New Agent Shows Promise Over Imbruvica in Treatment of CLL

The second-generation Bruton's tyrosine kinase (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. This research was presented at the 2015 meeting of the American Society of Hematology (ASH), a gathering of more than 25,000 hematologists and other hematology/oncology professionals1 and reported simultaneously in The New England Journal of Medicine.2
 
In the phase 1/2 study, 57 of 60 evaluable patients achieved a partial response, including six patients with lymphocytosis, for an overall response rate of 95 percent, lead study author John C. Byrd, said when discussing the results at the ASH meeting. In patients with a 17p deletion (31 percent), the response rate was 100 percent.
 
Most adverse events (AEs) were grade 1 or 2. The most common grade 1/2 AEs were headache (43 percent), diarrhea (38 percent), increased weight (25 percent) and upper respiratory tract infection (23 percent). Severe diarrhea, rash, arthralgia or myalgia, bruising, and bleeding events each occurred in a maximum of 2 percent 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 Imbruvica (ibrutinib) was approved by the FDA for the treatment of patients with CLL in February 2014. Imbruvica, shown to be a well-tolerated agent, has demonstrated a 95 percent 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 Imbruvica, where these toxicities have been reported, according to Byrd.
 
In an interview with CURE, 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 Imbruvica.

CURE: What details can you share regarding acalabrutinib?

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.

What are some of acalabrutinib’s unique properties?

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 two 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.

There were data presented at the 2015 ASH Annual Meeting with lymphoid biopsies that showed that twice daily dosing with another irreversible selective BTK inhibitor might actually provide better target coverage.

Who are the most appropriate patients for this agent?

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 one 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.

What are the most significant findings of this study?

The trial was a multicenter study in the United States and Europe. Patients received acalabrutinib either once daily or, later on in the phase 2 portion, twice daily. In the big, phase 2 cohort of the twice daily dosing, the response was very high with a 95 percent 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 percent — only a very small subset still had persistent lymphocytosis. At 14 months, the results were quite promising in that there was only one patient who progressed. There is one 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 Imbruvica. In fact, there is a randomized phase 3 study comparing Imbruvica to acalabrutinib.
 

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