Second-Generation BTK Data in CLL

Transcript:

Tara Graff, DO, MS: The ELEVATE-TN trial looked at up-front treatment of CLL [chronic lymphocytic leukemia] with acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or chlorambucil-obinutuzumab. To be clear, acalabrutinib monotherapy was not being compared with acalabrutinib plus obinutuzumab. It was acalabrutinib and acalabrutinib plus obinutuzumab compared with chlorambucil-obinutuzumab. This is a question that has come up over the last month—looking specifically at what is happening with acalabrutinib versus acalabrutinib plus obinutuzumab. The 2 of them were not in competition. This was compared with chlorambucil and Gazyva [obinutuzumab].

The data were actually pretty amazing. Seventy-five percent of the patients in the trial had high-risk cytogenetics. That’s a majority of the patients. And with that, the acalabrutinib and acalabrutinib-obinutuzumab arms faired very, very well.

In terms of efficacy in the ELEVATE-TN trial, the acalabrutinib-obinutuzumab 24-month progression-free survival was 93%. It was 87% in the acalabrutinib monotherapy arm compared with 47% in the chlorambucil-obinutuzumab arm, which is pretty amazing. This means you don’t need to absolutely add in the obinutuzumab right away, because you’re getting a wonderful PFS [progression-free survival] with acalabrutinib monotherapy.

If you switch gears and actually look at the iLLUMINATE trial of obinutuzumab and ibrutinib, the progression-free-survival was only 79%. That’s pretty amazing when the only difference is the BTK [Bruton tyrosine kinase] inhibitor that you’re using; and you’re getting a great response with acalabrutinib monotherapy and/or the acalabrutinib-obinutuzumab, leaving another option on the table. And when you’re actually looking at the 2, the safety profile of acalabrutinib is much more favorable than it is with ibrutinib.

That being said, there are still adverse effects. You can’t get any of these therapies—I don’t care if they’re oral and how great they are—without having some adverse effects. The biggest things that led to discontinuation of ibrutinib, or intolerance and dose reductions, were the atrial fibrillation [AFIB], fatigue, and the arthralgias.

Bleeding plays a role, but the bleeding risk is close to 30% in both acalabrutinib and ibrutinib. That’s just grade 1, grade 2. If we’re looking at grade 3 bleeding, it’s 1.7%. It’s very, very low. Whatever bleeding is, it’s hard to define.

When you’re looking at AFIB, the risk of that with acalabrutinib monotherapy or acalabrutinib plus obinutuzumab is less than 4%. It’s 1.7% for a grade 3 event.

When you’re looking at AFIB in ibrutinib, no matter which study you’re looking at—whether it’s ibrutinib monotherapy, or ibrutinib compared with Rituxan [rituximab] or obinutuzumab—the risk of AFIB is on the order of 12% to 17% specifically with ibrutinib. And when you look at the discontinuation rates of patients on ibrutinib because of AFIB, it’s as high as 25% in the treatment-naïve group. So acalabrutinib is offering the BTK inhibitor without that risk of atrial fibrillation, or at least a much lower risk.

A lot of patients have issues with arthralgias from BTK inhibitors. That risk is much less in acalabrutinib versus ibrutinib. Fatigue was about 10% less. Hypertension was 5 times higher in patients treated with ibrutinib compared with acalabrutinib. Again, we’re not comparing these head to head, but when you’re looking at specific adverse effects that lead to discontinuation of medications, it really leads to a more favorable safety profile with acalabrutinib. When you think about going back to the biochemistry of it all, and the selection for the BTK inhibitor, as I said earlier, acalabrutinib is much more selective with less off-target inhibition, which is likely 1 of the main reasons for its favorable safety profile.

Transcript Edited for Clarity