BTK Inhibition in B-Cell Lymphomas - Episode 3
Harry P. Erba, MD, PhD:Let’s now focus in on CLL [chronic lymphocytic leukemia]. Tell us about the data that led to the initial approval of ibrutinib in CLL.
Anthony R. Mato, MD, MSCE:Ibrutinib was initially studied in the relapsed/refractory setting in ultra-heavily pretreated, high-risk patients. This is sort of the patient population who, before the advent of this drug in the studies, would have died very quicklysuch as fludarabine-refractory patients, patients who would have been relegated to stem cell transplantation. The drug was incredibly active. It was relatively well tolerated, which led to a very prompt approval based on single-arm phase II data. This was a relatively small number of patients, less than 100.
And then that data, particularly active in patients with deletion 17p, led to the approval of the drug as a first-line therapy for patients with the deletion 17p. It is sort of unprecedented in oncology to have a drug not necessarily studied in a frontline setting, but because it was so active in the relapsed/refractory setting, it led to a frontline approval because there was nothing in the frontline that could have done as well for those patients.
Harry P. Erba, MD, PhD:So are you saying that the approval of ibrutinib in the frontline setting is only for the 17p deleted?
Anthony R. Mato, MD, MSCE:Initially.
Harry P. Erba, MD, PhD:Oh, so what’s changed?
Anthony R. Mato, MD, MSCE:So then a second study was conducted. Well, there have been several studies conducted. In the relapsed/refractory setting, there was the phase Ib/II data. And then there was the RESONATE trial, which compared ibrutinib to ofatumumab. And then there was the RESONATE-17 trial, which looked at ibrutinib in 144 patients with deletion 17p-positive CLL. That was all in the relapsed/refractory setting.
Then in the frontline, there was the RESONATE-2 trial, which compared ibrutinib to chlorambucil for patients older than age 65 who did not and could not have had a deletion 17p. The FDA took that information and then approved ibrutinib for all patients in the frontline setting based on the results of the RESONATE-2 trial.
It was then studied in the relapsed/refractory setting in the HELIOS trial, which was BR [bendamustine/rituximab] plus or minus ibrutinib versus placebo. This was a positive trial that has subsequently been studied in 3 recent trials in the frontline setting, one for which was called E1912, which was FCR [fludarabine, cyclophosphamide, and rituximab] versus ibrutinib plus rituximab. That was a positive trial for ibrutinib/rituximab, in terms of PFS [progression-free survival] and OS [overall survival]. An Alliance trial looked at ibrutinib plus or minus rituximab versus bendamustine/rituximab. That was, again, positive for progression-free survival for the ibrutinib-treated patients. Interestingly, there was no difference between ibrutinib and ibrutinib plus rituximab. So the CD20 seemed to add nothing.
Most recently there’s a trial called iLLUMINATE, which was, again, label-enabling. This was ibrutinib plus the glycoengineered anti-CD20, obinutuzumab, versus the CLL11 regimen, which was obinutuzumab plus chlorambucil. That was also a positive trial, which then modified the label, subsequently allowing ibrutinib plus obinutuzumab to be considered as a frontline therapy for CLL.
Harry P. Erba, MD, PhD:But let’s come back to that ECOG [Eastern Cooperative Oncology Group] trial. That was fludarabine/cyclophosphamide/rituximab versus….
Anthony R. Mato, MD, MSCE:IR [ibrutinib/rituximab].
Harry P. Erba, MD, PhD:Not all patients with CLL are the same. We just discussed that. And there are data from Germany and MD Anderson Cancer Center that reveal that the subpopulation of CLL patients with mutated CLL appeared to have a plateau on the progression-free survival curve that was around 50% after fludarabine/cyclophosphamide/rituximab chemotherapy. So with that, do we know how continuing therapy for years with ibrutinib/rituximab or ibrutinib alone would compare to fludarabine/cyclophosphamide/rituximab? What are you doing in your practice?
Anthony R. Mato, MD, MSCE:That’s a great question. So the data from the Germans, the Italians, the MD Anderson group really suggested that younger patients without ap53aberration, either by sequencing or by FISH [fluorescence in situ hybridization], who wereIGHV-mutated, could go on to have a very long progression-free survival. Agree, there’s a tail on the curve and people say that’s a cure fraction in probably 20% or less of all patients who are treated with fludarabine/cyclophosphamide/rituximab. The problem with the data from ECOG is it’s just not long enough of a follow-up to know if there is a tail on the ibrutinib curve. So right now, it’s a complicated conversation for those 5% or 10% of people who would be fludarabine/cyclophosphamide/rituximab-ideal candidates. We offer them both options. The ECOG data showed a clear difference for the unmutated patients.
For the mutated patients, the hazard ratio was like 0.4, favoring ibrutinib over fludarabine/cyclophosphamide/rituximab, but it was not statistically significantly different. And if you look at the curves, they actually look pretty similar. So I think the message with targeted therapies is that there really are 2 CLLsmutated and unmutated. And we’re not talking about other targeted agents today, but across the board, all of the classes seem to be similar when you compare them to chemoimmunotherapy in theIGHV-mutated patients.
Harry P. Erba, MD, PhD:And it’s pretty evenly divided between mutated and nonmutated. Most studies I’ve seen are about 50/50.
Anthony R. Mato, MD, MSCE:I’d say like 60/40 for unmutated to mutated.
Harry P. Erba, MD, PhD:Can I come back to the testing for that?
Anthony R. Mato, MD, MSCE:Sure.
Harry P. Erba, MD, PhD:Because that’s specialized testing. You have to do a sequence analysis and look for deviations from germline. It’s more than what, 2% of the sequence?
Anthony R. Mato, MD, MSCE:Yes.
Harry P. Erba, MD, PhD:Before we knew about that, there were other assays that were quite en vogueZAP-70, CD38—which correlated in some way with the mutational status. Do you think we can rely on those other assays, or we should be doing the mutation analysis?
Anthony R. Mato, MD, MSCE:Personally, I don’t think so. At one time, these were good surrogates forIGHVmutational status, when that was more difficult to obtain. But they’re not perfectly correlated. They’re very subjective. ZAP-70 is often based on flow cytometry, for example, so you can really have an inaccurate result. If it were up to me, if I were designing a CLL prognostic panel, I would remove CD38 and ZAP-70. When I was at the University of Pennsylvania, I asked them to remove them because I don’t think they provide any information.IGHVmutational testing is available at academic centers, through commercial laboratories. It’s pretty much available to everyone. The NCCN [National Comprehensive Cancer Network] recommends it. The iwCLL [International Workshop on Chronic Lymphocytic Leukemia] recommends it. When you look across real-world registries, only 5% to 7% of patients have it checked before their first therapy. This is a major area where education needs to be implemented. At my former institution, it was as easy as adding an order into the EMR [electronic medical record] versus a paper requisition, which changed our use of it dramatically. It’s just that people don’t necessarily know how to order it as well, as easily.
Transcript edited for clarity.