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Novel BTK Inhibitor Promising for Mantle Cell Lymphoma

June 23, 2020

Peter Martin, MD, Weill Cornell Medicine, New York, New York, discusses the data that led to the recent accelerated approval of zanubrutinib for the treatment of patients with mantle cell lymphoma.



Zanubrutinib was studied in mantle cell lymphoma based largely on the success of prior Bruton's tyrosine kinase inhibitors, specifically ibrutinib and acalabrutinib, which had both been approved in 2013 and 2017.

BTK inhibitors we know are active in mantle cell lymphoma. They have a reasonably high response rate. Two‑thirds of patients will respond, and the average progression‑free survival tends to be in the range of 1 year, 18 months in most studies. So there's clearly activity, but there's also room for improvement.

Most companies trying to develop Bruton's tyrosine kinase inhibitors are taking the approach that they need to design an inhibitor that will be more specific to Bruton's tyrosine kinase, which essentially means that they'll inhibit fewer off‑target enzymes, other TEC‑family kinases, or other tyrosine kinases, including EGFR.

Doing so should continue to maintain high rates of efficacy, but will hopefully also reduce the adverse event profile, which is not considerable when we compare it to standard chemotherapy regimen.

But certainly, people who have been taking Bruton's tyrosine kinase inhibitors for several months or years, some of them will stop taking those medications. Improving that safety profile is of value while maintaining the efficacy profile.

Zanubrutinib, or the company developing zanubrutinib also wanted to prove that their drug had a high rate of inhibiting the BTK enzyme in lymph nodes themselves as opposed to the usual assays, which are done just in peripheral blood.

They additionally differentiated themselves there by doing pre‑clinical studies and clinical studies showing that in one of the phase 1 trials, indeed, they had optimized dosing to ensure that BTK was inhibited in lymphoma cells, in lymph nodes, in a durable way.

Zanubrutinib was a promising drug to test in mantle cell lymphoma based both on the pharmacology and the activity of prior BTK inhibitors.

Mantle cell lymphoma is a large enough population that phase 2 clinical trials can be done in a reasonable timeframe, as well as a population for which BTK inhibitors have been approved on the basis of phase 2 clinical trials.

In other words, phase 3 clinical trials have not been necessary for accelerated approval. Programmatically, from the company's perspective, it was also a good opportunity.

Two, large clinical trials were done: one international trial, one largely done in China. Indeed, they both confirmed the activity of zanubrutinib in patients who have mantle cell lymphoma.

Both trials enrolled close to a hundred patients. One trial had a slightly higher overall response rate than we would typically see in mantle cell lymphoma, closer to 80% with accompanied response rate closer to 60%. That was primarily a trial that was done in China.

In another clinical trial that was international, led by Constantine Tam from Australia, the complete response rate was a little bit lower.

When you put all of these things together, you see that overall and complete response rates that are certainly promising, potentially a little bit better than we've seen with ibrutinib or acalabrutinib.

I'm not prepared to say that any one of those drugs is better than any of the others in cross comparison, across clinical trials. That's always a little bit dangerous. But it is clear that BTK is a valid target in mantle cell lymphoma and this drug does that.

In terms of that safety profile, patients in both clinical trials had generally tolerated the medication pretty well. The adverse event profile was consistent with what we've seen with other Bruton's tyrosine kinase inhibitors.

Specifically, there's some neutropenia, some thrombocytopenia. Both of those are relatively mild. There were some patients who developed infections. That can be the result of certainly BTK inhibition, potentially. But also, mantle cell lymphoma and prior therapy for mantle cell lymphoma I'm sure play a role there.

In almost all BTK inhibitor trials, we see some diarrhea, some rash, some bruising. Again, those were present in the zanubrutinib trial.

So far, we don't see major bleeding or atrial fibrillation in a significant way. That may be because there's less of those with this drug.

It may also be because too few patients have been treated and follow‑up has not been sufficiently long enough, so that patients who have been exposed to it for a long enough period of time develop those adverse events in a clinically meaningful way.

The same thing goes for discontinuation for adverse events. In that, I think we tend to see more of those in patients who are on the drugs for long periods of time, like in CLL and Waldenström's macroglobulinemia. It may be a little bit early to comment on that from this clinical trial.

In summary, I think it's great that we have another BTK inhibitor for patients who have mantle cell lymphoma. All of these drugs have some differences in pharmacology. All of these drugs are clearly active. All of these drugs are pretty well‑tolerated. The more options we have available for people with mantle cell lymphoma, the better.

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