Emerging BTK Inhibitors in Mantle Cell Lymphoma


John P. Leonard, MD: For the next section of our discussion, I want to get into some of the exciting new things. We just came out of ASH [American Society of Hematology Annual Meeting], and a lot of data were presented, some of which touched on mantle cell lymphoma. I want to ask Andy, what is your take on some of the next group? And there seem to be several. As I said, every meeting I go to it seems like there are a few more names I haven’t heard of or recognize. But we’ve got a few more BTK [Bruton tyrosine kinase] inhibitors on the horizon. What’s your take on those? Are they more of the same, or do they have some new and potentially useful properties for some settings?

Andrew D. Zelenetz, MD, PhD: We have some of both: more of the same and some new stuff. The tirabrutinib is actually the Ono Pharmaceutical, Inc, Ltd drug, which a number of years ago we were all excited about because it had a much more restrictive kinome, and then the development got held up. It is a highly active BTK inhibitor, but it’s a covalent inhibitor, like the approved drugs. Orelabrutinib is another covalent BTK inhibitor out of China. We saw data presented—a much more narrow kinome— more like actually acalabrutinib in terms of its kinome, so the adverse-effect profile looks like acalabrutinib. It’s quite safe and highly effective, and it has once-a-day dosing, so that’s 1 small advantage of that agent potentially. Obviously the big disadvantage is it’s got a long way to go.

The drug I’m most excited about is LOXO-305. It’s really the new kid on the block because it has a shiny new toy. It acts by noncovalent inhibition. It does not depend on the cysteine 481. In fact, if there’s a cysteine 481 serine, the drug is active. We have seen that mostly in the CLL [chronic lymphocytic leukemia] population because that’s a rare mutation in mantle cell lymphoma. Michael Wang presented the data for LOXO-305 in mantle cell lymphoma. They were pretty impressive: 93% of the patients who went on that study had had a prior BTK inhibitor, and there was still a 52% response rate. Data are early. We need more follow-up to know about durability, and we really need to know more about resistance of mantle cell lymphoma to BTK inhibitors. Because the typical mutations that we see in CLL, the BTK mutation, the PLC-gamma mutation, we don’t see very frequently in mantle cell lymphoma.

There are different mechanisms, and we need to understand those mechanisms and to know what it is about: LOXO, can they really overcome those mechanisms? But the preliminary data look quite exciting for patients, many of whom progressing on BTK inhibitors are responding to this drug. Why is that important? Because it adds another drug to our armamentarium. It prolongs the time we can stay on a BTK inhibitor before we need to think about a CAR [chimeric antigen receptor] T cell or something else.

John P. Leonard, MD: I want to follow up on what Andy said and ask Krish your sense of, in particular, the LOXO-305 compound. What’s the difference between covalent and noncovalent? Explain to the audience. It’s potentially an important distinction. We’ll see how it matters clinically, but as Andy said, it may be useful in the resistant setting.

Krish Patel, MD: The LOXO-305 drug is, as you mentioned, a noncovalent inhibitor, so it doesn’t permanently bind to BTK. Whereas our approved BTK inhibitors all bind irreversibly or covalently. When patients develop resistance to our current generation, 1 of the common resistance mechanisms is the mutation of cysteine at the 481 site, and that basically renders our irreversible inhibitors as reversible inhibitors. But they’re not very good reversible inhibitors, so they fall off the target and they don’t really inhibit BTK. LOXO is designed to overcome that. It doesn’t bind permanently, but it binds in a different way that allows it to be active in patients who have that mutation.

Transcript Edited for Clarity

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