CLL: Rationale for Ibrutinib and Sequencing

Susan M. O’Brien, MD: Another important point about the use of ibrutinib up front as initial treatment for CLL is that some of the poor prognostic features for progression-free survival with chemotherapy are not poor features in terms of ibrutinib. And so, for example, unmutated IGHV status, which is associated with a significantly shorter progression-free survival with chemotherapy, and 11q deletion—again, significantly short of progression-free survival with chemotherapy—don’t have any impact so far in the progression-free survival that we see with ibrutinib. And we know that from the RESONATE-2 trial, which was the randomized trial that led to the approval of ibrutinib as a frontline therapy. So, it appears to be better in the high-risk subset. It’s better overall in that older population compared with chlorambucil, but particularly better in the high-risk subset who don’t do as well with chemoimmunotherapy.

The RESONATE-2 trial now has a 3-year follow-up, and we still have not reached a median progression-free survival showing how durable these frontline remissions are. We also have some data from patient-reported outcomes, and they also showed that in all factors that were looked at—fatigue, etc—all of them improved over time with ibrutinib, and they improved much more significantly than with chlorambucil.

The longest follow-up that we have with ibrutinib is 5 years, and that’s actually from the phase II data. There were 2 cohorts of patients originally: a pretty small frontline cohort of 31 patients, all of whom were over the age of 65, and then a larger cohort of 101 relapsed/refractory patients.

What we have shown is that in the frontline patients, we still have not reached a median progression-free survival with this 5-year follow-up, but I’ll caution that it’s a small cohort. I think the data are more robust in the relapsed/refractory patients, who I’ll also mention had a median number of 4 of prior regimens—so, very substantially, heavily pretreated in that group, and our median progression-free survival with ibrutinib was 52 months. I’ll point out that for the high-risk patients—namely, those with 17p deletion or 11q deletion—that median progression-free survival in this highly relapsed cohort was better than any frontline progression-free survival curve for either of those 2 groups, really showing the tremendous activity of this agent.

In terms of sequencing small molecules, because we have several now, including ibrutinib, idelalisib, and venetoclax—although venetoclax, strictly speaking, currently is limited to 17p deletion patients but probably will have a wider approval by the end of the year—I generally would start with ibrutinib. That is the only 1 that has a frontline indication. And from there, it depends on if they’re resistant or intolerant. If they’re intolerant of ibrutinib, they can do pretty well with either drug. However, if they’re resistant to ibrutinib and we switch them to another kinase inhibitor, the median progression-free survival is short, and they do much better once they switch to venetoclax.