Mazyar Shadman, MD, PhD, on Doublet for Treatment-Naive CLL/SLL

Here in Chicago for ASCO 2025 and today I presented the data from the Sequoia trial. Sequoia is the phase three study that looked at zanubrutinib in the first-line setting for CLL and SLL and the study has different cohorts. So today the presentation was on cohort D, which is the combination of zanubrutinib and venetoclax again for treatment-naive CLL in patients with abnormal P53 including deletion or mutation of that gene or those without those abnormalities. So in terms of the other cohorts of Sequoia, the first cohort which was a randomized study of zanubrutinib versus BR is already presented and published. And also we also had a presentation today on RMC. So to focus on the RMD, there is a lot of interest and rationality. Combine BTK inhibitors and BCL-2 inhibitors. The two classes have distinct modes of action and they also have non-overlapping adverse events. So the question was whether or not zanubrutinib plus venetoclax is an effective and safe option. Picking zanubrutinib makes sense, it's a very important BTK inhibitor. This is the only BTK inhibitor that has superior efficacy compared to ibrutinib in a randomized trial including patients with del17P. And venetoclax is the only BCL-2 available right now. So the study design was as follows. Patients started with zanubrutinib for three months. Venetoclax was started on cycle 4 and patients continued both drugs. Zanubrutinib was given at least for 27 cycles and after that until progression, intolerance, or meeting the stopping rule criteria. Venetoclax was given between 12 to 24 cycles depending on whether or not patients achieved an undetectable MRD and met the stopping criteria based on that. So the study used a very stringent and very strict criteria for stopping. So in order for patients to be eligible to stop treatment, they had to meet all the following criteria. They had to have a CR or CRi which was confirmed by a bone marrow biopsy. And after that we had to confirm that patients had uMRD in peripheral blood twice 12 weeks apart and then two undetectable MRD tests from the bone marrow biopsy 12 weeks apart as well as this treatment with zanubrutinib and venetoclax for the minimum of 12 and 27 cycles respectively. In terms of efficacy, the combination was extremely effective regardless of presence of P53 abnormalities and we had high CR/CRi rate in the range of 47%. Also the best uMRD rate was extremely high at 59 to 60% regardless of having abnormal P53 gene. So this is important and an important finding was the fact that when we look at the timeline of becoming or the timeline of having a best uMRD rate focusing on the normal P53 cohort, by cycle 16, 43% of patients had an undetectable MRD and by cycle 28 it went up to 60%. Now the rate for abnormal P53 cohort was initially 21% but that also went up to 49% after additional almost a year of therapy. So this is important indicating that the duration of therapy even for a fixed-duration regimen is not known. And maybe in high-risk patients as we showed continued therapy makes sense because these responses tend to, from what we saw, deepen and the quality of responses get better and the rate of uMRD actually improves. In both arms, the PFS rate was extremely high. For the high-risk population, we had a 24-month PFS rate of 94% and then at 36 months it was 88%. For the low-risk cohort, the 24-month estimate of PFS was 88%. So it should be noted that the duration of follow-up was shorter in the low-risk population because that cohort started later than the high-risk population. It's also noteworthy that despite the very strict stopping rules and also despite the relatively short follow-up, 11 patients met the criteria for stopping treatment. And from those 11 patients, only one patient had progressive disease and that patient had high-risk features. From the safety standpoint, we did not detect or report any new safety signal. These patients had expected side effects that you would see with BTK inhibitor or BCL-2 inhibitor. We have 5 deaths due to adverse events, but no deaths due to COVID-19 or cardiac reasons. So in summary, this study shows that combination of zanubrutinib and venetoclax is highly effective measured by the quality of responses by complete response and also undetectable MRD rate regardless and irrespective of presence of P53 deletion and mutation. We also showed that duration of response and PFS is comparable between the two groups. We learned that maybe for a high-risk group, duration of response matters and longer treatment may provide conversions from positive MRD to uMRD. And we also showed that the safety profile is as expected. So this data looks favorable and compared to the other all-oral combinations. We also show that zanubrutinib could be combined with BCL-2 inhibitor to provide a time-limited option. And I think from the clinical standpoint, it's important for us clinicians to know that in the era of novel agents and combination of novel agents, Zanu and venetoclax combo is also a viable option, which is effective not only in low-risk patients, but also in patients with del17P/P53 population. It should be noted that for example, the amplified study that compared acalabrutinib plus venetoclax versus chemoimmunotherapy did not include patients with abnormal P53 gene and the data with Acala plus VEN that looks promising for high-risk population uses the combo in addition to an anti-CD20 antibody. So Sequoia RMD was an all-oral without a CD20 antibody.