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Acalabrutinib MCL Approval Raises Sequencing Questions

Angelica Welch
Published: Wednesday, Nov 15, 2017

Owen A. O'Connor, MD, PhD
Owen A. O'Connor, MD, PhD
The October 2017 FDA approval of acalabrutinib (Calquence) for patients with mantle cell lymphoma (MCL) added another BTK inhibitor to the armamentarium while contributing to the growing discussion of sequencing with other available agents, explained Owen A. O'Connor, MD, PhD.

This approval, which arrived several months ahead of the FDA’s Prescription Drug User Fee Act, was based on findings from the phase II trial ACE-LY-004, where the investigator-assessed objective response rate (ORR) was 81% with acalabrutinib (95% CI, 73%-87%). The partial response (PR) rate was 41% and the complete response (CR) rate was 40%.

At a median follow-up of 15.2 months, the ORR by independent review committee was 80% (95% CI, 72%-87%), which was comprised evenly of CR and PR rates of 40%. The median duration of response was not yet reached at the time of analysis, with responses ongoing at more than 20 months. Additionally, the median time to best response was 1.9 months.

Complete results from ACE-LY-004 have not yet been formally published or presented, as data from the study were solely released in the package insert along with the FDA approval. AstraZeneca, the company developing the drug, told OncLive that the data are slated to be presented at a medical meeting later this year.

Outside of BTK inhibitors, the potential of chimeric antigen receptor (CAR) T-cell therapy is also bringing excitement to the treatment landscape of this hematologic malignancy.

In an interview with OncLive during the 35 Annual CFS®, O’Connor, professor of medicine and experimental therapeutics, director of the Center for Lymphoid Malignancies, co-program director of the Lymphoid Development and Malignancy Program in the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, discussed the utilization of acalabrutinib, how it sequences with other approved therapies, and the promise for CAR T-cell therapy in MCL.

OncLive: Could you comment on the recent FDA approval of acalabrutinib in MCL?

O’Connor: Bortezomib (Velcade) was the first drug ever approved for MCL more than 20 years ago. There have been gigantic leaps in our ability to refine treatment ideas and treatment recommendations for specific patients. One of the big advances that we have made came biologically, which was recognizing that MCL is not one disease. Many of the studies that we do—even the more recent ones—tend to lump all patients into one pot. Increasingly, we recognize that the proliferative rate of Ki-67 is an important determinate for many patients. Those with aggressive disease might benefit from more aggressive therapy upfront versus patients with less aggressive disease, who we can maybe take a more conservative approach like we are used to doing in patients with indolent follicular lymphoma.

Unquestionably, over the years, approvals of proteasome inhibitors including bortezomib, lenalidomide (Revlimid), ibrutinib (Imbruvica), and now acalabrutinib, have broadened that portfolio of agents that we have available to manage the disease. We still do not know a lot about how these agents work as a function of that biological context. With that being said, acalabrutinib is a next-generation BTK inhibitor; from the data with ibrutinib, we know this is a highly favorable class. Acalabrutinib is said to be a clearer and more selective BTK inhibitor.

Therefore, if you look at the KINOMEscan, you see that acalabrutinib hits far fewer kinases than ibrutinib. The thought is that selectivity translates into better tolerability; [perhaps it will not necessarily affect efficacy], but if you are hitting fewer off-target effects, you might reduce some of that associated toxicity. That has been the story for acalabrutinib development in chronic lymphocytic leukemia (CLL), where many of those side effects that we see with ibrutinib, such as atrial fibrillation or bruising, generally seem to be less with acalabrutinib. What we see in MCL is fairly encouraging. We see very, very good response rates and a very good complete response rate. When we look at the time-to-event analysis, [we see that] we haven't reached the median duration of response yet.


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