William G. Wierda, MD, PhD: I wonder, Anthony, if you could comment. You’ve done a lot of work with real-world data, and what are your thoughts on these 3 randomized trials that we’re seeing and how that might [have an] impact on what’s happening out in the practicing community.

Anthony R. Mato, MD: I think that’s a great question. I think that for patients who are—so first of all, I think there’s probably less of a difference between academic and community practitioners who are taking care of patients with CLL than we think. Most of the real-world data that we’ve collected, just as a disclaimer, has largely been from academic sites. And so—and I hate to say that those data sets represent what’s going on in community practice. There are increasing representations because, I think, we’ve recognized that that’s important to make sure it’s included.

I think that there are a subset of practitioners, both in academics and [the] community, who are going to continue to use chemoimmunotherapy combinations regardless of what these data show. I think that this will not be a paradigm shift, but it will be an incremental shift toward use of novel agents.

In terms of real-world data, I think that it’s nice that cooperative groups are very broad. And so I would never argue that a cooperative group represents the top 10 largest cancer centers in the country. They actually represent a lot of small practices. And so for me, these—at least the first 2 randomized studies that we talked about, or the second 2, the Alliance [A041202] and the ECOG [Eastern Cooperative Oncology Group] data—probably are closer to real-world than almost any of the other trials that have been presented for novel agents before. And so I suspect that that’s why, when we’re seeing a little bit of a higher discontinuation rate due to AEs [adverse effects], then it’s closer to the observations that we’ve made retrospectively.

I think that we are getting a window into what ibrutinib, Rituxan, or ibrutinib as a monotherapy will look like in a real-world multicenter setting. So I think [there is] probably less of a difference there. That’s 1 of the most important pieces of this data: that ECOG sites, for example, could be 1 of the largest cancer centers in the country, or it could be a small community practice.

Susan M. O’Brien, MD: Right, right. Yes. And I think, you know I have, in talking to guys in practice, I’ve heard this kind of a scenario. “Well, even if ibrutinib is better than BR [bendamustine plus rituximab] up front, BR up front is not bad. It can buy me, say, 4 years or longer” because I believe the median PFS [progression-free survival] in this trial, in the trial, was about 41 months. So 3 and a halfyears. And we know that when people progress, they don’t necessarily need retreatment immediately. So presumably the time to retreatment is even longer. So let’s say it buys them 4 or 5 years. What they’re thinking, and I get it, [is], “I’m not curing anybody, for the most part, with CLL, so I’ve got to sequence my therapies.” Well, what’s the easiest time to give people chemo? They’re not getting any younger, right? So, up front. So let me give it up front, when they’re in a pretty good shape. That’ll buy me 4 years or more. And so that’s 4 years of that patient’s life that I’ve just now saved without even having to go to the novel agents. So I still think that there’s going to be quite a bit of frontline use, but that trial did not show a survival advantage.

Matthew S. Davids, MD, MMSc: And I think that’s also true in the younger patients. You know there you have 1 chance probably of curative potential with FCR [fludarabine, cyclophosphamide, rituximab]. And if you start with ibrutinib and with or without rituximab and you wait a few years, then they’re older, they’re more comorbid, they’re not going to tolerate the FCR. So it’s really a strong argument.

Alexey V. Danilov, MD, PhD: Patients of the age of 65, they would have over 20 years of life expectancy. And so that’s 20 years of ibrutinib potentially. And I agree with Susan, that you could save, if you carefully select your patients, you could buy 7, 8 years for them.

Anthony R. Mato, MD: I think the paradigm shift that has to happen isn’t regarding development of a new class of agents. I think it’s actually changing the way that centers, maybe community practice more than academics, address the management of these patients. So community practices are really equipped to deal with chemotherapy, 6 months, how to manage the toxicity, see them every 21 or 28 days. I think that in order to make the clients [respond] using pure and novel agents in the front line or in the relapsed [or] refractory setting, you have to have a structure that actually will deal with the toxicity’s long-term management, 7 years of continuous ibrutinib in terms of answering phone calls, holding medications before every dental procedure, and so on and so forth.

So I think the structure of cancer centers has to change in order to deal with the biological advances that we’ve seen with these therapies, and that isn’t happening that quickly.

Transcript Edited for Clarity.