Shuo Ma, MD, PhD: Ibrutinib has been the first-in-class BTK [Bruton tyrosine kinase] inhibitor that has the longest studied history, and we know a lot about its long-term clinical outcome as far as the safety profile. And now there’s also the new generation, a second-generation more selective BTK inhibitor, such as acalabrutinib, which recently received FDA approval.

The ELEVATE-TN trial, which was reported at ASH [American Society of Hematology annual meeting] 2019, compared acalabrutinib versus acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab. This 3-arm study has demonstrated similarly to the first-generation BTK inhibitor that acalabrutinib either used alone or in combination, is superior to the chlorambucil plus obinutuzumab combination in progression-free survival [PFS]. Interestingly, even though the previous study in Alliance showed that when rituximab is added to ibrutinib it did not seem to show much benefit comparing to ibrutinib alone. In this study, in the ELEVATE study, the addition of obinutuzumab to acalabrutinib actually shows a small benefit in progression-free survival when compared to acalabrutinib alone. So I think that is interesting new information we learned.

The second-generation BTK inhibitor with acalabrutinib, and there are some other drugs on the market, but not yet approved for CLL. Those are all new-comers that are more selective in BTK and have less off-target effect and have the potential of hopefully reducing some adverse effects associated with the BTK inhibitors.

William Wierda, MD, PhD: We have had chemoimmunotherapy and there was a randomized trial looking at chlorambucil monotherapy versus chlorambucil, rituximab versus chlorambucil, obinutuzumab. That trial ultimately showed improvement in outcomes with obinutuzumab over rituximab plus chlorambucil or chlorambucil monotherapy.

Now we’re seeing more data recently with, as you say, 3-arm randomized trials with BTK inhibitor-based therapy with either rituximab or obinutuzumab. I wonder if I can get Stephen’s opinion on what the current thought is on CD20 antibodies and CD20 antibodies in addition to BTK inhibitor-based therapy. And is there a superior antibody or does it add to the BTK inhibitor-based therapy?

Stephen Opat, MBBS: In general, when we look at ibrutinib trials, it’s difficult to find a substantial benefit by adding rituximab, or Rituxan, to ibrutinib. But the ELEVATE-TN study, which looked at the combination as Dr Shuo mentioned of obinutuzumab with acalabrutinib did show a PFS benefit. The reason may be that ibrutinib has inhibitory action against Tec and iTAK kinases, which may impact antibody-dependency or cytotoxicity, but it may also be the nature of the antibody. So obinutuzumab seems to be a more potent antibody, it induces higher rates of MRD [minimal residual disease]-negativity than rituximab. It may be that using a strong antibody with a BTK inhibitor, which has less inhibitory reactions on perhaps one of the main mechanisms of action of the antibodies, is a sensible combination.

The question certainly in Australia will come down to a cost-effectiveness question, whether the added benefit of adding an antibody is warranted. And it’s not just a cost question, there’s also safety and tolerability. There are increased rates of neutropenia, potentially increased rates of infection if you combine multiple agents. Certainly with obinutuzumab there’s risk of infusion reaction. So, there’s a cost both financial and also in terms of adverse effects with the combination. I think the follow-up is also very short, so it’s really difficult to know where this will fit in, but they are encouraging data.

Carolyn Owen, MD: I have to say I feel very much in agreement that it’s too early to say that the obinutuzumab clearly adds, and it’s a real shame that the study was designed in such a way that they didn’t intend for the 2 arms to be compared with and without antibody. So, the study isn’t powered for that end point, which is an end point that everybody is so interested in, and obviously in hindsight, maybe they didn’t recognize at the time that everybody would want to know this. When you look at the ibrutinib, obinutuzumab arm of the iLLUMINATE study, clearly those were quite a high-risk patient population. Not allowed to do cross-trial comparisons but that doesn’t really appear to be, they certainly didn’t do any better with the antibody.

And so, I think that without strong knowledge that the antibody truly does add, we can all feel comfortable using acalabrutinib without obinutuzumab. And again, community treaters don’t have to feel like their choice is between a combination that includes IV [intravenous] therapy, it’s offered for the patient, it’s much more difficult to give. I think you could look at either BTK inhibitor as monotherapy, and only if the data proved strong with time. Because it is very short follow-up at this point, and the curves really seem to be separating right around the point at which the median follow-up is. I don’t know that that’s the most confident time point to make that decision.

William Wierda, MD, PhD: There are clear data that don’t support rituximab with BTK inhibitor, and I think everybody, I hear a consensus there, would be interested in looking and seeing more follow-up and are comfortable with BTK inhibitor-based therapy. If it’s monotherapy, either ibrutinib or acalabrutinib, and are not real enthusiastic about combination therapy with CD20 antibody.

Jacqueline Barrientos, MD: No, and the rate of infections was also much higher in the combination strategy. So, I would be hesitant to recommend it.

Stephen Opat, MBBS: The 1 issue is that the ECOG 1912 study had IR [ibrutinib, rituximab] as the investigational arm. There was no single agent ibrutinib, so while we haven’t been able to show a benefit adding rituximab to ibrutinib, it’s very hard when you’re deviating away from the trial and some of these wanted to say, use FCR [fludarabine, cyclophosphamide, rituximab]. I’m not sure you can then say single agent ibrutinib is adequate because that trial hasn’t been done.

William Wierda, MD, PhD: Now that you mention that trial, that trial was really the only large phase III trial that showed an overall survival difference. Maybe you could comment on that and what the current thought is about that difference that’s being reported, with few events.

Stephen Opat, MBBS: There has been a small number of events. The ECOG 912 was a trial in patients who were eligible for FCR [fludarabine, cyclophosphamide, rituximab]-based therapy and it compared FCR [fludarabine, cyclophosphamide, rituximab] with ibrutinib with Rituxan, or rituximab, and it made its primary end point, which was progression-free survival. And then there’s also a small difference in overall survival. There were a few progressions, but I think from memory roughly half of them were due to progressive chronic lymphocytic leukemia.

At the moment, even with the update at the ASH 2019 meeting, there’s still a benefit to investigational arm—ibrutinib, rituximab—but follow-up is short. And we know with drugs like ibrutinib over time there’s an accumulation of toxicities, there’s hypertension, and atrial fibrillation, and bleeding. And so whether or not there’s a follow-up when you’re getting some of the favorable patients who received FCR [fludarabine, cyclophosphamide, rituximab], you might see the curves flip.

At this stage we haven’t seen that, but I think particularly in the favorable patient with mutated immunoglobulin gene and no adverse other biological features, I think the question is not answered.

Transcript Edited for Clarity