Examining the Role of Frontline BTKi Monotherapy in CLL - Episode 1

Approved BTKi Frontline Treatments for CLL

Jennifer R. Brown, MD, PhD, highlights newly FDA approved Bruton’s tyrosine kinase inhibitor (BTKi) monotherapy therapies for the treatment of CLL (chronic lymphocytic leukemia).

Jennifer R. Brown, MD, PhD: BTK [Bruton tyrosine kinase] inhibitors have become a mainstay of therapy for CLL [chronic lymphocytic leukemia] over the last 5 to 10 years. The frontline use began following the randomized trial RESONATE-2, which looked at the first-in-class drug, ibrutinib, compared with chlorambucil in previously untreated patients of older age with CLL. Now we have the 5-year follow-up of that study, and the progression-free survival for those patients is about 70%, although there’s also been a 40% discontinuation rate, primarily because of adverse events. We know that these include cardiac adverse events, bleeding, infections, sometimes cytopenias, as well as arthralgias. The RESONATE-2 study was followed up by multiple randomized trials that have compared ibrutinib with more standard frontline chemotherapy immunotherapy regimens.

We have the Alliance North American Intergroup Study A041202, which looked at patients over age 65, previously untreated, who were randomized between single-agent ibrutinib, ibrutinib-rituximab, and bendamustine-rituximab. That study showed a significant progression-free survival benefit for both the ibrutinib and ibrutinib-rituximab arms, although no difference in overall survival. Of note, there was no difference with the addition of rituximab compared with single-agent ibrutinib.

The ECOG-E1912 study looked at a younger patient population, under age 70, and randomized them between ibrutinib-rituximab and FCR [fludarabine, cyclophosphamide, rituximab] and also found a significant progression-free survival benefit. In both studies, most of the benefit is driven by the higher-risk subgroups of CLL, in particular the unmutated IGHV group. The mutated IGHV group had similar outcomes with all the regimens. Ibrutinib was also studied in combination with obinutuzumab compared with obinutuzumab-chlorambucil, and again had a very significant improvement in progression-free survival.

Since then there has been the development of next-generation still-covalent BTK inhibitors that also bind covalently to cysteine 481. The first of those has been acalabrutinib, which is now an approved CLL therapy in any line of therapy, including in the front line. That was on the basis of the ELEVATE TN treatment-naïve randomized trial, which compared acalabrutinib, acalabrutinib-obinutuzumab, and obinutuzumab-chlorambucil and showed significant benefit for both the acalabrutinib arms compared with the obinutuzumab-chlorambucil. Interestingly, there was also a 6% improvement in progression-free survival with the addition of obinutuzumab to acalabrutinib, although this was not a planned comparison. Further follow-up will be needed to further that. With the approval of both these agents in the frontline setting, we have a choice of BTK inhibitors for patients with CLL. There’s also another ongoing randomized trial comparing zanubrutinib, another covalent next-generation more specific BTK inhibitor to bendamustine-rituximab, also expected to eventually lead to approval in a frontline setting for zanubrutinib.

Transcript edited for clarity.