ASH 2024 | Zanubrutinib versus BR in previously untreated CLL: five-year follow-up from the SEQUOIA trial

At ASH 2024, we presented the five-year follow-up of the Sequoia trial. As a quick reminder, Sequoia was the frontline study investigating zanubrutinib for first-line treatment of CLL. This follow-up was on cohort one, which was the randomized cohort comparing zanubrutinib as monotherapy versus bendamustine and rituximab. I should mention that the results were concurrently published at the JCO Journal. So they’re available for a more detailed, basically, analysis by our viewers. But basically, a quick reminder, again, one-to-one randomization, BR versus zanubrutinib. These are patients who did not have del17p and 240 patients approximately on each arm. So what we showed was the continued advantage of zanubrutinib over bendamustine rituximab for PFS with a hazard ratio of 0.29, which was statistically significant. We are seeing that advantage of zanubrutinib over BR in both mutated and unmutated IGHV status, which is important. And I think one of the important findings of the study was the very impressive, in my opinion, the CR and CRi rate, which is now around 21%. This is with monotherapy of zanubrutinib, and these drugs in general are not the type of drugs that we expected, a high CR rate, but with a five-year follow-up at 21%, it was important to note. In terms of the safety profile, we reported the same expected adverse events that you would see with zanubrutinib with no new safety signal. In fact, focusing on adverse events of interest and looking at the exposure-adjusted incidence for some select adverse events, we reported that atrial fibrillation or a flutter. Again, the exposure adjusted incidence rate was 0.13 versus 0.09 in the BR arm. So when you do a kind of an unplanned statistical comparison, the P-value was not significant and these rates were not different between zanu and the background risk, which is chemoimmunotherapy. and same with hypertension, in fact, 0.5 versus 0.38. And the hemorrhage rate was higher with zanubrutinib, 1.6 versus 0.35 as expected. But the major hemorrhage was at a much lower rate, 0.18 for the zanubrutinib. So I think in conclusion, with now more than 61 months of follow-up or more than five years of follow-up, zanubrutinib continues to show superior efficacy from the PFS standpoint over BR. That benefit is shown in mutated and unmutated IGHV patients and also the CR rate of around 21% with the safety profile that kind of is highlighted by low rate of AFib and a flutter infection and also the cumulative incidence of hypertension and a flutter remaining low and comparable to the background risk which was the chemoimmunotherapy arm or BR.

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