Zanubrutinib Demonstrates Durable Efficacy in CLL/SLL, ASCO 2025 Data Reveal
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New long-term data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting underscores the effectiveness of zanubrutinib (Brukinsa) – both as a monotherapy and in combination with venetoclax (Venclexta) – in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The findings, stemming from the phase 3 SEQUOIA trial (NCT03336333), offer encouraging news for patients, particularly those with high-risk genetic profiles.
The SEQUOIA trial results were the focus of a recent “Between the Lines” program hosted by CancerNetwork®, featuring insights from leading hematologists Andrew H. Lipsky, MD, of Columbia University Herbert Irving Comprehensive Cancer Center, and Mayzar Shadman, MD, MPH, of Fred Hutch Cancer Center. The experts discussed the implications of these findings for the evolving treatment landscape of CLL/SLL.
Zanubrutinib Monotherapy Shows Promise in High-Risk Patients (Arm C)
Data from Arm C of the SEQUOIA trial revealed remarkably durable efficacy with zanubrutinib monotherapy in treatment-naïve CLL/SLL patients harboring the del(17p) genetic aberration – a marker historically associated with poorer prognosis. The 5-year progression-free survival (PFS) rate reached 72.2% (95% CI, 62.4%-79.8%), rising to 73% when adjusted for potential disruptions caused by the COVID-19 pandemic (95% CI, 63.3%-80.6%). Notably, PFS rates remained high across different IGHV mutation statuses, at 74.6% (95% CI, 56.9%-85.9%) for mutated IGHV and 70.7% (95% CI, 57.4%-80.6%) for unmutated IGHV.
Overall survival (OS) also remained high, with a 5-year OS rate of 85.1% (95% CI, 76.9%-90.6%), increasing to 87% (95% CI, 79%-92.1%) after COVID-19 adjustment. The overall response rate (ORR) was an impressive 97.3%, with complete response (CR) or complete response with incomplete hematopoietic recovery (CRi) achieved in 18.2% of patients.
“That data compares favorably with other data we’ve seen in CLL,” stated a senior official. One of the key takeaways for Shadman was the observed CR/CRi rate and the sustained PFS rates.
The study enrolled 117 patients with del(17p), who received zanubrutinib 160 mg twice daily until unacceptable toxicity or study completion. Participants were selected from those with previously untreated CLL/SLL, measurable disease, and were deemed unsuitable for fludarabine, cyclophosphamide, and rituximab regimens. The primary endpoints assessed were PFS, ORR, OS, and safety.
A significant proportion of patients enrolled in Arm C were 65 years or older (85.6%), with good performance status (ECOG 0 or 1 in 87.3%). Furthermore, 39.6% had bulky disease, 52.3% were TP53-mutated, 99.1% had del(17p), and 42.3% carried both del(17p) and TP53 mutations. A majority (60.4%) were IGHV unmutated, and 27.9% had complex karyotype abnormalities.
“My takeaway for the SEQUOIA arm C data is that, within this high-risk subgroup of patients in the front-line setting, zanubrutinib as a BTKi continued to be well-tolerated as a monotherapy,” Lipsky noted.
Regarding safety, the most common grade 1 and 2 treatment-emergent adverse events (TEAEs) included hemorrhage (n = 54), infection (n = 49), second primary malignancy (n = 23), and skin cancers (n = 22). More serious grade 3 or higher TEAEs included infections (n = 33), neutropenia (n = 16), hypertension (n = 8), and second primary malignancy (n = 7). Treatment-related deaths occurred in 6 patients (5.4%). Shadman indicated that patients on BTKi therapy are generally “easier” to monitor, with routine visits every 3 months.
Shadman emphasized the importance of these findings for patients who often feel discouraged by a del(17p) diagnosis, stating, “Many times, when you get the results of a study from a patient, and they see del(17p), they go on the internet and read about it. They feel like treatments will not work for them. It’s nice to be able to provide this data and tell them, ‘Yes, this is a known risk factor, and for some treatments, it does predict the response, but we have treatments that can easily trump that.’”
Zanubrutinib Plus Venetoclax Demonstrates Deep Responses (Arm D)
Arm D of the SEQUOIA trial investigated the combination of zanubrutinib and venetoclax in treatment-naïve CLL/SLL. With a median follow-up of 31.2 months, the median PFS was not reached, and the 24-month PFS rate was an impressive 92% (95% CI, 85%-96%). The ORR and CR/CRi rates were 97.4% and 48.3%, respectively.
Subgroup analysis revealed consistently high efficacy in patients with del(17p) and/or TP53 mutations, with a median follow-up of 38.7 months showing an unreached median PFS and 24- and 36-month PFS rates of 94% (95% CI, 85%-98%) and 88% (95% CI, 75%-94%), respectively. ORR and CR/CRi rates were 98.5% and 47% in this group. Patients without del(17p) and/or TP53 mutations also experienced favorable outcomes, with an unreached median PFS and a 24-month PFS of 89% (95% CI, 76%-95%). ORR and CR/CRi rates were 95.7% and 48.9%, respectively.
The rate of undetectable minimal residual disease (MRD) was 58.8% overall, with similar rates observed in both patient groups (59.1% with del(17p)/TP53 mutation and 59.6% without). MRD negativity deepened over time, with rates of 21% and 49% at cycles 16 and 28 in the del(17p) group, and 43% and 60% in those without del(17p).
“It is nice to see dedicated, time-limited oral doublet data for a particular subgroup, and the data itself looked great,” Lipsky commented. He suggested that the study design, specifically the requirement to achieve CR and MRD activity before discontinuing venetoclax, may have contributed to the compelling results.
A total of 114 patients were enrolled in Arm D, with 66 having del(17p) and/or a TP53 mutation and 47 lacking del(17p). All patients received zanubrutinib plus venetoclax, following a schedule of zanubrutinib monotherapy for the first 3 months, followed by a ramp-up phase with both drugs, and then continuous zanubrutinib monotherapy based on MRD status and tolerability.
Shadman noted that the high-risk cohort was enriched for patients with unmutated IGHV and complex karyotypes, as expected.
Grade 1 or 2 TEAEs of special interest included infections (n = 68), hemorrhage (n = 50), second primary malignancies (n = 13), and skin cancers (n = 11). Grade 3 or higher TEAEs included neutropenia (n = 23), infections (n = 12), hypertension (n = 10), and second primary malignancies (n = 5). Importantly, no deaths were attributed to COVID-19.
“Overall, this study provides important information that, number one, this combination is safe. We have finished it, and it’s available and extremely effective,” Shadman concluded.
These latest findings from the SEQUOIA trial reinforce the growing role of targeted therapies like zanubrutinib in the treatment of CLL/SLL, offering hope for improved outcomes, even in patients with historically challenging genetic profiles.
