Christian Buske, MD, Discusses Ibrutinib for Treating Patients With WM

In this video, Christian Buske, MD, Medical Director at the Comprehensive Cancer Center and the Institute of Experimental Cancer Research at the University Ulm, Germany, discusses data surrounding ibrutinib for the treatment of Waldenström macroglobulinemia (WM).

This discussion is moderated by Steven Treon, MD, PhD, Director of the Bing Center for Waldenström macroglobulinemia at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, Massachusetts.

This video was modified from an original recording published on Oncology Learning Network. Visit their website for the full discussion covering 3 Bruton’s tyrosine kinase (BTK) inhibitors active in the treatment of WM: ibrutinib, acalabrutinib, and zanubrutinib.

Transcript

Dr Steven Treon:  This is Steven Treon. I'm a professor of medicine at Harvard Medical School, and Director of the Bing Center for Waldenström's macroglobulinemia at the Dana-Farber Cancer Institute in Boston, Massachusetts.

This time, I just want to introduce our faculty. We have Dr Christian Buske. Christian, do you want to introduce yourself?

Dr Christian Buske:  Yeah, my name is Christian Buske. I'm coming from Germany Comprehensive Center in Ulm, and I'm involved in European trials for Waldenström’s.

Dr Treon:  Great. I thought we would probably start off with Dr. Buske, who will present us a brief overview of studies involving ibrutinib, the first Bruton's tyrosine kinase to be investigated in Waldenström’s macroglobulinemia. Christian?

Dr Buske:  Thanks, Steve. It's really a pleasure, and I think we have first to say that actually ibrutinib was the first BTK inhibitor which really changed the treatment landscape in Waldenström’s, which was more or less based before on rituximab plus or minus chemotherapy proteasome inhibitors, so it's really a new era with ibrutinib.

Thanks to you, Steve, we had this pivotal phase 2 trial in relapsed Waldenström patients, 63 patients. It was a US study, which actually demonstrated that ibrutinib as a single agent is the most, let's say, powerful drug as a monotherapy in Waldenström we have.

What we saw in this trial was that it's actually possible to achieve an overall response rate in around 90 % of patients in this relapsed setting. When we look at the major response rate, it's between 70 and 80%, so it's very encouraging data.

The progression-free survival was above 50%, 5-year progression-free survival in this trial, and the 5-year overall survival was nearly 90%. Very high single-agent activity for ibrutinib.

What we also saw in this pivotal trial was that it's well-tolerated, probably we'll come back to this, but the fraction or proportion of patients not tolerating ibrutinib or actually stopping treatment because of serious side effects was very low.

What we also saw was, perhaps what was discussed in the community was, despite this really exciting data, perhaps 2 limitations of ibrutinib. One which probably is still not solved is that we have to give it as a permanent treatment, so after progression, it's not timely fixed-duration, also in this pivotal trial.

The other issue which is still discussed is that it showed some dependency on the genotype on the mutation status of two genes, which is MYD88 and CXCR4—I'm sure we'll come back to this—with a drop in the major response rate depending on this genotype, from 90, to 60, to 0% when you look at MYD88-mutated, CXCR4 wild-type, double-mutated, and double wild-type patients.

This was also reflected by the observation that the time to response can be substantially delayed when you have these more unfavorable genotypes.

When you have double-mutated genotypes, the time to response drops or is delayed, prolonged from roughly 2 months to around 7 months, which makes a clinical difference in some of the patients. These were observations from this first pivotal trial.

The efficacy of ibrutinib, done again by you, Steve, could be confirmed also in treatment-naïve patients. I think that's important. A smaller number of patients, but very clear.

We see also the same as expected efficacy and toxicity profile in treatment-naive patients, but based on these observations, of course we have in the community the goal to improve on ibrutinib with regards to the efficacy in these different genotypes.

One idea was to combine ibrutinib with rituximab, and this was an international trial, phase 3 trial, with 150 patients, 75 patients were randomized per arm, and they were randomized between ibrutinib-rituximab, and placebo-rituximab. This study actually, not surprisingly, showed of course that ibrutinib-rituximab is much, much better than rituximab-placebo.

A quite interesting observation was that, in the combination with rituximab, ibrutinib had an efficacy largely independent of genotype when we look at the major response rates, of course with the limitation that the wild-type patients were smaller in this study.

I have to add, these were including relapsed and treatment-naïve patients, so it was a mixture. At least for the double-mutated, where you have more patients in this trial, it looks quite robust that the addition of rituximab to ibrutinib can improve major response rates.

This also seem to be true, again, I think we have still to be cautious, for the time to response for the double-mutated, which appear to be shorter than in the single-agent ibrutinib study.

With this, probably I close. It's a short summary of these 2 key trials, which I think set the stage where we want to go with respect to genotype-independent efficacy, and perhaps the new BTK inhibitors. We will listen now to Marie Jose and Judith make a difference.