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Zanubrutinib/Venetoclax Yields Deep Responses in Treatment-Naive CLL Regardless of Del17p/TP53 Mutational Status

Mazyar Shadman, MD, MPH, discusses key efficacy and safety findings from arm D of the SEQUOIA trial of first-line zanubrutinib plus venetoclax in CLL/SLL.

Mazyar Shadman, MD, MPH

Mazyar Shadman, MD, MPH

Efficacy and safety data with the all-oral regimen of zanubrutinib (Brukinsa) and venetoclax (Venclexta) may redefine clinical practice by providing a safe and adaptable approach to first-line therapy for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to Mazyar Shadman, MD, MPH.

The phase 3 SEQUOIA trial (NCT03336333) investigated zanubrutinib across several arms of patients with previously untreated CLL/SLL. Results from arm D of the trial were presented at the 2025 ASCO Annual Meeting.At a median follow-up of 31.2 months (range, 0.4-58.0), the overall response rate (ORR) was 97.4% in all patients (n = 114). 1 This included a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 48.3%. Among patients without 17p deletions (del17p) or TP53 mutations (n = 47), at a median follow-up of 29.6 months (range, 0.6-31.9), the ORR was 95.7%, including a CR/CRi rate of 48.9%. Among those with del17p and/or TP53 mutations (n = 66), at a median follow-up of 38.7 months (range, 0.4-58.0), the ORR was 98.5% and the CR/CRi rate was 47.0%.

“Altogether, we showed that zanubrutinib plus venetoclax is a highly effective combination, and more importantly, it's effective regardless of the presence of TP53 [mutations],” Shadman said in an interview with OncLive®. “Patients achieved undetectable minimal residual disease [uMRD] irrespective of those abnormalities, the response rates were high and there were no [new safety signals]. With this new era of CLL therapy, it's important to have these additional data to guide our practice.”

In the interview, Shadman discussed the rationale and design of arm D of SEQUOIA; key efficacy and safety findings from this arm; and how these data emphasize the importance of continued, time-limited, MRD-guided therapy for patients with high-risk disease.

Shadman is an associate professor in the Clinical Research Division, medical director of Cellular Immunotherapy, the Innovators Network Endowed Chair, medical director of the Bezos Family Immunotherapy Clinic, a member of the Immunotherapy Integrated Research Center, and an affiliate investigator in the Translational Science and Therapeutics Division at the Fred Hutchinson Cancer Center; as well as an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

OncLive: What was the clinical rationale for the SEQUOIA trial?

Shadman: SEQUOIA is a registration trial that [evaluated] zanubrutinib in patients with previously untreated CLL and SLL and included several cohorts and arms. The first cohort of the study was a randomized portion that compared zanubrutinib with bendamustine plus rituximab [Rituxan; BR]. The initial results and the long-term follow-up data [from this cohort] have been [previously] published and presented. [A presentation] at the 2024 ASH Annual Meeting, followed by a publication [in the Journal of Clinical Oncology], showed that zanubrutinib as monotherapy was superior to BR and was a well-tolerated and effective treatment. Long-term follow-up data from arm C of this study, which were presented at [the 2025 ASCO Annual Meeting], showed that zanubrutinib in patients with del17p also resulted in high efficacy and had a favorable safety profile.

Arm D was a combination arm. There's a lot of interest in, and rationale for, combining BTK inhibitors with BCL-2 inhibitors given their distinct modes of action and nonoverlapping toxicity profiles. Many studies have investigated different BTK inhibitors combined with BCL-2 inhibitors, namely venetoclax. SEQUOIA arm D was also an effort to do that by combining zanubrutinib—one of the next-generation BTK inhibitors with high efficacy and a favorable safety profile—with venetoclax.

What was the design of cohort D?

[SEQUOIA is] a unique study in that [it is investigating] an all-oral regimen and included a significant number of patients with del17p and TP53 mutations. Arm D comprised 2 cohorts of patients [who displayed] either del17p or TP53 mutations [vs those who did not]. The total size of cohort D was 114 patients, and 66 patients were in the high-risk cohort.

This was an MRD-guided regimen, and the study intentionally had stringent stopping criteria based on MRD. To be more specific, we required that patients first achieved a CR or CRi as confirmed by a bone marrow biopsy. After that, patient needed to have uMRD4 measured by flow cytometry twice, at least 12 weeks apart. That had to be confirmed with 2 bone marrow biopsy results that showed uMRD4. On top of that, patient needed to have received at least 12 cycles of therapy with venetoclax and at least 27 cycles of therapy with zanubrutinib.

What were the efficacy findings from arm D?

[There were] 31.2 months of follow-up for the entire cohort. Patients with TP53 aberrancy, including both del17p and TP53 mutations, had 38.7 months of follow-up because that cohort started [treatment] a bit earlier. The combination was extremely effective, regardless of TP53 aberrancy status. We saw high CR or CRi rates of 45.5% to 48.9% across the 2 [risk-stratified] groups and in the entire population.

An important finding from this study was the high rate of uMRD4. The best uMRD4 rate was 59% regardless of the presence of TP53 abnormalities. That's important, because this is an all-oral regimen that does not include an anti-CD20 antibody. When we looked at the time points of best MRD by cycle 16, we saw that that number was 43% within the normal TP53 group, and it increased to 60% by cycle 28. In the high-risk population, this rate was lower—21%— at cycle 16 but increased to 49% by cycle 28. [This speaks] to the importance of continued therapy in patients, at least those with high-risk disease. Patients will eventually get to that uMRD state, but it may take longer if they have abnormal TP53 genes in terms of size.

In terms of long-term PFS, when we looked at the abnormal TP53 group, at 24 months, the estimated PFS rate was 94%, and it was 88% at 36 months. In the normal p53 group, the 24-month PFS rate was 89%. It's also important to mention that despite the stringent stopping rules and the relatively short follow-up, 11 patients were able to stop treatment. Out of those 11 patients, only 1 had progressive disease, and that patient had a normal TP53 gene.

What were the safety findings from arm D?

The safety profile was favorable. We did not observe any new safety signals with the combination. The atrial fibrillation rate was low, at 3%. There were no deaths due to either COVID-19 or cardiac reasons, which is important. Five patients died due to adverse effects. The combination had a safety profile that one would expect from the combination of a BTK inhibitor plus a BCL-2 inhibitor.

What questions did this analysis generate?

It's important and helpful to have these data presented and published in detail, both from the safety and efficacy standpoints, and to show that zanubrutinib plus venetoclax is an option for patients. One of the important points we learned and will continue to learn [about] with longer follow-up is the optimal duration of therapy, especially in patients with abnormal TP53 genes. The best uMRD rate in these patients was similar to that in patients with normal TP53 genes, but it may take longer for [the patients with TP53 abnormalities] to get there. We have data showing the conversion of uMRD rate from 21% to 49% [in patients with TP53 abnormalities] after almost 1 year of additional therapy, and the best uMRD rate [in this cohort was] even higher, at 59%. Patients continue to have improved and better-quality responses and deeper responses over time. With longer follow-up, it would be interesting to see how long it takes for patients to get to these deep remissions. This study used a strict and comprehensive MRD assessment, so we may learn a lot about [this].

In general, the main question in the field remains: What is the optimal combination of a BTK inhibitor plus a BCL-2 inhibitor? We can look at the data and decide what would be the best and most effective BTK inhibitor, either covalent or noncovalent. Currently, venetoclax is the only approved BCL-2 inhibitor. However, there are drugs like sonrotoclax [BGB-11417] that are also under development. Phase 1 data [from the BGB-11417-101 trial (NCT04277637) investigating the] combination of zanubrutinib and sonrotoclax showed high efficacy and a high rate of uMRD [in patients with first-line CLL]. The phase 3 CELESTIAL-TNCLL study [NCT06073821] finished enrollment, and that study compared sonrotoclax plus zanubrutinib vs venetoclax plus obinutuzumab [(Gazyva) in patients with treatment-naive CLL]. It will be important to see those results. We also are waiting for the results of the phase 3 MAJIC trial [NCT05057494], which compared acalabrutinib [Calquence] plus venetoclax vs venetoclax plus obinutuzumab [in patients with previously untreated CLL/SLL].

There are many more studies that we're eagerly waiting for results from, including the phase 3 CLL17 trial [NCT04608318]. In the next few years, we'll learn more about these combinations, and then hopefully we can come up with the ideal duration of therapy with an all-oral regimen that does not require an intravenous CD20-directed antibody.

Reference

Shadman M, Munir T, Ma S, et al. Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: results in SEQUOIA arm D. J Clin Oncol. 2025;43(suppl 16):7009. doi:10.1200/JCO.2025.43.16_suppl.7009


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