Expert Sheds Light on Role of Next-Generation Agents in CLL

Susan M. O'Brien, MD

The treatment paradigm for relapsed/refractory chronic lymphocytic leukemia (CLL) is slowly expanding, with clinical trials starting and a new generation of drugs being ushered in, says Susan M. O'Brien, MD.

OncLive: Can you share some insight about emerging treatments for relapsed/refractory CLL?

In an interview with OncLive, O’Brien, MD, hematologist, oncologist, UC Irvine Health Chao Family Comprehensive Cancer Center, discusses upcoming novel treatments in relapsed/refractory CLL, such as the next generation of inhibition with BTK, SYK, and PI3K, as well as the outcomes of the recent RESONATE-2 trial.O'Brien: We have 2 B-cell receptor inhibitors that are approved—ibrutinib (Imbruvica) and idelalisib (Zydelig). Ibrutinib is a BTK inhibitor and idelalisib is a PI3K inhibitor. Both of those enzymes are pathways in the B-cell receptor signaling. There is another enzyme in that pathway called SYK, which is also being targeted; however, we don't have any commercially available drugs.

There are a very large number of next-generation BTK inhibitors, SYK inhibitors, and PI3K inhibitors in clinical trials as we speak. The one that is closest to being approved—potentially—is duvelisib, which is a PI3K delta and gamma inhibitor. It is now in a pivotal registration trial versus ofatumumab (Arzerra). Therefore, that one is probably the closest and could potentially be available if it's a positive study in the next 2 years.

We don’t know if these are just me-too drugs, or if they are actually better than the first-generation drugs, in some way. There are 2 ways they could potentially be better, one of which is higher efficacy.

We know with the B-cell receptor inhibitors, most of the responses are partial responses, so there is obviously room for improvement to be complete responses. That would also be very nice because, if we can get people into complete remission, then we have the potential to stop therapy—which we generally don't do right now with these drugs. People take them for very long periods of time.

The other way the next-generation drug could be better is if it had a different toxicity profile. We think of these drugs as generally well tolerated, but they do have their own significant toxicities. For example, ibrutinib can cause bleeding which is minor—but it can be more than that—and atrial fibrillation. Idelalisib can cause pneumonitis and late colitis, so there are side effects where, if the next-generation drug didn't have them or had them to a lesser extent, that would potentially be very favorable.

Are there any interesting upcoming trials?

For all of these drugs, there are some hints here and there, but it's still very early in development for most of them.TGR-1202, which is a PI3K inhibitor is about to go into a registration trial. There is also a next-generation BTK inhibitor called acalabrutinib, which used to be called ACP-196, and the data for the phase I was recently published in The New England Journal of Medicine. That pivotal trial is a head-to-head comparison of acalabrutinib versus ibrutinib in relapsed high-risk patients with CLL, including 17p and 11q deletions.

What are your thoughts on the RESONATE-2 data?

These are just a few. There are quite a large number of clinical trials going on with these agents.The RESONATE-2 trial, which looked at frontline randomized chlorambucil in patients 65 years or older, clearly showed better progression-free and overall survival with ibrutinib. The question now is, “Is there anyone I might not want to give ibrutinib to, for which I would want to stick to chemoimmunotherapy?” Potentially, there is. Several recent publications on long-term outcomes with FCR are all showing a significant plateau on the progression-free survival curve in some of these patients as well as a potential cure fraction.

Obviously, the question is, “Can we identify those patients?" We can. They tend to come from the group that are mutated—no 17p, no 11q—and, in particular, the presence of trisomy 12.

If you look at the data from The University of Texas MD Anderson Cancer Center, the plateau and the curve for the mutated patients is up almost around two-thirds at 12 to 16 years. This is a population where they get 6 months of chemotherapy, they have extremely durable remissions if not cured, and they are not taking pills everyday. That is a patient population where I would need to sit down with the patient and have a discussion of the pros and cons, versus taking a pill that has less acute side effects but no 10-year data.

That will be a discussion that we would have to have with the patients. In older patients or patients without these mutations, I would probably would go straight to ibrutinib.