New BTK Drugs Durable But Raise AE Concerns

When it comes to adverse events and duration of response, next-generation BTK inhibitors in chronic lymphocytic leukemia compare favorably with ibrutinib.


Though ibrutinib “has limitations, I think it’s a fabulous drug and a breakthrough in the treatment of CLL, but from an efficacy and toxicity standpoint, there is potentially room for improvement,” said O’Brien, medical director of the Sue and Ralph Stern Center for Clinical Trials & Research.

O’Brien’s talk covered phase III results for acalabrutinib (ACP-196) in CLL, phase I data for ONO (GS-4059) in non-Hodgkin lymphoma, and phase I findings for BGB-3111 in B-cell malignancies.

Reviewing a dose-escalation trial of ONO, O’Brien noted that whereas bleeding and atrial fibrillation are serious concerns with ibrutinib, the AE profile of ONO is somewhat different. Among 28 patients, there were some grade 1/2 incidents of bruising, hematoma, and petechiae, with 1 grade 3/4 incident each for hematoma and petechiae. “I wouldn’t necessarily add them together, because I don’t know that they couldn’t all be in the same patients, but the point is that we are seeing that phenomenon here,” O’Brien said.

“This may be due to an inhibition of TEC. I can tell you that the IC50 for TEC is very similar for the ONO drug as it is for ibrutinib,” she said.

The ONO progression-free survival curve for CLL showed durable remissions of over 2 years. Also, there were improved platelet counts and hemoglobin concentration, which is revealing about the performance picture for ONO, O’Brien said. “A lot of times when we’re seeing the data, we’re seeing it in terms of efficacy—in terms of reduction in volume of disease—and not a lot about whether these drugs are reducing the cytopenias…ONO is also very good at reducing cytopenias,” O’Brien said.

She sounded a note of warning about acalabrutinib, saying it may result in a higher risk for bleeding than ibrutinib, given an IC50 score for TEC of 97 for acalabrutinib versus 7 for ibrutinib.

On the other hand, based on a median 14.3 months’ follow-up, the drug appears to be well tolerated, with one incident of grade 4 febrile neutropenia. “There were no episodes of atrial fibrillation, but the atrial fibrillation rate with ibrutinib is probably about 7% or 8%, so to be fair, in a phase I study, you may not see it. It is comforting to know that it wasn’t seen in this group,” O’Brien said. There was no major bleeding, and 1 death was reported from pneumonia.

The drug was initially given once a day and then eventually as a twice-a-day dose, and the overall response rate was “quite high” at 95%, O’Brien said.

A phase I trial of BGB-3111 showed little difference in IC50 for this drug versus ibrutinib, looking specifically at TEC, which suggests, “we’re not going to see any difference in atrial fibrillation or bleeding,” O’Brien said. The trial enrolled 14 patients with CLL, and an update can be expected this year, she predicted.

O’Brien noted the incidence of petechiae, contusions, and bruising for BGB-3111. “Keep in mind that these were older patients. Easy bruisability is not uncommon as we age, and so it’s a little hard to know how to interpret this. Response rates were good for CLL, mantle cell lymphoma, and

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