BTK Inhibition Continues to Show Promise in Relapsed/Refractory MCL

Krish Patel, MD

Long-term follow-up findings recently presented with the BTK inhibitors acalabrutinib (Calquence) and ibrutinib (Imbruvica), and updated data with the next-generation agent zanubrutinib (BGB-3111), continued to demonstrate clinical activity in patients with relapsed/refractory mantle cell lymphoma (MCL).

Moreover, the updated results on the efficacy and safety profiles could affect physicians’ treatment decisions when comparing these BTK inhibitors, explained Krish Patel, MD.

“In particular, the late toxicity data and the overall rate of continuation of the medication is a really important feature and that may be an important difference between some of these agents,” said Patel, an oncologist at the Swedish Cancer Institute.

Data presented during the meeting included longer follow-up from the phase II ACE-LY-004 trial of acalabrutinib. Initial results from the trial led to the FDA approval of acalabrutinib in October 2017.

Additionally, promising findings were presented for zanubrutinib; the BTK inhibitor induced an overall response rate of 83.5% and a manageable toxicity profile in patients with relapsed/refractory MCL. In January 2019, the FDA granted zanubrutinib a breakthrough therapy designation for the treatment of adult patients with MCL who have previously received at least 1 prior therapy.

OncLive: Could you discuss some of the most significant MCL abstracts presented during this year’s ASH Annual Meeting?

In an interview with OncLive, Patel discussed some of the most significant MCL data presented during the 2018 ASH Annual Meeting and how the use of BTK inhibitors will evolve going forward.Patel: The first one I thought was really interesting is in the frontline setting. There was an abstract presented from a combination of 2 phase II clinical trials that were done at Dana-Farber and Washington University in St. Louis, as well as some patients who were treated off clinical trial. In that particular abstract, what the investigators were looking at were overall responses, progression-free survival (PFS), and overall survival (OS) using an induction regimen of bendamustine/rituximab (Rituxan) given for 3 cycles. If patients were having an appropriate clinical response, they went on to get 3 cycles of rituximab/cytarabine before getting an autologous stem cell transplant.

What updates were there in the relapsed/refractory setting?

I thought that abstract was particularly interesting because we don't really know what the optimal induction regimen is. We know there are a lot of different induction regimens people use and I think what this trial presents is another modern option to think about that needs to be studied in additional randomized prospective studies, but really it provides some compelling evidence that combining bendamustine and cytarabine may be a good platform prior to autologous transplant. So, I thought that one was pretty [thought] provoking and obviously it will need to be studied further, but it's an interesting option to think about.For the relapsed/refractory setting, I think there is a lot of knowledge and understanding about the importance of BTK inhibitors in MCL. What I thought was fairly interesting was to highlight some of the long-term data that have been reported or highlighted at this meeting for several of the BTK inhibitors. The first one was an abstract by Jeff Sharman, MD, and the US Oncology Research group where they actually looked at real-world patients treated off clinical trial with ibrutinib and they were basically trying to find what the response for the population of patients was like and how did they compare to patients treated in a clinical trial with ibrutinib, as well as also reporting on toxicities in the real world.

I think what stood out is really 2 things. First of all, I think the overall responses and the clinical benefit in terms of PFS looked pretty similar to what's been reported in clinical trials, so that gives us some additional information that what we see in the real-world population can mirror what we see in clinical trials. I thought another take-home that was important in that study was that, overall, in the real world, the discontinuation rate seemed to be higher than in the clinical trials. That was primarily driven by disease progression, but importantly, about a quarter of patients actually had to stop therapy with ibrutinib due to toxicities. That is a little higher than what has been reported in prior clinical trials, so that is an interesting outcome to note from a real-world population and I think we'll need to further understand and define why that could be. I think that's important when we're thinking about applying our evidence to patients in practice.

With that, I think it's interesting to then talk about 2 other BTK inhibitors and long-term data that were presented. Acalabrutinib is approved for use in relapsed/refractory MCL. That initial approval was based on a median follow-up of about 15 months from a phase II clinical trial. At this meeting, there was a report of 24-month follow-up data, and essentially, what I think is an important takeaway from that abstract is overall the response rate at 24 months is quite comparable to what was reported earlier. More than 80% of patients had a response to therapy, with a similar proportion of patients having complete responses and partial responses, so about half the patients had that complete response, and about half of the patients had partial response and that was true at the 24-month follow-up period.

I think the toxicity data [are also important]. Much of what was described from the early follow-up in the clinical trial seemed to be true in the long-term follow-up, so there didn't really appear to be a clear emergence of any late toxicities, which is important, and most of the patients were able to continue to stay on therapy at the 24-month follow-up. I think those are 2 important findings, especially when thinking about long-term follow-up from these types of trials.

Based on these trials, where is the field headed?

The last abstract I thought was interesting was an oral presentation of zanubrutinib in relapsed/refractory MCL. Zanubrutinib is another BTK inhibitor. That study particularly highlighted patients treated in China with relapsed/refractory MCL. What they reported in that study overall was that, again, the response rates were quite high. Interestingly, in their study the complete response rate was reported at around 58% or so, which is a little bit higher than what has been reported in some of the other studies. Obviously, it's hard to make comparisons across the different BTK inhibitors because they are not randomized trials, but it will be interesting to see in the long-term follow-up data whether that holds true or in subsequent randomized trials whether there could be some increase in complete responses with that agent. I think the other overall take-home for that study was that the toxicities with zanubrutinib seemed to be quite manageable, so a low incidence of grade 3/4 toxicities, [and] a generally low rate of discontinuation of that drug as well.I think we've long known that BTK inhibitors have a very important role in the relapsed/refractory setting. I think what these data tell us is that there may be some interesting differences between these agents, particularly in terms of toxicity. I think that is going to be important because right now the model of BTK inhibitors in MCL is as continuous therapies. Our patients are on these medicines, even when they're having good responses to therapy, they continue on them. I think in particular, the late toxicity data and the overall rate of continuation of the medication is a really important feature and that may be an important difference between some of these agents. Of course, we really would want to study these agents in randomized trials so that we're really looking at the same types of patients on these agents to make sure if there are differences, they really are from the different drugs themselves, not due to differences in trial populations or designs, so I think that is an important take-away from those abstracts.

Is there anything else you would like to highlight?

The other thing that will be interesting is that now I think where the field is going forward with these agents is to combine them with BCL-2 inhibitors, like venetoclax (Venclexta). Those studies are being done in slightly different ways, where some of those studies might actually have a fixed duration of therapy, so it will be interesting to see how those different agents with potentially different toxicity profiles work combined with a BCL-2 inhibitor like venetoclax.I think another piece that will be an interesting space to look at in MCL is how the CAR T cell story evolves. Like other lymphoid malignancies, there is a lot of excitement about that. I think it's too early on for us to know what the ultimate impact of those therapies will be, but I myself am particularly excited to see where that goes, and as I mentioned previously, watching for some of the readouts of the some of the combination studies that are now being done with BCL-2 inhibitors.

Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 148.