William Wierda, MD, PhD: Ibrutinib has been studied in the frontline setting. There was a cohort of patients who were treated several years ago, 31 patients who received ibrutinib in the frontline setting, so we have long-term follow-up from that limited population of patients. That limited population of patients has done extremely well over time. I think there have been 2 events among the 31 patients, where one patient had a Richter’s transformation and came off and a subsequent patient came off more recently. But for the most part, those patients have done exceptionally well.

Subsequent to that experience was a randomized trial, referred to as RESONATE-2, that was conducted to evaluate in patients over 65 years old frontline chlorambucil versus frontline ibrutinib, where patients were randomly assigned to one of those treatments and then followed for their outcomes. That trial was very positive, favoring a longer progression-free survival for patients who received ibrutinib over chlorambucil as their first treatment. So, that was the first randomized trial showing improvement in outcomes associated with ibrutinib.

There is some criticism that gets thrown out there with regard to that trial design, particularly with the choice of the comparator arms. People would not think of chlorambucil today as a fair comparator because it’s really what we think of as an inferior frontline treatment. A better standard treatment today would be chlorambucil/obinutuzumab or bendamustine/rituximab. But other than that criticism, the trial clearly showed an improvement in outcomes associated with ibrutinib therapy.

That trial excluded patients with 17p deletions. We have limited data for patients with 17p deletion receiving ibrutinib in the frontline setting, particularly in terms of what the expectation is for their progression-free survival. We don’t know how long their remission will last with ibrutinib monotherapy in the frontline setting. Patients with 17p are rare in the frontline setting; it’s in about 5% to 8% of frontline patients. My expectation is certainly that the progression-free survival will be longer for frontline 17p deletion than for salvage 17p deletion. Regarding patients who have relapsed disease with 17p deletion and who receive ibrutinib, as I mentioned, their progression-free survival is about 32 months. The expectation for those frontline patients is that they’re going to have a longer progression-free survival, a longer median survival, than 32 months. But it may be more limited than non-17p deletion.

The major concern with ibrutinib is that in the frontline setting, it’s an exceptional treatment and patients do exceptionally well. But it’s a treatment that doesn’t get a good deep remission. Patients have to remain on treatment indefinitely. If they stop treatment, we expect that their disease will grow again and they will need treatment and the length of time between when they stop ibrutinib and the next treatment will vary. But certainly, they will most likely need to be retreated if they stop ibrutinib.

The main reason that patients in the frontline setting have been stopping ibrutinib isn’t because it’s not working any longer, it’s because they experience some ibrutinib associated toxicity that makes them come off it: things like arthralgias, myalgias, rash, oral ulcers, or fatigue. Those things can be treatment limiting with regard to ibrutinib, more so than the drug not working for patients who are receiving it in the frontline setting.

Transcript Edited for Clarity