ELEVATE-RR and ALPINE Trials in Relapsed CLL

Nitin Jain, MD: Moving on to the next segment, we’ll talk about head-to-head BTK trials. I’ll pass it to Dr Furman.

Richard R. Furman, MD: Thank you. I want to make some remarks on the prior discussion. When we talk about using a BTK inhibitor—ibrutinib, acalabrutinib, or zanubrutinib—or venetoclax and obinutuzumab, once a drug is approved, it can be used for any reason or indication and it’s important to tailor our therapies to what’s going to be the best data-driven treatment for our patients. As of now, we don’t have a lot of information on obinutuzumab or any anti-CD20 having a significant effect compared with the actual novel agent. It’s important to consider the role of the toxicities associated with obinutuzumab: the infusion reactions, tumor lysis, impact on COVID-19 immunity, or even just coming into the office and weighing that against everything else.

For the rest of the conversation, I’m going to focus on the BTK inhibitors that we have available. We have 2 trials that are designed to compare ibrutinib with acalabrutinib: the ELEVATE-RR on relapsed/refractory disease and the ALPINE study, which looked at zanubrutinib vs ibrutinib. I want to caution everyone that these trials were done in different populations and the data can’t be extrapolated from 1 trial to another. We fortunately have an embarrassment of riches in CLL [chronic lymphocytic leukemia], so we have a lot of good options. It affords us the opportunity to be a little choosy.

The first study looking at ibrutinib vs acalabrutinib was done in patients who had 17p deletion or 11q deletion and relapsed. The vast majority of these patients relapsed after chemoimmunotherapy. The original inclusion for 11q was based on early data suggesting that 11q deletion predicted a worse outcome compared with trisomy 12, 13q deletion, and no abnormality by interphase FISH [fluorescence in situ hybridization]. Of course, 17p deletion has always been the worse predictor of outcome with chemoimmunotherapy and BTK inhibitors. Interestingly, subsequent data showed that 11q deletion lost its poor prognostication with BTK inhibitors. But the study was designed to look at patients with 11q and 17p deletions who had relapsed. These represented the worst of the worst.

Patients were randomized 1:1 to acalabrutinib 100 mg twice a day or ibrutinib 420 mg daily, and we were following for progression-free survival. The overall response rate was an important evaluation as well. With the median follow-up of about 40 months, the median progression-free survival was equal for both arms at about 38 months, showing that there was noninferiority of acalabrutinib to ibrutinib.

The rest of the data generated were using a hierarchical assignment, where they were able to look at different criteria as long as there was statistical significance. Once they had criteria that didn’t meet statistical significance, they couldn’t comment statistically in the subsequent assessments. The first assessment was going to be based on the rate of atrial fibrillation [AFib]. If that proved statistically significant, then they could look at the risk of infections and then Richter transformation.

They didn’t see a statistically significant increase in atrial fibrillation with ibrutinib as compared with acalabrutinib. This rate was about 16% vs 9%. It’s hard to compare across trials because these were also patients who were beaten up by prior chemoimmunotherapy and likely had significant comorbidities, so we might see the atrial fibrillation rate a little higher in this patient population. The subsequent analysis showed that there was no difference in infection risk, so that was the last assessment made.

The second trial, ALPINE, is looking at zanubrutinib vs ibrutinib. It used overall response rate as a primary end point and showed an improved overall response rate by iwCLL [International Workshop on Chronic Lymphocytic Leukemia] indication for zanubrutinib compared with ibrutinib. But there’s an important caveat: the overall response rate determination only used CR [complete response] and PR [partial response] and excluded PR with lymphocytosis. Using just the CR and PR criteria, we see an improvement in overall response rate for zanubrutinib compared with ibrutinib. This wasn’t statistically assessed, but when using PR with lymphocytosis, the difference becomes numerically much smaller.

Subsequently, the data were looking at adverse events, and there was also a significant reduction in cardiovascular and atrial fibrillation with zanubrutinib compared with ibrutinib. We have these 2 studies showing at least equivalency among the 3 BTK inhibitors in terms of efficacy, but with diminished cardiovascular adverse events for acalabrutinib and zanubrutinib compared with ibrutinib.

Nitin Jain, MD: That’s a very nice summary. One thing to point out, which you highlighted, is that the median follow-up of these 2 trials was quite different.

Richard R. Furman, MD: Yes.

Nitin Jain, MD: There’s almost 4 years for acalabrutinib and just over 1 year for the zanubrutinib ALPINE study. If you look at a cross section of the atrial fibrillation rate and the cross-trial comparison, you may think that 9.4% AFib with acalabrutinib seems much higher than 2.5% with zanubrutinib. But you have to take into consideration the time these patients were followed. There was much longer follow-up for the acalabrutinib trial, so more patients had time to get those events. With the ALPINE study with the longer follow-up, the rate of atrial fibrillation also increased with time. We’ll have to see with a longer follow-up how the AFib rate plays out, but it should hopefully stay significantly less compared with ibrutinib.

Richard R. Furman, MD: One aspect of atrial fibrillation that’s very relevant to discussion is it looks like the rate of atrial fibrillation has a dramatic increase during the first 2 years and then levels off. The slope from 2 years beyond for acalabrutinib, ibrutinib, and zanubrutinib all look to be the same and probably equal to what might be considered age-related rates of developing AFib. The first 2 years are so critical in trying to assess the effect of the BTK inhibitor on the development of atrial fibrillation.

Nitin Jain, MD: I have a question for you about these head-to-head trials. In your practice or in general rounds, are you using second-generation BTK inhibitors for your patients based on these data in the relapsed and frontline settings?

Richard R. Furman, MD: I am exclusively. It’s nice to have at least the acalabrutinib and zanubrutinib to avoid the adverse events that are likely going to be most problematic for the individual patient.

Nitin Jain, MD: Right. That has been the practice of our group, moving to the second-generation BTK inhibitors as opposed to ibrutinib after these data. Plus the early phase data were also indicated toward better tolerability of second-generation agents compared with ibrutinib.

Transcript Edited for Clarity