Role of BTK Inhibitor Monotherapy in CLL Frontline Setting


Daniel Wojenski, PharmD, discusses use of BTK inhibitors, primarily ibrutinib, as monotherapy vs in combination therapies as frontline treatment for CLL.

Katie Culos, PharmD, BCOP: Dan, you mentioned that at your institution typically a BTK [Bruton tyrosine kinase] inhibitor, ibrutinib, in most cases will probably be your first thought for newly diagnosed patients. Can you provide us some of the data that support it in the first-line setting, whether as monotherapy or in combination potentially with an immunotherapy agent? It’s more selective. A second-generation agent, acalabrutinib, was recently approved, and there were some data at ASH [American Society of Hematology Annual Meeting] talking about the noncovalent BTK inhibitor LOXO-305. Give us the gist of where we’re at with our BTK inhibitors in the frontline treatment setting.

Daniel Wojenski, PharmD, BCPS, BCOP: Thank you, Katie. In terms of BTK inhibitors, I’ll get started with ibrutinib and the data that we have about using that in the frontline setting. We have several trials that were presented to us, including A41202, ECOG 1912, the RESONATE-2, and iLLUMINATE trial. A lot of these were very exciting for us especially in the last few years to see how well ibrutinib did in our first-line setting for a variety of patients. Just to look at the options that we saw there with ECOG 1912.

The exciting data here were when we were comparing our ibrutinib therapy arm with patients who were receiving FCR [fludarabine, cyclophosphamide, rituximab]. This was generally the gold standard approach. Therefore, finding improved overall survival and progression-free survival of this patient population was an exciting finding. Even though our patients receiving FCR [fludarabine, cyclophosphamide, rituximab] did have higher MRD [minimal residual disease] negativity and CR [complete response] rates, we still found that the survival curves were benefiting those who were receiving the ibrutinib arm, which is exciting for us to see.

The other study that was important in this was the A041202 trial, which was looking at patients who had previously untreated CLL, greater than or equal to 65 years of age, who had bendamustine or rituximab, ibrutinib monotherapy, and ibrutinib-rituximab. Although bendamustine-rituximab in this group also had increased CR rates and MRD negativity compared with ibrutinib, there was superior progression-free survival [PFS] in both ibrutinib arms.

Rituximab did not appear to improve outcomes of progression-free survival at 2 years, with 87% and 88% of those, respectively, having progression-free survival at 2 years. In fact, if you’re looking at that data, the progression-free survival ran alongside, you would argue that rituximab did not add any benefits for those patients. This is very telling for us even though, in many studies, we’ve used anti-CD20 monoclonal antibodies when we are saying that we wanted to use additional benefits and gain benefits with that. But with the Alliance A041202 trial, we saw that we didn’t seem to gain benefits from it.

The argument can be that perhaps with our monoclonal antibodies, rituximab is not the ideal option because we knew that with CLL11, when we were treating patients with chlorambucil and obinutuzumab, chlorambucil and rituximab, as well as chlorambucil alone, obinutuzumab was a superior anti-CD20 agent that trended toward improved progression-free survival. Since then we saw that obinutuzumab was generally the CD20 monoclonal antibody that was favored in patients with CLL. But with these Alliance data, we didn’t see any difference. Therefore, most of our patients, all at my institution, receive a BTK inhibitor monotherapy without actually having a CD20 monoclonal antibody.

The ELEVATE-TN study with acalabrutinib, which I’ll get into in a bit more depth shortly, might show us more information as the data mature. We saw that with that 1, MRD rates were a little higher, and there were modest improvements in progression-free survival with the addition of obinutuzumab. But we didn’t compare that without using obinutuzumab. Therefore, it is a little bit of a challenge. With that information, we are not necessarily giving an anti-CD20 monoclonal antibody in the first-line setting with our BTK inhibitors. That’s pretty common practice at most sites.

When we’re looking at some of our other data with RESONATE-2, greater than 65 years old was an untreated CLL group, comparing ibrutinib and chlorambucil monotherapy. The interesting thing is that in 5-year follow-up, progression-free survival of these patients at 5 years was 70% with the ibrutinib arm and 12% for the chlorambucil. We’re not surprised for the chlorambucil arm, but we have to remember that these studies were a little older. Generally, coming out of these studies is the profound follow-up with ibrutinib and the 5-year follow-ups of progression-free survival and overall survival [OS] that benefited that group. Overall survival at 5 years with RESONATE-2 was 83% with patients who received ibrutinib vs 68% with chlorambucil. The benefits of ibrutinib were seen in all prognostic factor risk factors, such as TP53 mutations, 11q deletions, and unmutated IGHV.

A poster presented at ASH 2020 by Dr [Jan] Burger and colleagues combined patients in the ibrutinib arms in the RESONATE-2 and iLLUMINATE trials. It compared the ibrutinib arms with patients who received chlorambucil on both those studies. The study focused on reviewing outcomes in high-risk prognostic features like deletion 17p, unmutated IGHV, BRC3, NOTCH1, SF3B1, or XPO1, and all other mutations that have been important in terms of resistance with CLL treatments.

What we’ve identified is that with a median follow-up of 49.1 months, ibrutinib-based therapy improved overall response rates and PFS compared with chlorambucil arms. At 42 months, progression-free survival rates compared with all high-risk subgroups were 63% to 82% in your ibrutinib arms and 6% to 34% in the chlorambucil group, so that’s a drastic difference. It was nice to see that we’re able to maintain those responses in a high-risk group. That data were refreshing to see with the combination of the RESONATE-2 and iLLUMINATE trials.

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