Acalabrutinib MCL Approval Raises Sequencing Questions

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.

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

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.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.

Would acalabrutinib be best used in patients who have failed ibrutinib?

I just started my first patient on this drug last week, and it’s a patient who came in with a cardiac history—why tempt fate? We started acalabrutinib first. We will see how that patient does. However, for my other patents with MCL, using ibrutinib or lenalidomide plus rituximab (Rituxan) has been game changing, particularly for patients with indolent disease, for whom you are really trying to manage [their disease] with the least toxic approach possible.That’s a good question, because that isn't the indication. The label is just for patients with relapsed or refractory MCL. [Looking at] the way that the studies were done, they were not done with an intent to position it behind ibrutinib. The label does not say that patients must have failed ibrutinib; so, your question is spot on. What is going to be the decision making that doctors use to decide between one or the other? I don't think it is entirely clear. People might look at side effect profiles. Physicians are creatures of habit; if they have a good experience with ibrutinib, then they might be more inclined to stick with that. It is very early; it hasn't been approved for that long, but this is going to be an issue.

The bigger issue is going to be, if a patient receives one of these BTK inhibitors, does that kill the opportunity to use the other member in the class? We don't know. Our myeloma colleges have spent years debating that, if they give lenalidomide, how does that take benefit away from pomalidomide (Pomalyst)? If you get bortezomib, how does that portend benefit from carfilzomib (Kyprolis)?

What is your current strategy for patients who progress on ibrutinib?

It’s possible that there may be a benefit down the road. If patients can get ibrutinib, then they can manage the disease as a chronic [condition], then perhaps they can come back to a BTK inhibitor down the road. Perhaps that could be a rationale to use the safer one later—where the patient might be more beat up—and less able to tolerate agents. It’s totally unknown, but this will probably be the big question.It depends where they are getting ibrutinib in that line of therapy. It depends a lot on their disease growth, symptoms associated with the disease, and the bulk of the disease. If I haven't used lenalidomide, then I might use that. We have a number of clinical trials at Columbia University Medical Center that are also good options for us, but maybe not everyone in the community. We have had very good success with lenalidomide, and I want to point out that in the original study done by Dr Andre Goy, they used 25 mg for 3 weeks out of 4. In that trial, they had good enough response rates and time-to-event metrics that got the drug approved.

What are your thoughts on CAR T-cell therapy possibly entering the MCL landscape?

Increasingly, we are finding that using a lower dose of lenalidomide, maybe more similar to what our colleagues in CLL are doing, we might use 10 mg or 20 mg and keep them on without a break. We will add rituximab, and we find that the maintenance of lenalidomide without the break actually has less toxicity. The addition of the rituximab, depending on how long it has been since their last [cycle with] rituximab, gives us pretty good results.There are a number of CAR T-cell therapies coming along. MCL expresses CD19, and there are some very nice data from the University of Pennsylvania group that are showing early but promising observations. We are going to need to be extremely diligent about where we look at CAR T-cell therapy in this setting because we need to balance the risks and the benefits. We are going to need to evaluate the toxicities with CAR T-cell therapy, and I would suggest that the kind of patient you take into those studies is the kind of patient who has a chance of benefitting. If we start concentrating on those patents with indolent-behaving disease that may have a lot of alternatives in terms of their management, maybe they are not ideal [choices for CAR T-cell therapy].

How do you see this field evolving over the next couple of years?

My guess is, on the other end of the spectrum, you are enriching for aggressively behaving diseases. Therefore, we will need to find regimens that are going to “cool the disease off” before you get them into the CAR T program. It might not be as easy in MCL than it is in other diseases. It tends to be a disease that is characterized by rapidly acquired drug resistance. Therefore, failure to respond to a frontline combination therapy or the multiple relapse setting enriches for highly drug-resistant disease. That may be a scenario where drugs, such as acalabrutinib, ibrutinib, PI3-kinase inhibitors, or lenalidomide, can enter the equation—where maybe you can get some disease control and good remission prior to CAR T-cell therapy. It is an area of enthusiasm, but an area where we still have a lot more to learn.[These advances] make medicine today exciting, but could make it daunting. There is a lot of new material. It is important to not only keep up with the drugs, indications, and toxicities, but to try to appreciate some of the subtleties in the biology as your platform and then build on that. What we are going to see for several years are newer generation PI3-kinase inhibitors, BTK, or other kinase inhibitors. You can build that on a solid base of information and then it will be easier to understand how to use those drugs in practice.