SOHO 2021 | Seizing the day with BTK inhibitors in CLL

This year, we’ve had a lot of updates on the use of BTK inhibitors in CLL, both as single agents in many different settings and in combination with BCL-2 inhibitors. The updates in terms of single agent BTK inhibitor studies, we’ve seen long term data from a number of the more mature studies of ibrutinib and acalabrutinib. We have seen follow up at about six and a half years for patients who were originally treated on the Resonate-2 trial, and that was the study for patients aged 65 and older, randomized to ibrutinib versus chlorambucil, which led to the FDA approval of ibrutinib and CLL. And we see that at six years, about 61% of people remain progression-free. So, people are continuing to have very durable remissions with that drug for long periods of time in the front line setting. We also have seen four year data on the ELEVATE TN study, and that was the phase three trial that led to the FDA approval of acalabrutinib in the front line setting, where patients were randomized to chlorambucil plus obinutuzumab, acalabrutinib alone or acalabrutinib plus obinutuzumab.

And at four years, 78% of patients treated with acalabrutinib alone were progression free, 87% of patients treated with acalabrutinib plus obinutuzumab were progression-free, so that drug is well in the front line setting as having very phenomenal long-lasting remissions. We also have seen the head-to-head studies of ibrutinib versus acalabrutinib, the ELEVATE-RR study, which show that acalabrutinib is non-inferior to ibrutinib in terms of progression-free survival and has less toxicities in things like atrial fibrillation, hypertension, and then some of the less dangerous but annoying side effects we sometimes see with ibrutinib, things like arthralgia and bruising. We also have seen the head-to-head study of ibrutinib versus zanubrutinib and this study showed that the overall response rate was higher for zanubrutinib than ibrutinib in the relapse setting, with very short follow up progression-free survival also favored zanubrutinib. So, two second generation BTK inhibitors now showing excellent results in comparison to ibrutinib.

We also have seen data from the Captivate Fixed-Duration cohort recently. This was a study of ibrutinib plus venetoclax in the front line setting. This included primarily younger patients and showed very durable… High rates of minimal residual disease, undetectable states at the end of one year of treatment. And as far as we’ve seen for just a couple years of follow up, durable remissions. We also saw the first look this summer at the GLOW study, which is ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab, in the front line setting. This trial actually included older patients than were on the CAPTIVATE study and does show superiority of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab. It does appear that there is some toxicity with this regimen that may lead to some therapy discontinuations, but overall, this is a very promising regimen.