Acalabrutinib vs Zanubrutinib for Relapsed/Refractory CLL | Adam Kittai, MD | ASCO 2023

Hey, my name is Adam Kattay. I am an assistant professor at The Ohio State University, and I specialize in the treatment of chronic lymphocytic leukemia and Richter's transformation. On Monday at ASCO, I'll be presenting a poster that compares acalabrunib and xanabrunib in a make analysis. So in this particular study, we looked to compare statistically acalabrunib versus xanabrunib. The importance of this is that these are both second generation BT inhibitors that have not been compared head to head and most likely will not be compared head to head in a phase three randomized control trial. There were two trials that were recently published in Relapse Refractory CLL, Elevate RR and Alpine. Elevate RR compared acalabrunib to abrutinib and Alpine compared xanabrunib to abrutinib. Both of these trials occurred in the Relapse Refractory setting and both showed a significant side effect benefit of the second generation BT inhibitors acalabrunib and xanabrunib versus abrutinib. What was interesting was the xanabrunib versus abrutinib study, Alpine, also showed an efficacy benefit of xanabrunib. And so there was a lot of talk about comparing these two specific trials, Elevate RR versus Alpine and assuming that xanabrunib might be the superior BTK inhibitor to use in the Relapse Refractory setting, even though it's never been compared to acalabrunib. The problem with comparing these two specific trials is that Elevate RR only included patients with deletion 11q and deletion 17p disease, making a cross trial comparison for these two studies not a great idea as there is two different patient populations. So what we did was we compared the ASCEND study, which was acalabrunib versus Physicians' Choice Benamustine plus rituximab or Idelalicib plus rituximab to the Alpine study, which I just stated was xanabrunib versus abrutinib using a MAKE analysis. So a MAKE analysis is a statistically validated way of comparing two trials without doing a phase three randomized controlled trial where it doesn't matter whether or not the drugs were compared to the same competitor. So this is called an unanchored MAKE when the comparator arm is not the same, whereas an anchored MAKE would be comparing two trials that had the same comparator arm. So this is unanchored MAKE that compared the patients who were on the ASCEND trial versus those patients who were on the Alpine trial. So how do you do an analysis like this? So we have individual patient data for those patients on the ASCEND study and we look to see which characteristics were prognostic of survival and then we take those prognostic characteristics and we weight each patient on the ASCEND study to match those patients on the Alpine study. That way we are making sure that the patient populations that are contributing to the survival analysis are similar. That's how you make sure that each of the arms are matched. That's why it's called the MAKE, a match adjusted indirect comparison. So when we did this we found that the progression free survival for patients treated with a-calibrutinib was the same as those that were treated with Xanibrutinib. They had equal efficacy in the ASCEND arm as they did to the Alpine arm. This wasn't too surprising because when you look at the median progression free survival for patients treated on ASCEND for a-calibrutinib it was very similar to what was seen on Alpine. And actually when we looked at the Kaplan-Meier curve for patients treated with a-calibrutinib on the ASCEND study it was overlapping once we did the MAKE adjustments. So there really wasn't a change in the efficacy of a-calibrutinib. Next we look to see at the side effect profiles of a-calibrutinib and Xanibrutinib and saw if there is any difference once we made this adjustment. And what we found was that patients treated with a-calibrutinib had a slightly better side effect profile than those treated with Xanibrutinib for hypertension, hemorrhage, and any grade 3 adverse event. So this is also not surprising because when you look at the tables of side effects for patients treated with a-calibrutinib and Xanibrutinib, hypertension was pretty significant in the Alpine study. And so it was not surprising to find this difference in side effects for patients treated with a-calibrutinib even when we did the MAKE analysis. So overall the take-home points here is using the MAKE analysis, the efficacy of a-calibrutinib in the relast refractory setting was similar to the efficacy of Xanibrutinib when we compared the ASCEND trial versus the Alpine trial, which we think is the more appropriate study to compare in the relast refractory setting of a-calibrutinib as opposed to the Elevate RR study. We also found some improved safety signals for patients with a-calibrutinib versus Xanibrutinib specifically for hypertension. So overall I think that this is just good data that just shows us that the second-generation BD-CAMDRs appear to have equal efficacy and that they are likely to be interchangeable. But you know this is all hypothesis-generated because this is only a statistical adjustment and what is really needed is a phase 3 randomized current trial, which I'm not sure will happen.