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CD20-Targeted Antibodies With Novel Agents for CLL

Panelists: William G Wierda, MD, University of Texas MD Anderson Cancer Center; Alexey V Danilov, MD, PhD, University School of Medicine in Portland, Oregon; Matthew S Davids, MD, MMSc, Dana-Farber Cancer Institute; Anthony R Mato, MD, Memorial Sloan Kettering Cancer Center; Susan M. OBrien, MD The University of California, Irvine Medical Center
Published: Friday, Jan 25, 2019



Transcript:

William G. Wierda, MD, PhD:
We had some discussion about a BTK [Bruton tyrosine kinase] inhibitor plus CD20 antibody. I wonder, Susan, if we talk about venetoclax and BCL2-directed therapy, what are your thoughts? Is it different than this discussion we had previously with BTK plus CD20 antibody? Is there synergy? Do we need a CD20 antibody?

Susan M. O’Brien, MD: I do think there’s a difference, and to be fair, the ibrutinib data which does not show any difference is clearly with rituximab. So I guess the jury is still out on whether obinutuzumab would make ibrutinib better, and certainly, as I mentioned from the ILLUMINATE trial, that CR [complete response] rate of 40% is much higher than you can get with ibrutinib alone and higher than rituximab/ibrutinib. So I think the jury is still out on whether obinutuzumab adds anything to ibrutinib.

Certainly, we know from 2 trials now that rituximab does not, other than getting more rapid response. Because, of course, when you add in the antibody, you abrogate the lymphocytosis, you get to your PR [partial response] much more quickly. But we now have 2 randomized trials of ibrutinib plus or minus rituximab, clearly showing that the progression-free survival curves are exactly the same. I think in stark contrast to that is the venetoclax data where we saw, in the original phase I, that the MRD [minimal residual disease]-negativity rates were about 20%. And then in the phase II relapsed trial in combination with rituximab, the trial that led to that combination being used in MURANO, the phase II rituximab/venetoclax had an MRD-negativity rate of about 55%. That was recapitulated in the MURANO trial; well it was about 60%.

And we do have very little data with obinutuzumab and venetoclax from the safety lead-in for the CLL14 trial. So the CLL14 trial, which we haven’t heard about yet, is the randomized trial of obinutuzumab and chlorambucil versus venetoclax and obinutuzumab. And before that trial commenced, there was a safety lead-in to find out if they could safely give—because this is a much older population—venetoclax and obinutuzumab. There were about 12 patients there, and 1 patient had a very bad infusion reaction to the obinutuzumab and came off. But of the other 11 patients, something like 10 become MRD-negative. So really tiny numbers, but certainly suggestive that there’s some kind of synergy going on there.

I think whether you talk about the antibody being rituximab or obinutuzumab, and they may not be the same, there does seem to be a major advantage to adding that to venetoclax, which raises an interesting question on the ibrutinib/venetoclax combination trials. There are so many going on now, and we touched on them earlier. If the antibody adds to 1 small molecule but it doesn’t add to the other, do you need it with the combination? I don’t think we know the answer to that. There are some phase II trials that have antibody in there, some phase II trials that don’t. So, perhaps, comparing across trials is the way we’re going to get a handle on that. But, certainly, with single-agent venetoclax as opposed to being combined with ibrutinib, I think the antibody makes a huge difference.

William G. Wierda, MD, PhD: And we’re developing a study right now at [The University of Texas] MD Anderson [Cancer Center] that will be a randomized trial of an early CD20 antibody with BTK plus BCL2. And the endpoint will look at MRD and depth of remission with a fixed duration of treatment. So, hopefully, with that trial, we’ll be able to get some insight into if there’s a benefit to the CD20 antibody. I think there is. I think the depth, there’s potential there. Particularly, where we’re moving is taking fixed duration and treatment and giving that to patients, and progress will be in terms of depth, increasing the depth of remission with the combinations that we’re giving and shortening the treatment time. I’m interested in regimens that will get patients where they need to be as quick as possible and hopefully will reduce cost.

Susan M. O’Brien, MD: Although there were some data presented at ASH [the American Society of Hematology meeting] about the timing of antibodies, suggesting that it actually might be better to give it later in the course of the small molecule therapy and some data to suggest CD20 was upregulated. And hence, coming in with the antibody later might be better. And that was very interesting because in all of the trials that we have so far, the antibody is front loaded.

Matthew S. Davids, MD, MMSc: Although that was specific to ibrutinib, right?

Susan M. O’Brien, MD: Yes.

Matthew S. Davids, MD, MMSc: Not to venetoclax.

Susan M. O’Brien, MD: Not to venetoclax.

Matthew S. Davids, MD, MMSc: We don’t know yet for venetoclax.

Susan M. O’Brien, MD: Correct.

William G. Wierda, MD, PhD: That was ibrutinib, it was Andy Rawstron ,PhD, I think.

Susan M. O’Brien, MD: Right.

William G. Wierda, MD, PhD: Ibrutinib, and obinutuzumab was added after patients had been on ibrutinib-based therapy.

Transcript edited for clarity.
 

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Transcript:

William G. Wierda, MD, PhD:
We had some discussion about a BTK [Bruton tyrosine kinase] inhibitor plus CD20 antibody. I wonder, Susan, if we talk about venetoclax and BCL2-directed therapy, what are your thoughts? Is it different than this discussion we had previously with BTK plus CD20 antibody? Is there synergy? Do we need a CD20 antibody?

Susan M. O’Brien, MD: I do think there’s a difference, and to be fair, the ibrutinib data which does not show any difference is clearly with rituximab. So I guess the jury is still out on whether obinutuzumab would make ibrutinib better, and certainly, as I mentioned from the ILLUMINATE trial, that CR [complete response] rate of 40% is much higher than you can get with ibrutinib alone and higher than rituximab/ibrutinib. So I think the jury is still out on whether obinutuzumab adds anything to ibrutinib.

Certainly, we know from 2 trials now that rituximab does not, other than getting more rapid response. Because, of course, when you add in the antibody, you abrogate the lymphocytosis, you get to your PR [partial response] much more quickly. But we now have 2 randomized trials of ibrutinib plus or minus rituximab, clearly showing that the progression-free survival curves are exactly the same. I think in stark contrast to that is the venetoclax data where we saw, in the original phase I, that the MRD [minimal residual disease]-negativity rates were about 20%. And then in the phase II relapsed trial in combination with rituximab, the trial that led to that combination being used in MURANO, the phase II rituximab/venetoclax had an MRD-negativity rate of about 55%. That was recapitulated in the MURANO trial; well it was about 60%.

And we do have very little data with obinutuzumab and venetoclax from the safety lead-in for the CLL14 trial. So the CLL14 trial, which we haven’t heard about yet, is the randomized trial of obinutuzumab and chlorambucil versus venetoclax and obinutuzumab. And before that trial commenced, there was a safety lead-in to find out if they could safely give—because this is a much older population—venetoclax and obinutuzumab. There were about 12 patients there, and 1 patient had a very bad infusion reaction to the obinutuzumab and came off. But of the other 11 patients, something like 10 become MRD-negative. So really tiny numbers, but certainly suggestive that there’s some kind of synergy going on there.

I think whether you talk about the antibody being rituximab or obinutuzumab, and they may not be the same, there does seem to be a major advantage to adding that to venetoclax, which raises an interesting question on the ibrutinib/venetoclax combination trials. There are so many going on now, and we touched on them earlier. If the antibody adds to 1 small molecule but it doesn’t add to the other, do you need it with the combination? I don’t think we know the answer to that. There are some phase II trials that have antibody in there, some phase II trials that don’t. So, perhaps, comparing across trials is the way we’re going to get a handle on that. But, certainly, with single-agent venetoclax as opposed to being combined with ibrutinib, I think the antibody makes a huge difference.

William G. Wierda, MD, PhD: And we’re developing a study right now at [The University of Texas] MD Anderson [Cancer Center] that will be a randomized trial of an early CD20 antibody with BTK plus BCL2. And the endpoint will look at MRD and depth of remission with a fixed duration of treatment. So, hopefully, with that trial, we’ll be able to get some insight into if there’s a benefit to the CD20 antibody. I think there is. I think the depth, there’s potential there. Particularly, where we’re moving is taking fixed duration and treatment and giving that to patients, and progress will be in terms of depth, increasing the depth of remission with the combinations that we’re giving and shortening the treatment time. I’m interested in regimens that will get patients where they need to be as quick as possible and hopefully will reduce cost.

Susan M. O’Brien, MD: Although there were some data presented at ASH [the American Society of Hematology meeting] about the timing of antibodies, suggesting that it actually might be better to give it later in the course of the small molecule therapy and some data to suggest CD20 was upregulated. And hence, coming in with the antibody later might be better. And that was very interesting because in all of the trials that we have so far, the antibody is front loaded.

Matthew S. Davids, MD, MMSc: Although that was specific to ibrutinib, right?

Susan M. O’Brien, MD: Yes.

Matthew S. Davids, MD, MMSc: Not to venetoclax.

Susan M. O’Brien, MD: Not to venetoclax.

Matthew S. Davids, MD, MMSc: We don’t know yet for venetoclax.

Susan M. O’Brien, MD: Correct.

William G. Wierda, MD, PhD: That was ibrutinib, it was Andy Rawstron ,PhD, I think.

Susan M. O’Brien, MD: Right.

William G. Wierda, MD, PhD: Ibrutinib, and obinutuzumab was added after patients had been on ibrutinib-based therapy.

Transcript edited for clarity.
 
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