BTK Inhibitors Boost Outcomes in B-Cell Malignancies, But Challenges Remain

Kami J. Maddocks, MD

The emergence of BTK inhibitors in both the frontline and relapsed settings have improved outcomes for patients with B-cell malignancies, according to Kami J. Maddocks, MD, who added that newer agents are emerging that could potentially address challenges still faced with this approach and continue to move the needle forward.

Three key BTK inhibitors have received regulatory approvals in this space: ibrutinib (Imbruvica), which was the first to enter the treatment arsenal, acalabrutinib (Calquence), and zanubrutinib (Brukinsa), which is the newest addition. These inhibitors have demonstrated comparable efficacy when examined in single-agent phase 2 trials, according to Maddocks, although they have largely been not compared head to head.

“There is some suggestion that the toxicities of the agents are different,” Maddocks explained. “[For example], ibrutinib was the first approved and there were concerns of cardiac toxicity, such as atrial fibrillation, hypertension, and bleeding. While that has been reported with the newer BTK inhibitors [as well], at least to date with the data we have, there are maybe less of those toxicities observed.” Maddocks added that headaches appear to be more commonly reported with acalabrutinib, while neutropenia is a toxicity associated with zanubrutinib.

Newer BTK inhibitors are also under exploration, according to Maddocks. “[These newer agents] might have activity because they don't develop a mutation in the binding site. That's potentially exciting, especially if someone experiences a great response to treatment and progresses because of a mutation and they're able to be retreated with a different type of BTK inhibitor,” Maddocks explained.

In an interview with OncLive, Maddocks, an associate professor of Clinical Internal Medicine in the Division of Hematology at Ohio State University –James, discussed the utility of BTK inhibitors in B-cell malignancies, challenges that are still faced in the space, and areas primed for additional development.

OncLive: Could you start by providing an overview of the role of BTK inhibitors in B-cell malignancies? Where are they currently used in the course of treatment?

Maddocks: BTK inhibitors are used in several different B-cell malignancies and have been approved in both the frontline and relapsed setting. In mantle cell lymphoma (MCL), 3 BTK inhibitors are approved for use in the relapsed setting and they are often the first choice of treatment at the time of relapse. In chronic lymphocytic leukemia (CLL) specifically, 2 BTK inhibitors are approved in both the frontline and relapse setting. While they were initially more frequently [used] in the relapsed setting, it's fairly common now for patients to receive a BTK inhibitor as their initial choice of therapy, especially [for those with] higher-risk disease. Waldenström macroglobulinemia is another [disease for which] BTK inhibitors are approved for use; 1 BTK inhibitor is approved in both the relapsed and frontline settings. Also, ibrutinib has received approval for use in the relapsed setting for patients with marginal zone lymphoma (MZL).

Could you expand on the agents that are currently approved? What factors do you consider when selecting among these inhibitors?

Three BTK inhibitors are currently approved. Ibrutinib was the first approved BTK inhibitor; this was followed by acalabrutinib and zanubrutinib, which most recently received approval in November 2019. All 3 are approved for [patients with] relapsed MCL, so that is really where you have a choice of all 3 agents. Ibrutinib and acalabrutinib are approved [for those with] CLL, and ibrutinib [also has indications] in Waldenström macroglobulinemia and MZL.

Currently, only 1 trial has examined these [agents] in a randomized fashion. Specifically, investigators examined ibrutinib [versus] zanubrutinib in [patients with] Waldenström macroglobulinemia. Otherwise, many our comparisons for these agents come from single-agent, phase 2 studies; it is a little hard to compare them because they have not [been compared against each other] in a randomized trial. It really looks like they have fairly similar overall activity when you take into consideration the criteria for patients going on trial and the way that response was assessed in the trials. There are not a lot of data [indicating] that they greatly differ in that [regard].

Certain differences do exist with regard to [toxicities. For example], acalabrutinib tends to cause more headaches. In a randomized trial, more neutropenia was seen with zanubrutinib. There are some differences and randomized trials will tell us exactly what those are. However, based on the data we have, there is a suggestion that maybe acalabrutinib or zanubrutinib have less of these cardiac toxicities.

What data do we currently have to support the use of zanubrutinib? How do you see this agent impacting the treatment of B-cell malignancies in the future?

We have data looking at [this agent] in [patients with] relapsed and high-risk CLL with deletion 17p and relapsed MCL, [as well as] in those with Waldenström macroglobulinemia; it has been shown to be highly effective. There was a randomized trial comparing this agent with ibrutinib in patients with Waldenström macroglobulinemia. Although the trial did not meet its primary end point, differences in toxicity profiles were observed; less atrial fibrillation and bleeding were seen with zanubrutinib. This agent is another option and a potentially improved safety profile over the others. At this point, we can't say that the activity is higher or better with zanubrutinib. We need more follow-up on the studies that we have and to see the results of ongoing studies to [answer that question].

What challenges do you think still need to be addressed? Where should research efforts focus going forward?

Currently, BTK inhibitors are approved as single-agent therapies and they're continued [indefinitely], as long as patients are tolerating them and are [achieving] a good response. Some of the [current] question include: Can we use these agents more in frontline [setting]? Which combinations produce deeper remissions and potentially allow for limited therapy?

[For example], if we have 2 or 3 drugs that we use for 1 or 2 years and are able to achieve deep remissions or minimal residual disease–negative remission, are patients able to be on these therapies for a shorter amount of time instead of continuing on treatment forever? That obviously helps decrease long-term toxicity. If patients do that, are they able to be retreated with these therapies? If they achieve a deep remission and are on a combined therapy for 1 year and they relapse in 2 years or 5 years, are we able to retreat and achieve a remission again with those therapies?

In some of the diseases like MCL where [BTK inhibitors are] used uniformly in the relapsed setting, but do not have approvals in the frontline setting, how can we add these agents to frontline therapies to improve outcomes in those patients?

Are any drugs in development or any trials nearing completion that you're excited about?

If you look at BTK inhibitors in general, newer BTK inhibitors are emerging that bind differently and potentially could be either active in patients who have not received prior treatment with BTK inhibitors or even in those who have progressed on these agents.

Newer therapies are emerging in all disease [types]: CAR T-cell therapy has obviously been an exciting development that is being explored in some of these diseases; hopefully, we'll continue to [see improvements with this approach] with regard to response and toxicity. Some of the bispecific antibodies in some of the B-cell malignancies have also looked promising. there Lastly, some antibody-drug conjugates are in development that have shown encouraging results, as well.