Indirect Comparison of Acalabrutinib Versus Zanubrutinib in RR CLL: Safety Analysis


Key safety data from the indirect comparison study of acalabrutinib versus zanubrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.


Alan P. Skarbnik, MD: Now, we looked at safety analysis and we evaluated the odd ratios of adverse events from the treated patients. Here, we have included 148 patients for acalabrutinib, 324 for zanubrutinib. Again, we used the artificial data cutoff to compare the adverse event frequencies. It was at the 28-month median follow up.

Alan P. Skarbnik, MD: The same variables from the efficacy analysis were used for matching there. Here, looking at non-cardiovascular adverse events, The overall safety profile was similar across non-cardiovascular adverse events with acalabrutinib versus zanubrutinib. As you can see here, rates of arthralgia, fatigue, infections, neutropenia, rash, and second primary malignancy in the pre- and post-matched analysis were very similar between those 2 agents.

Ryan W. Jacobs, MD: Were there any differences that were shown to be statistically significantly different?

Alan P. Skarbnik, MD: None of these, no. They're minor differences. They're equivalent here on this side effect. But looking at hypertension, AFib, hemorrhage, and events of clinical interest here, so the risk of hypertension was higher with zanubrutinib. Any grade, the odds ratio was 0.18 in favor of acalabrutinib, and grade 3 or higher, the odds ratio was 0.22. These were statistically significant. This hemorrhage difference was also lower with acalabrutinib versus zanubrutinib. Any grade was 0.54 odds ratio. With high grade hemorrhage though, there was no difference. With major hemorrhage, there was no difference. But all hemorrhage had a difference. If you look at percentage, it was 28% versus 42.3% in terms of all hemorrhage. Looking at hypertension, any grade was 5.2% in the post-matched analysis versus 23.5% with zanubrutinib. AFib was similar, it was 5.2% with zanubrutinib, 6% with acalabrutinib. Even grade 3 or higher was 2.5 versus 1.5% in a small number of events. There was not statistically significant difference there. It does reflect what we saw in the other studies. When you saw the zanubrutinib versus ibrutinib, AFib was lower in ALPINE. However, hemorrhage was similar. Hypertension was fairly similar. Whereas acalabrutinib versus ibrutinib on ELEVATE-RR, now looking at safety, not really efficacy, there was an improvement in AFib, which is ibrutinib-based superior with against ibrutinib as well. There was an improvement in bleeding and hypertension as well. So, it's going along those same lines.

Ryan W. Jacobs, MD: AFib seems similar, but maybe some points of differentiation could be all grade hemorrhage, and then of course hypertension.

Alan P. Skarbnik, MD: Absolutely. Looking just at cardiovascular events again, just in a different format of what we just discussed, AFib, similar, no differences there. However, lower risk of hypertension of any grade or grade 3 or higher, and lower risk of hemorrhage of any grade, but not major hemorrhage, or just specifically grade 3 or higher between acalabrutinib versus zanubrutinib. Similar risk of AFib any grade, high grade AFib, high grade hemorrhage between those 2 agents. Here's a summary of treatment safety. Looking everything that's left of the dotted line favors acalabrutinib, everything that's right of the dotted line favors zanubrutinib. Again, showing the same factors, hemorrhage of any grade, hypertension of any grade or high grade. Those are the main differences. There were less adverse events leading to dose reduction in the acalabrutinib arm. To some extent, this may be because of trial design. There were more opportunities in the zanubrutinib study to dose decrease than there were in the ASCEND trial. What timing was the adverse event occurrence? If it was the second or third time, with acalabrutinib, you could go and decrease it a third time. And zanubrutinib, because of the dosing, you could decrease a little sooner. That may explain the difference because when you look at the ease leading to treatment interruption, they were similar.

Ryan W. Jacobs, MD: It looks like the discontinuation rates were similar.

Alan P. Skarbnik, MD: Correct, yes. The discontinuation rates and treatment interruption were the same. This is more about trial design than a real difference. Looking at the actual incidence of dose side effects or adverse events, they were the differences that we discussed before. Going a bit more deeply, the risk of an AE [adverse event] leading to dose reduction, as I said, the odds ratio is 0.3. We've got to take that with a little grain of salt because of trial design differences, but severe adverse events of any grade were 31% with acalabrutinib and 42% with zanubrutinib, and with riskier, higher, adverse events, it was 58% versus 67.3% overall, 4% versus 12% dose reduction. Treatment discontinuation was similar, 18 versus 16.4. Treatment interruption was 40% versus 50%. No difference there, as we mentioned before. Again, looking at this lower risk of a serious adverse event overall, 0.621 odds ratio, it almost doesn't seem statistically significant, but it is 0.39, 0.97. That’s something you need to look at carefully. As I said, for the dose reduction, we need to consider trial differences here to look at that. More importantly, treatment discontinuation was pretty much the same.

Ryan W. Jacobs, MD:I think the dose reduction issue is an interesting one. There's more significant data with ibrutinib that you can dose reduce, and it doesn't necessarily seem to reduce the length of PFS necessarily. We don't necessarily know that with the newer novel second-generation BTK inhibitors. It'll be interesting as we get more data to see if we can as comfortably dose reduce acalabrutinib and zanubrutinib as we were with ibrutinib.

Alan P. Skarbnik, MD: Absolutely. Just to remind everyone, the difference in the dosing, because acalabrutinib is 2 [tablets per day], is 1 tablet of 100 mg in the morning and at night, so you can just dose reduce 1. You can drop it by half. Zanubrutinib is four pills [per day]. We have a little more leeway in terms of dose reduction. There it becomes logistically a little easier, possibly explaining for the difference there as well.

Transcript edited for clarity.

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