Nicole Lamanna, MD: We’re still focusing on BTK inhibitors in frontline just for a moment before we jump into the combos. What about antibodies and ibrutinib? We have several clinical trials, the ILLUMINATE trial and others, looking at the addition of either rituximab or obinutuzumab with ibrutinib or acalabrutinib. What do people feel about frontline, a monoclonal antibody with ibrutinib or acalabrutinib?

Javier A. Pinilla-Ibarz, MD, PhD: I think Jan Burger definitely can comment on that later. It’s always been questionable, at least something that initially we were excited to really combine CD20 monoclonal with ibrutinib. And it makes sense because we are using monoclonal for most of our lymph node malignancies, right? Early data from Jan and The University of Texas MD Anderson Cancer Center, very nicely collaborated in the ALLIANCE trial, did not show any benefit from the addition of Rituxan. Why? It’s still not clear. Maybe some rationale for the lack of activity with monoclonals in the combination with ibrutinib because of some specific target of some kinases that could be involved in this effect.

The bottom line is, in my opinion and with the trial that we have, it doesn’t seem the monoclonal adds much to a BTK inhibitor. At least with ibrutinib, and I think obviously in the IR [ibrutinib, rituximab], in the ECOG trial that compares ibrutinib-Rituxan with FCR [fludarabine, cyclophosphamide, rituximab], we don’t have the ibrutinib alone, so we may not really conclude that. It seems to really make this association and really believe that it is not.

Obviously the ILLUMINATE trial doesn’t have a BTK alone. It’s important to really notice that obviously obinutuzumab is a second-generation monoclonal antibody that is more powerful if you compare it with Rituxan. However, we did not have this comparator arm. We can discuss maybe the Elevate trial, with limited information in terms of how these 2 arms were compared. It may be slightly different, but it still is not clear to me. In my opinion for now, I don’t really see a role, but I would love to hear Jan comment.

Nicole Lamanna, MD: Yeah, because obviously the Elevate trial did have the monotherapy with acalabrutinib. What do you think about that data?

Jan Burger, MD, PhD: Yeah, I think outside clinical trials, BTK inhibitors should be used as single agent, especially for ibrutinib. You are right, the second-generation agent, acalabrutinib, was studied in a randomized fashion as a single agent rather than in combination with obinutuzumab. There was a small benefit in terms of progression-free survival from the addition of obinutuzumab, but also it added toxicity. For that reason I personally wouldn’t, outside clinical trial, combine it. The role in the future could be, if we are thinking about combination studies as a gateway to a limited-duration therapy, maybe then we can take advantage of the fact that CD20 antibodies get patients into deeper remission or get them into remission faster, and maybe then some patients, especially the low-risk patients, could stop treatment for a while.

Richard R. Furman, MD: I do want to add to that, though. I do think we all have to keep an eye toward progression-free survival as probably the more important end point. For the BTK inhibitors, we really don’t have data that MRD [minimal residual disease] or depth of response is actually going to be predictive of progression-free survival, though we suspect so. It’s important to keep in mind, when you’re talking about combining an anti-CD20 with a BTK inhibitor, that right now we don’t have any data that really add anything. It is important to focus on the depth of remission, but right now it’s an interesting end point but not 1 that’s been clinically justified.

Nicole Lamanna, MD: We’re going to get to MRD. Hold your thoughts.

Javier A. Pinilla-Ibarz, MD, PhD: We have to add mainly that although we all discuss it, this is a small difference that Jan was really attributing. This study was not powered to really compare the ACALA [acalabrutinib]. I think that’s an important thing, because there seems to be a difference. Did you really go to the statistical evaluation? We should not really make a clear conclusion for these data. It seems like they are very exciting.

Nicole Lamanna, MD: Yup.

Farrukh Awan, MD: One thing Jan said, and I think it’s very important, is that the biggest or the leading cause of morbidity and mortality in our patients is infectious complications. Adding on a CD20 monoclonal antibody might give you slightly longer progression-free survival, but for a lot of our patients the infectious complications might be a bigger issue. Maybe, again, in the select patient that might be easier, but does it really help us in the long run? How much are we adding to the progression-free [survival] and at what cost? That question is still up in the air, even though there might be a trend to it, a slightly better progression-free survival with the addition of obinutuzumab as compared with the historic rituximab combinations. I still feel that should not be the standard of care, and I think most of us would agree.

Transcript Edited for Clarity