Evolution of BTK Inhibitors in CLL

Transcript:

Tara Graff, DO, MS: CLL [chronic lymphocytic leukemia] has changed a lot in the last few years. The evolution of CLL has been changed by the new treatments we have available—specifically, the BTK [Bruton tyrosine kinase] inhibitors. There has been a shift in the paradigm of treatment from conventional chemotherapy—IV [intravenous] chemotherapy—combined with immunotherapies to oral agents that are now available, either alone or paired with an additional IV immunotherapy.

Ibrutinib has been around for a few years. It was the first BTK inhibitor—first generation—and it really changed how physicians treated their patients. It has been very, very favorable—an overall response rate of 86%, 87%. And now, several years out when reevaluating the data, patients have still responded at about an 86% response rate.

That being said, most of them continue to experience only grade 1 and grade 2 adverse events [AEs]. However, we do know that ibrutinib has a high rate of atrial fibrillation—which has led to substantial amounts of discontinuation in patients—as well as high blood pressure. We know that with ibrutinib, while the other AEs remain stable, hypertension actually gets worse over time. Again, this may lead to possible dose reductions or discontinuation by patients.

Acalabrutinib is 1 of our second-generation BTK inhibitors. It actually has a more selective binding to the BTK inhibitor and also has less off-target inhibition of other factors, such as EGFR, which has actually proven to be 1 of its benefits—in terms of its overall better safety profile and tolerance—because it doesn’t hit other targets the same way the first-generation BTK inhibitor ibrutinib does.

Specifically, look at rituximab [Rituxan] plus ibrutinib. There really was no difference in progression-free survival or overall survival, and it didn’t make the adverse effects worse or better. This was actually studied in the Alliance trial, which compared ibrutinib plus rituximab, ibrutinib monotherapy, versus bendamustine-Rituxan. So conventional chemoimmunotherapy.

Both the ibrutinib-Rituxan arm and ibrutinib monotherapy arm were better in terms of progression-free survival and overall response rate when compared with the bendamustine-Rituxan arm. However, looking at the ibrutinib-alone arm versus ibrutinib-Rituxan arm, there was a 1% difference between the 2 arms. So Rituxan did not really add an additional benefit. Ibrutinib alone would have been sufficient and has been proven superior to chemoimmunotherapy.

The ECOG trial looking at young, fit patients compared FCR [fludarabine, cyclophosphamide, rituximab]—conventional chemoimmunotherapy, which was the regimen to go to, again, for young, fit patients—against ibrutinib and Rituxan. It’s actually no surprise that Ibrutinib and Rituxan did much better in terms of efficacy over FCR [fludarabine, cyclophosphamide, rituximab], specifically in the higher-risk patients. Patients who had deletion 17p and high risk cytogenetics did not fare well with FCR [fludarabine, cyclophosphamide, rituximab]. Yes, it was thought that giving FCR [fludarabine, cyclophosphamide, rituximab] would have produced these durable responses for 8-plus years. However, when you’re specifically taking the high-risk group in a younger population, they actually benefited significantly with the ibrutinib-Rituxan arm versus FCR [fludarabine, cyclophosphamide, rituximab]. Again, changing the landscape by showing that an oral drug paired with an antibody was actually better than getting conventional chemoimmunotherapy. Once again, shifting that paradigm.

Again, going back to what we spoke to before, the FCR [fludarabine, cyclophosphamide, rituximab] versus ibrutinib-rituximab, the ECOG trial looked at younger, fit patients. The Alliance trial that looked at BR [bendamustine, rituximab] versus ibrutinib monotherapy versus ibrutinib paired with Rituxan was in the older population. Again, ibrutinib paired with the anti-CD20 antibody, or ibrutinib alone, was far superior to conventional chemoimmunotherapy. Not that that’s not a good option. But with patients who are higher risk, we’re giving them a better treatment option over chemotherapy, which can lead to bone marrow suppression for years and other long-term sequela that you don’t see as much of with the oral BTK inhibitors paired with the anti-CD20 antibodies.

Transcript Edited for Clarity