Expert Discusses Emerging Agents in CLL

Jennifer Brown, MD, PhD

In the treatment of chronic lymphocytic leukemia (CLL), ibrutinib (Imbruvica), idelalisib (Zydelig), and obinutuzumab (Gazyva) have been approved in the past few years. Though effective, these agents are rather non-specific, says Jennifer Brown, MD, PhD.

The BTK inhibitor ibrutinib targets many kinases, which may contribute to its high rate of toxicities. In patients with CLL that is difficult to treat, the novel agent acalabrutinib has shown promise as it binds to the same site as ibrutinib, but does not inhibit ITK. Acalabrutinib, and another novel BTK inhibitor, BGB-3111, could potentially have less toxicity than ibrutinib, says Brown.

With PI3 kinase inhibitors, researchers are hoping to build on the success of idelalisib with the investigational agent duvelisib.

“The toxicity pattern does seem to be different, it does not seem to have the same degree of autoimmune toxicity we see with the other delta inhibitors. Whether this is because it’s not hitting the target as effectively, or because it has other targets like casein kinase remains to be determined,” says Brown.

OncLive: What are some of the most exciting emerging agents in CLL?

There are 3 molecules that are more specific than ibrutinib that are all making their way through phase I to phase III trials. The first is acalabrutinib, the next one is BGB-3111, and the other is ONO-4059.

Acalabrutinib is the most advanced, it’s in two ongoing phase III registration trials. Both acalabrutinib and BGB-3111 have very carefully optimized their binding to BTK. They bind to the same site as ibrutinib with a covalent bond—so very similar to ibrutinib in that respect—but they do not inhibit ITK, which may allow them to interact more favorably with monoclonal antibodies, but may also reduce their beneficial effects on the immune system.

At the very least, acalabrutinib has less activity against TEC, which means there is potentially less bleeding. And so, what one might expect from these drugs is less toxicity—efficacy is too early to tell—but they are very highly effective. Response rates were almost universal and there have been very few relapses, but the follow-up is about a year.

Then in the PI3 kinase inhibitor area there are 2 drugs that are in registration trials, they both inhibit PI3 kinase delta. The first, duvelisib, also inhibits PI3 kinase gamma, so it can also hit T cells and neutrophils. That has had high activity in CLL in the phase I setting—about 60% response rate in patients with a high likelihood of 17p deletion and the 2-year progression-free survival (PFS) is about 60%. That is in a registration trial versus ofatumumab that may read out later this year.

The other drug, TGR-1202, is an interesting drug. It hits delta, and has recently been described to have another target also—casein kinase 1 epsilon. It has had to go to very high doses and reformulate to achieve good PK in patients. The number of patients on those doses and the duration is still relatively limited. They have seen high response rates. I think durability is pending because of the short follow-up.

Syk is another potential target in CLL, also in the BCR pathway. Entospletinib, which is a drug in development that targets Syk, had data presented at ASH in the post-BTK and post-PI3 kinase setting. In that setting the response rate was only about 25% with a PFS of 6 months, which is not great, but the patients are very sick. The way in which this drug will be developed remains unclear, although it is an interesting target.

How do you predict the treatment landscape will change in the next 5 to 10 years?

Very interesting data also came out in Richter transformation that both nivolumab (Opdivo) and pembrolizumab (Keytruda) seemed to have significant activity, at least among a handful of Richter patients treated on trials. One trial is at Mayo Clinic and one at MD Anderson. So, there are larger trials planned with those checkpoint inhibitors in that setting.It is impossible to know how the treatment paradigm will evolve. My concern is that we are in an intermediate place where we are using most of these drugs as single agents and were planning to use them sequentially, even though we have very little data that we can actually use them very effectively sequentially.

So, what I think needs to happen over the next 5 to 10 years is that we need more combination trials, for example, BCR and BCL2 inhibitors, or either with a CD20 antibody, of time-limited therapy where we treat people for a year or 2, get deep remissions, we stop, and then they are in remission for many years. When they come out of remission we can treat them and they won't be resistant. The current model of the sequential single agents appears to just lead to resistance, and resistance is not generally a good thing.

In an interview with OncLive, Brown, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute, associate professor of Medicine at Harvard Medical School, discussed novel agents and the future treatment landscape of CLL.Brown: Many of the novel drugs are building on what we've learned with these recent approvals, and are attempting to hit the same targets in potentially more effective ways.