Byrd on Promise of Acalabrutinib in CLL

John C. Byrd, MD

The second-generation BTK inhibitor acalabrutinib (ACP-196) generated responses in a heavily pretreated population with relapsed/refractory chronic lymphocytic leukemia (CLL), including patients with high-risk prognostic factors, according to research presented at the 2015 ASH Annual Meeting¹ and reported simultaneously in The New England Journal of Medicine.²

In the phase I/II study, 57 of 60 evaluable patients achieved a partial response, including 6 patients with lymphocytosis, for an overall response rate of 95%, lead study author John C. Byrd, MD, said when discussing the results at the ASH meeting. In patients with a 17p deletion (31%), the response rate was 100%.

Most adverse events (AEs) were grade 1 or 2. The most common grade 1/2 AEs were headache (43%), diarrhea (38%), increased weight (25%), and upper respiratory tract infection (23%). Severe diarrhea, rash, arthralgia or myalgia, bruising, and bleeding events each occurred in ≤2% of patients.

There were no report cases of major hemorrhage or atrial fibrillation. One patient death, which was attributed to pneumonia, occurred during the trial.

The first-in-class BTK inhibitor ibrutinib (Imbruvica) was approved by the FDA for the treatment of patients with CLL in February 2014. Ibrutinib, shown to be a well-tolerated agent, has demonstrated a 95% response rate and deep remissions in these patients.

However, with acalabrutinib, there was no major hemorrhage, atrial fibrillation, tumor lysis syndrome, or pneumonitis that occurred in patients, suggesting an improved safety profile compared with ibrutinib, where these toxicities have been reported, according to Byrd.

OncLive: What details can you share regarding acalabrutinib?

What are some of acalabrutinib’s unique properties?

In an interview with OncLive, Byrd, who is chair of Leukemia Research and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, discusses the mechanism of action of acalabrutinib, efficacy and safety data for the drug, and how it compares with ibrutinib.Byrd: Acalabrutinib is a more selective, irreversible BTK inhibitor that came into the clinic last year. It is more selective for the target BTK, and it sort of voids some of the alternative targets that can cause side effects in patients receiving the drug. In preclinical work in CLL, this was also tested in dogs with lymphoma. This all showed promise, and that provided justification for bringing forth a clinical trial in CLL.It has some of the ideal properties of an irreversible inhibitor and it has a very short half-life. It is very selective for BTK, and it only really affects 2 other kinases. By virtue of that, you can really put a lot of pressure on BTK. BTK generally turns over every 24 or less hours, so dosing more frequently, with a more selective inhibitor, might provide the opportunity to be able to treat tumors that are growing quicker. That is an advantage of the selective BTK inhibitors.

Who are the most appropriate patients for this agent?

What are the most significant findings of this study?

There were data presented at the 2015 ASH Annual Meeting with lymphoid biopsies that showed that BID dosing with another irreversible selective BTK inhibitor might actually provide better target coverage.This study, which was also published in The New England Journal of Medicine, focused on relapsed/refractory patients. It was for those who received at least 1 prior therapy. There was no requirement for counts, so patients could have low platelet counts, low hemoglobin, they could have even had a transplant, or had prior effective therapy for CLL. It was generally open to any patient without a lot of limitations in terms of eligibility requirements.The trial was a multicenter study in the United States and Europe. Patients received ACP-196 either once daily or, later on in the phase II portion, twice daily. In the big, phase II cohort of the BID dosing, the response was very high with a 95% response rate. The responses were very quick.

With some of the other BTK inhibitors, with B-cell receptor kinase inhibitors, you see lymphocytosis doesn’t resolve, and you see it resolve very quickly with acalabrutinib. Of the patients that responded—the 95%—only a very small subset still had persistent lymphocytosis. At 14 months, the results were quite promising in that there was only 1 patient who progressed. There is 1 patient who discontinued because they had pneumonia. Overall, the side effect profile has been very, very good. The data really strongly support comparing it to ibrutinib. In fact, there is a randomized phase III study comparing ibrutinib to ACP-196.

You mentioned the side effect profile was very good. Can you detail what adverse events were reported with ACP-196?

The future of this drug is likely going to be moving it up early in the treatment of CLL because the safety appears better, although we need to do comparative studies. By being more selective, it is going to potentially be better to combine with other effective therapies that we have heard about at ASH. No drug is without adverse events. With ibrutinib, which is also a great drug, we tend to see more diarrhea, bruising, ecchymosis, and atrial fibrillation. With this drug, all of those adverse events were less…The side effects that probably stand out with this drug that are probably different from the other B-cell receptor inhibitors are some headaches, but they generally resolve; they’re not dose-limiting.

Also, there is a spattering of other things that occur, and there is no way to sort out if it’s the drug or placebo, such as arthralgia, bruising, and a little bit of diarrhea. However, it is generally very mild and resolves while patients are on therapy. Patients tolerate this drug very well.

As a testament, there is a study that is being done with ACP-196 in ibrutinib-intolerant patients. These patients have had side effects while on ibrutinib, to the point where they have not been able to keep taking the drug. Then, they go onto ACP-196 and those side effects have not occurred.

How does this drug compare with ibrutinib?

What else can you share regarding the phase III study?

Having 2 or more of these drugs available is going to be very important for patients. Even with ACP-196, some patients may not tolerate that, and they can go to ibrutinib, or vice versa. It is a great class of drugs; it is a very exciting time for patients with CLL. Both of these drugs are exceptional drugs. They both have different properties and I think they are both going to find an important place in management. As a second-generation BTK inhibitor, ACP-196 is likely going to afford some benefit in other patient populations. However, similar to the chronic myeloid leukemia days, Gleevec was a great drug—it’s still a great drug—but we have better TKIs in CML for some patients, and I would put these 2 drugs in that same class. They’re both great drugs, but ACP-196 probably has some advantages over ibrutinib. ACP-196 is being tested in the relapsed setting in comparison to ibrutinib. Also, there is an untreated study that is ongoing and comparing ACP-196 to several different treatments. I look forward to us hearing about this drug in CLL and other B-cell malignancies. It’s a really exciting time.

References:

1. Byrd JC, Wierda W, Jones J, et al. The Bruton tyrosine kinase (Btk) inhibitor ACP-196: marked activity in relapsed/refractory CLL with a favorable safety profile. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 831.
2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia [published online December 7, 2015]. N Engl J Med. doi:10.1056/NEJMoa1509981.