Acalabrutinib Shows Benefit in Ibrutinib-Treated Relapsed/Refractory CLL

Kerry A. Rogers, MD

Acalabrutinib (Calquence) elicited high response rates, showed survival benefits, and had good tolerability in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were intolerant to ibrutinib (Imbruvica) in a phase II trial, explained Kerry A. Rogers, MD.

In the study, 60 patients with relapsed/refractory CLL with prior exposure and intolerance to ibrutinib received oral acalabrutinib at 100 mg twice daily in 28‐day cycles until progressive disease or unacceptable toxicity. Results showed that the overall response rate (ORR; ≥partial response [PR]) was 72%, and the ORR plus ≥late PR (PRL) was 77%. The complete response rate was 5%; 67% had a PR, 5% of patients had PRL, and 8% had stable disease.

Data also showed that the 18-month PFS rate was 73.5% and the 18-month overall survival (OS) rate was 89.7%. The median PFS and OS was not reached at a median follow-up of 19 months.

At a median follow-up of 23 months, 62% of patients remained on acalabrutinib and 80% of patients remained on study. Of the 38% of patients who discontinued acalabrutinib, 16% stopped treatment due to progressive disease, 12% due to adverse events (AEs), and 7% were due to investigator decision, withdrawal, or other.

“The really important take-home message is that acalabrutinib is an excellent option for patients with CLL who would benefit from a BTK inhibitor and cannot tolerate ibrutinib. While it is currently off-label for CLL, this is supported in the National Comprehensive Cancer Network guidelines,” said Rogers, a hematologist/oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James. “I would suggest any physician treating a patient with CLL who should be taking a BTK inhibitor but is having problems with tolerability, consider using acalabrutinib off-label based on these data.”

In an interview with OncLive, Rogers highlighted the findings of the study examining acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory CLL and the next steps for the data.

OncLive: Could you share background on this trial of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory CLL?

Rogers: There has been a lot of exciting data with the first-in-class BTK inhibitor ibrutinib recently, including improvements in PFS when compared with chemoimmunotherapy. [Ibrutinib] is a very good [targeted therapy] in CLL in the first-line setting and has been demonstrated for several years to be an excellent [targeted therapy] in relapsed/refractory patients.

However, the main issue is that ibrutinib can be intolerable for some patients, with discontinuation rates in clinical trials at about 10% to 20%. In older, non-clinical trials, populations can be much higher. There is a need for therapies for patients who cannot tolerate ibrutinib, and therefore do not benefit from the outstanding disease control you get from targeting BTK.

There is a second-generation BTK inhibitor called acalabrutinib, which is more selective; this means it targets BTK but does not target as many other kinases. The greater selectivity translates into a different AE profile.

The idea behind the study was to give acalabrutinib to a group of patients who did not tolerate ibrutinib or discontinued due to poor tolerance to see if they tolerate and respond to that drug.

What were the findings of this study?

This study enrolled 60 patients and 100% of them had discontinued ibrutinib due to AEs, but they still needed active treatment for CLL. The patients started taking acalabrutinib at the 100 mg twice-daily dose.

We found most of these patients were able to tolerate acalabrutinib, with only about 12% of patients discontinuing due to AEs. That number sounds high, but in a group that discontinued ibrutinib for AEs, the drug appears to be very tolerable. None of the previously experienced AEs occurred at a higher grade than ibrutinib. Some of the AEs did recur, but not all of them, and [they] mostly occurred at a lower grade. This shows that acalabrutinib is a very tolerable drug in people who did not tolerate ibrutinib.

It is important to make sure that these patients are still responding to BTK inhibition, and we expect they would. The ORR, including PRs, is 77% with under 2 years of follow-up. I expect that remissions will continue to occur and deepen with time, as is seen with this class of drugs.

Are there any unanswered questions with these data that still need to be addressed?

This is a 60-patient study. Until you get a broader clinical experience, it will be hard to know which AEs might occur in a larger population. Some of the phase III studies with acalabrutinib will really help us learn what patients might be most suitable to receive the drug. Acalabrutinib is currently FDA approved in mantle cell lymphoma but not in CLL, despite several studies supporting its use and efficacy in that disease. Once we get more experience in CLL and a broader idea of the toxicity profile, it is clearly a great option for ibrutinib-intolerant patients.

I also think it might be a good option for patients who have underlying medical conditions that, due to AEs, would make ibrutinib not a good choice. Acalabrutinib might be a good option for those patients; it will be really exciting. Hopefully, this drug will be approved in CLL and we will get to see who might benefit from it upfront compared with those who are intolerant to ibrutinib.

What are the next steps for these data?

Longer follow-up in this population is important. All patients had to discontinue ibrutinib for intolerance, but they had varying amounts of ibrutinib exposure. While response rates are good, it will be interesting to see what PFS is in a longer follow-up in this entire population.

Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). J Clin Oncol. 2019;37(suppl; abstr 7530). doi: 10.1200/JCO.2019.37.15_suppl.7530.