EHA 2021 | Mavorixafor and ibrutinib in WM patients with MYD88 and CXCR4 mutations
Steven Treon, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, discusses the interim analysis from a Phase Ib study (NCT04274738) evaluating oral CXCR4 antagonist mavorixafor and ibrutinib in patients with Waldenström’s macroglobulinemia (WM) with MYD88 and CXCR4 mutations. MYD88 can be targeted by BTK inhibitors in WM but there has been little success thus far in identifying antagonists of CXCR4 mutations in WM. CXCR4 is an important signalling receptor in the trafficking of Waldenström cells to the bone marrow and can play an important part in BTK inhibitor drug resistance. Therefore, the CXCR4 receptor is a desirable target in the treatment of WM. Thus far, the study has shown that both drugs in combination are well tolerated, and there are improvements in hemoglobin levels in patients enrolled who are anemic. It is hoped data from this study will show more promising benefits for WM patients with further dose escalation. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.
Transcript (edited for clarity)
Yeah, I’m happy to be presenting at EHA this year, a interim analysis with a data cut-off of April 15 of this year, that is examining the oral antagonist, mavorixafor, that actually antagonizes CXCR4, along with ibrutinib, in patients with Waldenström’s Macroglobulinemia.
I’m excited about this trial because both the MYD88 and CXCR4 mutation were discovered in our laboratory, thanks to whole genome sequencing...
Yeah, I’m happy to be presenting at EHA this year, a interim analysis with a data cut-off of April 15 of this year, that is examining the oral antagonist, mavorixafor, that actually antagonizes CXCR4, along with ibrutinib, in patients with Waldenström’s Macroglobulinemia.
I’m excited about this trial because both the MYD88 and CXCR4 mutation were discovered in our laboratory, thanks to whole genome sequencing. And while we’ve done a lot of work translating the importance of targeting MYD88 to BTK inhibitors in this disease, where we know that BTK itself is activated by mutating MYD88, we have seen, so far, very little progress being made against antagonizing CXCR4. And I think this is actually one important trial, which I want to talk a little bit about why we’re very excited about this sort of approach.
So, as many of you recognize, CXCR4 is a receptor that actually signals in response to CXCL12. And it makes actually Waldenström’s cells traffic to the bone marrow, but it also creates drug resistance. And so, if you have some way of being able to block CXCR4 signaling, this might present a way for us to help advance therapy in Waldenström’s. And we know that CXCR4 can actually cause drug resistance against BTK inhibitors.
So, in a previous trial, we had looked at ulocuplumab, a CXCR4 antagonist, along with ibrutinib, and we were actually quite excited by that trial, because it showed us that we could get deeper responses faster by adding ulocuplumab.
Now in this trial that we’re going to be presenting at EHA, the potential to do this with an oral antagonist is being recognized. And unfortunately, we don’t have ulocuplumab anymore. BMS discontinued its development of this program, but we’re excited, on the other hand, that X4 is developing this oral antagonist. And this will also represent ease of convenience.
And so, I think this is going to be a very nice study, even though it’s an interim analysis. It’s showing us that the two drugs together are tolerated. We’ve seen, so far, that the IgMs go down and that the hemoglobins go up in the patients that are anemic. And so far, no, you know every reason to hope that we’re going to continue advancing this drug through dose escalation and further observation.
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Disclosures
Steven Treon, MD, PhD, has received research funding and consulting fees from Abbvie/Pharmacyclics, Janssen, Beigene, Eli Lilly and X4.
