Acalabrutinib Showcases Long-Term Tolerability Across B-Cell Malignancies

Richard R. Furman, MD

The second-generation BTK inhibitor acalabrutinib (Calquence) demonstrated favorable long-term tolerability in patients with B-cell malignancies, according to a pooled analysis spanning several hematologic malignancies, explained Richard R. Furman, MD, who underscored the importance of having a continuous, well-tolerated treatment.

The pooled analysis included 1040 patients with diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma (MCL), multiple myeloma, prolymphocytic leukemia, Richter syndrome, small lymphocytic lymphoma, and Waldenström macroglobulinemia who had been treated with at least 1 dose of single-agent acalabrutinib.

At a median follow-up of 26.4 months, 65% of patients were still on treatment. The median duration of treatment was 24.6 months (range, 0.0-58.5). Thirty-four percent of patients discontinued acalabrutinib, most commonly due to progressive disease (17%). Only 9% of patients discontinued acalabrutinib due to treatment-related adverse effects (AEs).

The most common AEs, which were headache (35%) and diarrhea (26%), were mostly grade 1/2 and occurred within the first 6 months of treatment. Secondary primary malignancies, atrial fibrillation, and hypertension were infrequent and of low grade.

“The drug is extremely well tolerated, and the tolerability profile is maintained throughout the entire course of treatment,” said Furman. “A number of patients do discontinue treatment early on primarily due to headaches and other AEs, but once patients get through the first couple of months of treatment, very few patients discontinue treatment for AEs.”

In an interview with OncLive, Furman, professor of medicine, Morton Coleman, MD Distinguished Professor of Medicine, director, CLL Research Center, Weill Cornell Medicine, and attending physician, NewYork-Presbyterian Hospital, discussed the findings from the analysis and highlighted the differences between first- and second-generation BTK inhibitors in CLL.

OncLive: Could you discuss the advent of covalent BTK inhibitors and their use in B-cell malignancies?

Furman: Currently, 3 BTK inhibitors are approved for use the United States––ibrutinib (Imbruvica), acalabrutinib, and zanubrutinib (Brukinsa)––all of which work by covalently modifying the BTK enzyme. All 3 agents covalently bind to the cysteine at the position 481 and block the BTK pocket, thereby rendering the enzyme ineffective. Currently, ibrutinib is approved in CLL, Waldenström macroglobulinemia, MCL, and marginal zone lymphoma (MZL), whereas acalabrutinib is only approved for MCL and CLL. Zanubrutinib is only approved in MCL. However, all 3 agents have similar efficacy outcomes, and we expect that their efficacy will be demonstrated or confirmed in the same histologies as ibrutinib has.

What distinguishes acalabrutinib from its earlier-generation counterpart ibrutinib?

Ibrutinib is a first-generation BTK inhibitor. Zanubrutinib and acalabrutinib are second-generation BTK inhibitors. Because all 3 agents covalently bind to the same residue and really work through the same mechanism in terms of efficacy, the only real difference is the specificity and the drug-drug interaction. Because of differences in specificity, you see fewer off-target effects with acalabrutinib and zanubrutinib than we do with ibrutinib. As such, we see different AE profiles. Also, because of the differences in how drugs are metabolized, we see differences in their interactions with other drugs.

What patients were included in this analysis? What did the results show in terms of the efficacy and safety of acalabrutinib?

This analysis looked across many different tumor types. We included 1040 patients, and a large number of the patients had CLL. We also included a large number of patients with myeloma and aggressive lymphoma, all of whom are going to experience very different AEs. Most of those AEs are likely going to be tumor related and not drug related. Because this was a heterogeneous population and was one that was by and large, sicker than what we might expect to see in just the CLL population, as well as a population of patients were acalabrutinib is not as efficacious as it is in CLL, we see a lot of AEs that are not related to the drug that make the agent’s profile look a little messier.

That’s important to keep in mind when you look at these data compared with what we might expect from a pure CLL population. In this study, we pooled patients on single-agent acalabrutinib from 9 different studies. The median follow-up for the patients in the study was approximately 52 months. We showed that acalabrutinib was well tolerated. Now that we have some long-term follow-up for patients on acalabrutinib, [we can say that the] tolerability we saw early on is maintained.

The most important aspect of this analysis is the fact that we saw fewer infections in patients in the long-term than we saw when patients first started therapy. A lot of that has also been demonstrated with ibrutinib, suggesting that we’re not making our patients [go into] agammaglobulinemia by shutting down the BTK enzyme. This is quite important since we intend the BTK inhibitors to be life-long therapy in order to control the disease. It’s very important for us to recognize that these drugs are tolerable and can be administered long-term.

A lot of patients who discontinued the drug had aggressive lymphomas, where BTK inhibitors are not efficacious. These patients discontinued the drug due to disease progression, not for AEs. In essence, acalabrutinib can be a long-term treatment for patients who benefit.

What are some of the differences between the first- and second-generation BTK inhibitors?

It’s also important to look at the difference between the first- and second-generation BTK inhibitors in terms of the AEs we've seen. Associated AEs with ibrutinib really fall into 6 groups. We see diarrhea, bruising, hypertension, atrial fibrillation, arthralgias, and nail and skin changes, all of which are related to on-target or off-target effects. Fortunately, with acalabrutinib and zanubrutinib, we see far fewer of those AEs.

With acalabrutinib, we really don’t see any diarrhea, and we see significantly less bruising. While the number of grade 1/2 bleeding events we see with acalabrutinib and ibrutinib are equal, there seems to be qualitatively less bleeding [with acalabrutinib] in terms of the fact that we might see grade 2 with ibrutinib and grade 1 with acalabrutinib.

With regard to hypertension, we see far less [with acalabrutinib]. That is a late AE with ibrutinib, and therefore 1 that may come up in acalabrutinib-treated patients with further follow-up. The atrial fibrillation really seems to be less, as do the joint aches. We don’t see the nail and skin changes that we see with ibrutinib. Therefore, acalabrutinib is better tolerated in terms of all those AEs.

The one difference we see with acalabrutinib that we don’t see with ibrutinib or zanubrutinib is headaches. The headaches are very intriguing because we don't understand why they occur. They tend to occur 1 to 2 hours after dosing the drug. They start on day 1, and patients often will actually become tolerant to the headaches after 2 to 4 weeks. Approximately 40% or 50% of patients have headaches, but the number of patients who have persistent headaches beyond 4 weeks is quite low, resulting in a very low number of treatment discontinuations.

Are the headaches generally well managed with acetaminophen?

Interestingly, the headaches are the most responsive to caffeine, so most patients are able to manage it with caffeine or acetaminophen. The one issue of course, is since acalabrutinib and zanubrutinib are both twice-daily drugs and the fact that the second dose of acalabrutinib occurs before bedtime, it's sort of difficult to take a caffeine-containing substance right before then and be able to sleep. If we get patients through the first 2 weeks, the headaches do ameliorate, and patients are usually able to stay on therapy without problems.

How might the use of non-covalent BTK inhibitors impact the use of covalent BTK inhibitors, if at all?

The interesting thing about the non-covalent BTK inhibitors is that they have to have continuous presence in the serum. Their area under the curve is basically 24 hours a day, 7 days a week. The concern when you have that much drug present is that you might run into a lot of AEs from off-target effects. Fortunately, these drugs are extremely specific and have demonstrated extraordinary tolerability. Tolerability wise, these drugs are going to be as well tolerated as acalabrutinib, ibrutinib, and zanubrutinib.

The question is whether or not they're going to afford a benefit in terms of efficacy. A significant number of patients who progress on BTK inhibitors do so by developing a mutation at the cysteine that acalabrutinib, ibrutinib, and zanubrutinib bind to. By converting that cysteine to a serine, you lose the [sole hydrogen] that the covalent BTK inhibitors need to bind to. As a result, they don’t bind to and inhibit the enzyme, and you end up with disease progression.

These reversible inhibitors are not dependent upon the cysteine at that location in order to inhibit the enzyme. In CLL, approximately 50% to 75% of patients who progress have a mutation at cysteine-481.

Reference

1. Furman RR, Byrd JC, Own RG, et al. Safety of acalabrutinib (acala) monotherapy in hematologic malignancies: pooled analysis from clinical trials. J Clin Oncol. 2020;38(suppl 15; abstr 8064). doi:10.1200/JCO.2020.38.15_suppl.8064