Covalent BTK Inhibitors and Common Challenges

Nicole Lamanna, MD: When we talk about BTK inhibitors, specifically the covalent BTK inhibitors, we’re very fortunate. We’ve had a lot of updates to the data. Remember, ibrutinib was the first to market in 2013; acalabrutinib came subsequently. Then zanubrutinib came, which is approved in some of the indolent lymphomas or mantle cell lymphoma but is not approved for CLL. But with the large amount of data available, that will likely get approved in the near future as well. When we talk about some of the highlights from the meeting and the recent data, we had a very nice update from the RESONATE-2 data by Paul Barr, which looked at ibrutinib vs chlorambucil. That was the study that looked at an older CLL population with 7-year follow-up data showing how the PFS [progression-free survival] has been maintained with ibrutinib therapy compared with chlorambucil and sustained. The PFS was 61% vs 9% in the chlorambucil arm. This was observed across all subgroups, including the unmutated IGHV. The overall survival at 6½ years was 78%, with an overall response of 92%, and CRs [complete responses] were increased.

With the BTK inhibitors, we know that complete responses are in the single digits for the first couple of years. The longer patients remain on a BTK inhibitor, their complete response can continue to improve over time, and the update showed at 6½ years the CR frequency increased to 34%. Extended PFS and overall survival benefit were seen with ibrutinib at this longer follow-up compared with chlorambucil. That’s reassuring, and there are no new safety signals. We also had updates regarding acalabrutinib, which is from the ASCEND relapsed study looking at acalabrutinib vs the physician choice of idelalisib-rituximab or bendamustine-rituximab. About 155 patients were in the acalabrutinib arm. In the investigator-initiated arm, 119 were on the idelalisib-rituximab arm and a smaller number on the bendamustine-rituximab arm. The PFS at 36 months was 61% for acalabrutinib vs 17% in the idelalisib-rituximab or BR [bendamustine, rituximab] arm. Overall survival is 80% in the acalabrutinib and 73% in the idelalisib-rituximab or BR arm. The study did also allow for crossover from the investigator arm to acalabrutinib, and about 50% of people had crossed over. It’s hard to know what to make about the overall survival, but what it shows is that even in the relapsed/refractory setting, acalabrutinib is favored over idelalisib-rituximab or bendamustine-rituximab in terms of PFS.

Zanubrutinib, which is not approved, has lots of data coming out from these meetings. In 1 presentation earlier this year, there was a 34-month follow-up in the relapsed setting. This showed a nice overall response in the 88% range at a 24-month PFS at around 80%. In other words, patients are having a nice response to zanubrutinib, similar to the other covalent BTK inhibitors. We’ll see longer follow-ups with those data but similar to the other covalent BTK inhibitors. We have lots of nice data in comparison with all the covalent BTK inhibitors, and hopefully we’ll talk about the adverse effects of the different agents.

This transcript has been edited for clarity.