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BTK Inhibition Continues to Show Promise in Relapsed/Refractory MCL

Shannon Connelly
Published: Tuesday, Jan 15, 2019

Krish Patel, MD
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.

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.

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

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.

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.

What updates were there in the relapsed/refractory setting?

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.

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