Transcript

I'm Paolo Ghia. I'm a professor of medical oncology in Milano at Universita Vita-Salute San Raffaele, where I coordinate the strategic research program on chronic lymphocytic leukemia.

At EHA this year, the virtual addition of the congress, we presented an abstract on the ASCEND study, which is a phase 3, randomized, international study that compares the acalabrutinib monotherapy with the physician choice between the bendamustine plus rituximab or idelalisib plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.

Acalabrutinib is a second-generation BTK inhibitor. We know that BTK inhibition is a pillar on the treatment in chronic lymphocytic leukemia nowadays.

We also know that, due to the continuous administration of the drug, patients may suffer adverse events that will lead to discontinuation or dose reduction and, therefore, a decrease of efficacy, overall, of the drug.

Acalabrutinib is, as I said, a second-generation. It is more specific for BTK, so has less off-target effects. This was the basis to think that it could indeed have less adverse events. It could be better tolerated in patients as also shown in phase 2 studies.

In the ASCEND study, as I said, 310 patients were randomized; 155 treated with acalabrutinib monotherapy, 155 with either idelalisib plus rituximab or bendamustine plus rituximab. The vast majority indeed chose idelalisib plus rituximab.

It's somehow the first trial that compares 2 novel therapies, a BTK inhibitor on one side and PI3 kinase inhibitors on the other side. Only 36 patients were enrolled to be treated with bendamustine plus rituximab.

An interim analysis have been already presented at EHA. Here, we presented the final results of the study that indeed confirmed a benefit in terms of progression-free survival.

Which is the median progression-free survival is not yet reached with acalabrutinib, while instead it was already reached in the interim analysis for idela plus rituximab or bendamustine plus rituximab in between 15 or 16 months with the 2 treatments.

The interesting point is that patients, even with a high-risk genomic feature, which may include patients with 17p deletion, patients with TP53 mutation, or patients with unmutated immunoglobulin genes, they also had exactly the same benefit when using the acalabrutinib. This benefit is maintained even with the 6-month longer follow-up.

The median follow-up of the study at the final stage was 22 months. On the other side, as I spoke, I mentioned about the safety and tolerability of the drug. The safety profile was indeed showing that patients were tolerating better acalabrutinib monotherapy rather than idelalisib plus rituximab.

Indeed, the rate of discontinuation, which was high as expected with idela combination, around 50%. It was much lower with acalabrutinib monotherapy, though the time of exposure was much longer. The most common adverse events were diarrhea, headache, which is typical of acalabrutinib, but short-lasting, a couple of weeks.

Anemia and neutropenia, and also infections, which is especially in the relapsed/refractory setting, quite common, after having the patients received many prior lines of therapy.

Talking about the adverse events of clinical interest, which are the one that are thought to be more likely related to BTK inhibition, frequency of atrial fibrillation and hypertension was low. The bleeding also was, interestingly, low, with 26% of the patients experiencing bleeding, the vast majority minor bleeding. Indeed, we didn't have any intracranial major hemorrhage.

Having said that, we can say and summarize that acalabrutinib, it's a second-generation BTK inhibitor that will be active in some region of the world, already approved and available to doctors, would be very likely also in other regions.

Based on the results of the ASCEND study and also the ELEVATE study, which is the first-line study, a phase 3 comparing acalabrutinib plus or minus obinutuzumab versus chlorambucil plus obinutuzumab in elderly patients, treatment-naive.

These 2 studies, ASCEND and ELEVATE, are the basis, as I said, for approval around the world. That will allow doctors to have another option when thinking about BTK inhibition, which seems to be well-tolerated and have also a prolonged and sustained efficacy. Thank you very much for your attention.