BTK and BCL-2 Inhibitors Reach New Milestones in CLL

Michael Choi, MD, an associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center

Michael Choi, MD,

Long-term data with BTK- and BCL-2—based treatment regimens have solidified their roles as standard frontline treatments for patients with chronic lymphocytic leukemia (CLL), and have set the stage for additional research aimed at delivering sustained remissions, according to Michael Choi, MD.

“We now have enough follow-up experience with BTK inhibitors and BCL-2 inhibitors to know that these drugs are active and safe,” said Choi. “The challenge we’re confronted with is having to decide between them. However, this might become an irrelevant question down the road when we start putting them together into perhaps even more active combinations.”

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Choi, an associate clinical professor of medicine at the University of California, San Diego (UCSD) Medical Center, shed light on the data with BTK and BCL-2 inhibitors in CLL and shared ongoing research being done with PI3K inhibitors and CAR T-cell therapy in the relapsed/refractory setting.

OncLive: Could you discuss the long-term data with frontline treatment regimens in CLL?

Choi: We now have longer follow-up data on some of the newest drugs. We’re seeing even more compelling data from the CLL14 trial, which evaluated the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva). The 3-year follow-up show a significant improvement in progression-free survival (PFS) and a high degree of undetectable minimal residual disease (uMRD). I also talked about the combination of venetoclax and ibrutinib (Imbruvica), as well as some of the newer BTK inhibitors, such as acalabrutinib (Calquence), which has been evaluated in combination with obinutuzumab alone and in combination with obinutuzumab and venetoclax. All of these drugs are extremely active. Many patients are achieving remission with no detectable disease and we expect them to remain in remission off treatment.

How are you navigating between the 3 available frontline treatment regimens?

There are two main standard categories: drugs that inhibit BTK, such as ibrutinib and acalabrutinib, and venetoclax in combination with obinutuzumab. This is a discussion I have with my patients. When it comes to BTK inhibitors, with 5- and 6-years of follow-up, we are able to speak with confidence that the drugs are safe and that most patients who remain on therapy will remain in remission. We do have a lot of information about mild, but usually manageable, adverse events (AEs) and we continue to get more experience on how to manage those toxicities.

With the venetoclax and obinutuzumab combination, I tell my patients that this is a 1-year treatment [regimen] with the expectation of many years of remission. We only have a few years of follow-up with this approach, but we have seen outstanding data [thus far]. Notably, the regimen is a little bit more intensive in that [we have to] closely monitor laboratory values and [watch for] tumor lysis syndrome. However, most patients can tolerate the combination. [The pivotal trial examining the regimen] was intended for older patients with other medical problems.

[With these data], we may be able to start making distinctions between the rates of atrial fibrillation or bleeding with BTK inhibitors, and the concern for tumor lysis syndrome with venetoclax, and tailor therapy to our patients’ preferences and goals for treatment.

Based on the data from the ELEVATE-TN trial, should acalabrutinib be used alone or in combination with obinutuzumab?

It's still unclear. It's nice to have as an option for patients in whom we want to induce a more rapid response. It’s also good to see some clarity as far as a rapid reduction in the lymphocytosis with the CD20 antibody. I'm still not convinced that obinutuzumab will provide a significant advantage in PFS in the long run. For that to be the case, the combinations with ibrutinib or acalabrutinib need to result in deep remissions with uMRD, or [lower MRD] with next-generation sequencing.

While I believe that the data are interesting, we'll need longer follow-up to see if they continue to show an advantage with obinutuzumab and acalabrutinib. At the same time, it’s reassuring that we have data to show us that we can safely give the combination to our patients, [when appropriate].

Could you discuss the data that have read out with ibrutinib and venetoclax?

My mentor, Thomas Kipps, MD, PhD, of UCSD Moores Cancer Center, likes to joke that “all oncologists must have played with Legos when they were younger because as soon as we have 2 things that work well, we put them together.” The efficacy data [with this combination] are very compelling; approximately 70% of patients reach uMRD after about 1.5 years of treatment. The all-oral aspect of the regimen is convenient for many patients. I wonder when it will become a standard treatment option.

I found the trial design very interesting. The investigators explored whether continued BTK inhibition would help patients regardless of whether they achieved an MRD-negative remission, knowing that those remissions are not definitive cures. [Ongoing treatment with the combination may] lead to a measurable extension of their remission. It’ll be interesting to see more data.

What are your thoughts on the triplet of acalabrutinib, venetoclax, and obinutuzumab?

It's reassuring to see that those drugs, which have pretty unique mechanisms of action, are pretty well tolerated both individually and when used in combination. [The triplet led to] a 100% response rate, which is certainly a great thing for patients. We'll need more time and additional studies to determine the advantage of the 3-drug combination versus the 2-drug regimens, which we know from CAPTIVATE and CLL14 are really outstanding. On that note, the ALLIANCE and ECOG groups are accruing patients to 2 very important trials that are comparing the 3-drug combination with ibrutinib and obinutuzumab.

Are most studies with venetoclax incorporating time-limited treatment into the trial designs?

For the most part, trials with venetoclax are administering the drug for about 1 year of 12 or 13 cycles, including 1 cycle of ramp up. Then, marrow and/or peripheral blood will be evaluated for detectable CLL cells. Some trials are stopping treatment regardless of those results. Some studies are then randomizing patients with residual disease to continue some amount of therapy. That sort of basic design is being used in all sorts of clinical trials with various combinations with PI3K inhibitors and acalabrutinib, as we’ve seen. These trials will provide us with more information down the road.

How do frontline therapy decisions impact what can be given in the relapsed/refractory setting?

Now, with defined durations of treatment, one expectation is that all of those treatment options will be maintained as options upon relapse because patients won't have progressed and won't have developed overt clinical resistance to any of those agents. However, that’s something that does need to be tested. There are some initial data showing that patients who had complete remissions on venetoclax, stopped, and then resumed venetoclax upon progression had equally excellent responses the second time around. If we see [those results] repeated in other trials, that will give us more confidence that we're preserving all of our treatment options with this strategy.

Otherwise, for patients who stay on a BTK inhibitor, progress on a BCL-2 inhibitor, or have to stop either agent due to toxicity, it’s pretty clear that switching to other drug classes is the standard of care in the second-line setting. We are fortunate to have many other treatment options in the second-line setting, such as PI3K inhibitors and clinical trials.

What is the role of duvelisib (Copiktra) in this space? How do you see the role of PI3K inhibitors evolving?

The strict label [for duvelisib] is for patients who have received 2 or more lines of therapy; right now, that means for patients who have received a BTK inhibitor and venetoclax. There may be exceptions for patients with a clear contraindication, such as a bleeding disorder or requirement for a strong anticoagulant. For those patients, it's good to have this drug class as an option. Many active trials with duvelisib and venetoclax or with obinutuzumab are ongoing. [Duvelisib] may be used in earlier lines of therapy [pending the results] of those trials.

What is some of the work that is being done with CAR T-cell therapy in CLL?

There's a lot of excitement about this approach and its potential to lead to long and durable remissions in patients with really just a vial of cells; it makes me feel very optimistic. We are fortunate that most of our patients will probably never need to take on the risk of CAR T-cell therapy because we have such excellent drugs. For patients with high-risk disease, especially those who develop resistance or are unable to use any of our main lines of therapy like ibrutinib, CAR T-cell therapy is something we could turn to. I'm hopeful that we’ll continue to see high response rates and high uMRD rates that lead to truly durable remissions.

Are any other emerging agents or combinations generating excitement in this space?

In the frontline setting, many of the combinations we’re seeing are with our main agents, including a BTK inhibitor, a BCL-2 inhibitor, and a CD20-directed antibody. In the second-line setting, other drugs classes are also under exploration, the main ones being the noncovalent BTK inhibitors that bind to BTK distinctly. As such, these agents should have activity in patients with BTK mutations and those who progress on ibrutinib. That is going to be one promising way to continue patients on a safe class of oral agents.

Other PI3K inhibitors are in development. Trials are exploring umbralisib with the CD20 antibody ublituximab; umbralisib is also being examined in combination with ublituximab and venetoclax. This research may expand on the work being done with other PI3K inhibitors [and we may] find an optimal way to use that drug.