, MD, PhD: Right. So the most common side effects of ibrutinib are the GI side effects. So diarrhea and nausea can occur, and typically it’s mostly grade 1 and 2 and tends to resolve after the first two or three months of treatment. But one important thing is that there is an increased risk of bleeding for patients who are taking ibrutinib. So you have to educate the patient to watch out for any signs of bleeding. But also, if your patient is going to go over any invasive procedure such as surgery or tooth extraction, then they have to consider holding the drug for a few days before and a few days after the procedure.

Another thing to watch out for is atrial fibrillation. In the randomized trials, there is an increased incidence of atrial fibrillation for patients who are taking ibrutinib compared to the ofatumumab arm in the RESONATE Study. For elderly patients, atrial fibrillation is not an uncommon problem. So, that's something you have to educate a patient on. Those are the most common side effects we'll be watching for.

William G. Wierda, MD, PhD: So you mentioned the RESONATE-2 trial. There's another trial that's being updated at this ASH meeting, and maybe Susan can comment on that, and that is the RESONATE-17 trial, which is an ibrutinib monotherapy–based trial.

Susan M. O’Brien, MD: So, that's actually the largest trial ever in the 17p-deleted population. I think it's about 144 patients. And that data, the clinical data, efficacy data, has been presented and it will be updated here. But the important point about what's being presented here is the results by molecular analysis. If we just look at the efficacy results we see, not unexpectedly as we saw in the prior trials, a very high response rate in 17p-deleted patients. There is no median progression-free survival yet, but that's because the follow-up is about a year, so we wouldn't have expected to see a median at that point.

This analysis is going to look at various different types of mutations—p53, Notch, BRK1, etc—and try to look at, is there any difference in response rate: a mutated versus unmutated, heavy chain gene, etc? And clearly showing that, thus far, and again can't say much about progression-free survival yet, but in terms of response, there's really no difference. So the patients who historically have what we would consider bad mutations or poor prognosis mutations, such as p53, for example, seem to respond just as well as patients who don't. Again, we'll see with longer follow-up what plays out in terms of progression-free survival. But at least we can say for response rates, they don't seem to make any difference.

William G. Wierda, MD, PhD: So in the era of ibrutinib, do you think 17p is still a high-risk feature?

Susan M. O’Brien, MD: Yes, I do.

William G. Wierda, MD, PhD: And are there subgroups among the 17p-deleted patients that potentially are at higher risk than others?

Susan M. O’Brien, MD: Well, we know from the paper that you published with the Mayo Clinic that that's true at diagnosis, right? If you take all patients with 17p at diagnosis, which is not a very common abnormality, 5% to 8%, about half of those patients require therapy within one year. This is what you might have intuitively expected based on the fact that it's high-risk disease. But then there was the whole subset of patients that went years without any therapy. And if we looked at them right there, they were more likely to be mutated, they were more likely to be RAI Stage 0, and the clone was smaller. However, I think that once a patient with 17p progresses to the point of needing therapy, I think there's very little—r if there is, I don't think it's very clear what it is—that mitigates their poor prognosis.

As Tom said earlier, there are occasionally people who can get a durable response with FCR, but they're such the minority that for practical purposes, I think it's just, if they progress to needing treatment and they have 17p, you almost don't even need to know anything. So that may turn out to not be correct, again, if we have longer PFS follow-up, and we may find out that Notch 1 mutation and 17p deletion are worse with ibrutinib. I don't think we're in a position to know that yet.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

William G. Wierda, MD, PhD:
Let's talk about the small molecule inhibitors. I think there's a lot of data that's being reported here at ASH 2015 with regard to the small molecule inhibitors. I think what we'd like to do is start with ibrutinib and have an idea from Susan how she thinks ibrutinib has changed the landscape in CLL.

Susan M. O’Brien, MD: Obviously, it's changed enormously. We touched on the fact that the biggest complication, and most frequent and most feared with chemoimmunotherapy, is myelosuppression and infection in a patient population who, for other reasons, tend to have infections already because of the immunosuppression associated with their disease, their dysfunctional T-cells, hypogammaglobulinemia, etc.

I think one of the biggest advantages of the B-cell receptor inhibitors, and this sometimes gets lost a little bit because the efficacy is so good that you focus on that, is that they're not myelosuppressive. And not only are they not myelosuppressive, but cytopenias actually improve. And that's really very interesting because we used to say that with chemotherapy, cytopenias will improve. But in the beginning they won't because you get myelosuppression and because you have to clear out the bone marrow, right?

Well, clearly, I don't know the exact mechanism of action here, but the cytopenias are improving even when the leukocyte count can be 100,000. So, it's a little more complicated than that. It's not the simplistic idea of clearing out the marrow. I think that's one of the hugest advantages of these new molecules, and that enables us to more easily give them to older patients, in particular where, again, if a 75-year-old gets pneumonia and they wind up in the hospital, they're going to be completely deconditioned by the time they get out.

So, obviously efficacy is good, durability is good, but I think one of the main advantages that changed the whole landscape is the lack of myelosuppression and some infections because of the nature of the population, not because we're myelosuppressing these people.

William G. Wierda, MD, PhD: Alessandra, you've done a lot of work at Anderson with the elderly population, and there's a trial that's being reported for the first time here at this ASH meeting referred to as the RESONATE-2 trial. I wonder if you could give us your opinion on the results of the RESONATE study. There hasn't been data necessarily yet reported—there was a press release—But perhaps you can comment on what your thoughts are on the RESONATE-2 trial.

Alessandra Ferrajoli, MD: Yes. The RESONATE-2 trial will be presented at this meeting, and it is a cooperative study to look at randomized ibrutinib versus chlorambucil. This was in elderly patients with indication for therapy. It's a trial where we already know the answer, and that is the results with ibrutinib are superior in terms of overall response rate, in terms of complete response rate. But there is also superiority in terms of survival, even if a crossover was allowed in this trial, although later and during the conduction of the trial.

I think what we are all surprised is how big of a difference we are seeing. Because the results show that the response rate is close to 90% with the ibrutinib and also the survival, and the difference in survival is quite marked with an 85% improvement in survival with that relative short follow-up, and therefore is going to be improved over time.

William G. Wierda, MD, PhD: Dr. Ma, I'm sure you've used quite a bit of ibrutinib. What are some of the things that you look for in patients who you're starting on ibrutinib? What are some of the side effects that you monitor for, and how do you mitigate those problems?

Shuo Ma, MD, PhD: Right. So the most common side effects of ibrutinib are the GI side effects. So diarrhea and nausea can occur, and typically it’s mostly grade 1 and 2 and tends to resolve after the first two or three months of treatment. But one important thing is that there is an increased risk of bleeding for patients who are taking ibrutinib. So you have to educate the patient to watch out for any signs of bleeding. But also, if your patient is going to go over any invasive procedure such as surgery or tooth extraction, then they have to consider holding the drug for a few days before and a few days after the procedure.

Another thing to watch out for is atrial fibrillation. In the randomized trials, there is an increased incidence of atrial fibrillation for patients who are taking ibrutinib compared to the ofatumumab arm in the RESONATE Study. For elderly patients, atrial fibrillation is not an uncommon problem. So, that's something you have to educate a patient on. Those are the most common side effects we'll be watching for.

William G. Wierda, MD, PhD: So you mentioned the RESONATE-2 trial. There's another trial that's being updated at this ASH meeting, and maybe Susan can comment on that, and that is the RESONATE-17 trial, which is an ibrutinib monotherapy–based trial.

Susan M. O’Brien, MD: So, that's actually the largest trial ever in the 17p-deleted population. I think it's about 144 patients. And that data, the clinical data, efficacy data, has been presented and it will be updated here. But the important point about what's being presented here is the results by molecular analysis. If we just look at the efficacy results we see, not unexpectedly as we saw in the prior trials, a very high response rate in 17p-deleted patients. There is no median progression-free survival yet, but that's because the follow-up is about a year, so we wouldn't have expected to see a median at that point.

This analysis is going to look at various different types of mutations—p53, Notch, BRK1, etc—and try to look at, is there any difference in response rate: a mutated versus unmutated, heavy chain gene, etc? And clearly showing that, thus far, and again can't say much about progression-free survival yet, but in terms of response, there's really no difference. So the patients who historically have what we would consider bad mutations or poor prognosis mutations, such as p53, for example, seem to respond just as well as patients who don't. Again, we'll see with longer follow-up what plays out in terms of progression-free survival. But at least we can say for response rates, they don't seem to make any difference.

William G. Wierda, MD, PhD: So in the era of ibrutinib, do you think 17p is still a high-risk feature?

Susan M. O’Brien, MD: Yes, I do.

William G. Wierda, MD, PhD: And are there subgroups among the 17p-deleted patients that potentially are at higher risk than others?

Susan M. O’Brien, MD: Well, we know from the paper that you published with the Mayo Clinic that that's true at diagnosis, right? If you take all patients with 17p at diagnosis, which is not a very common abnormality, 5% to 8%, about half of those patients require therapy within one year. This is what you might have intuitively expected based on the fact that it's high-risk disease. But then there was the whole subset of patients that went years without any therapy. And if we looked at them right there, they were more likely to be mutated, they were more likely to be RAI Stage 0, and the clone was smaller. However, I think that once a patient with 17p progresses to the point of needing therapy, I think there's very little—r if there is, I don't think it's very clear what it is—that mitigates their poor prognosis.

As Tom said earlier, there are occasionally people who can get a durable response with FCR, but they're such the minority that for practical purposes, I think it's just, if they progress to needing treatment and they have 17p, you almost don't even need to know anything. So that may turn out to not be correct, again, if we have longer PFS follow-up, and we may find out that Notch 1 mutation and 17p deletion are worse with ibrutinib. I don't think we're in a position to know that yet.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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