Zanubrutinib Therapies Yield Durable Results in High-Risk, Treatment-Naïve CLL/SLL

Among prevalent recent developments in CLL/SLL, updated results from arm C and arm D of the phase 3 SEQUOIA trial (NCT03336333) were presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.^1,2 In arm C, it was demonstrated that zanubrutinib (Brukinsa) monotherapy yielded durable efficacy in patients with treatment-naïve CLL/SLL with del(17p), overcoming the negative prognostic impact of the genetic aberration. Arm D revealed that the combination therapy of zanubrutinib plus venetoclax (Venclexta) achieved deep and durable responses in patients with treatment-naive CLL/SLL; subgroups such as those with del(17p) and/or TP53 mutations and without del(17p) and TP53 mutations were also included.

In the wake of these presentations, CancerNetwork® hosted a Between the Lines program focused on these new results from ASCO; the doctors included in the program were Andrew H Lipsky, MD, assistant professor of Medicine at the Columbia University Herbert Irving Comprehensive Cancer Center, and Mayzar Shadman, MD, MPH, professor in the Clinical Research Division, medical director of Cellular Immunotherapy, and Innovators Network Endowed Chair at Fred Hutch Cancer Center. Lipsky and Shadman discussed the data, as well as their implications across the treatment-naïve CLL/SLL treatment landscape, particularly in the high-risk subgroups utilized in SEQUOIA.

Discussing Arm C

The median progression-free survival (PFS) was not reached, though the 5-year PFS rate was 72.2% (95% CI, 62.4%-79.8%); when adjusted for COVID-19, the 5-year PFS was 73% (95% CI, 63.3%-80.6%). Among patients with mutated and unmutated IGHV status, the 5-year PFS rate was 74.6% (95% CI, 56.9%-85.9%) and 70.7% (95% CI, 57.4%-80.6%), respectively. The median overall survival (OS) was not reached, with a 5-year OS rate of 85.1% (95% CI, 76.9%-90.6%); when adjusted for COVID-19, the 5-year OS was 87% (95% CI, 79%-92.1%).

The overall response rate was 97.3%, with a complete response (CR) or complete response with incomplete hematopoietic recovery (CRi) in 18.2% of patients, nodular partial response (nPR) in 2.7%, PR in 76.4%, stable disease in 1.8%, and progressive disease in 0.9%.

“That data compares favorably with other data we’ve seen in CLL,” said Lipsky.

Additionally, Shadman mentioned that his top 2 takeaways from this dataset were the CR/CRi rate, as well as the PFS rates.

A total of 117 patients with del(17p) were enrolled in arm C. Patients received zanubrutinib at 160 mg twice daily until unacceptable toxicity or end of study. Eligible patients had untreated CLL/SLL, measurable disease by CT/MRI, and were unsuitable for fludarabine, cyclophosphamide, and rituximab. The key end points for this arm were PFS and ORR by investigator assessment, OS, and safety.

Shadman added, “Overall, as the field is moving towards fixed-duration therapy, it's good to remind ourselves that the best data from an efficacy standpoint is with [Bruton’s tyrosine kinase inhibitor (BTKi)] monotherapy for this population. This is a solid prospective data set that we, hopefully, continue to see long-term.”

Most patients enrolled in this arm were 65 years or older (85.6%), with an ECOG performance status of 0 or 1 (87.3%) and CLL (90.1%). Additionally, 39.6% had bulky disease defined as a longest diameter of 5 cm or more, 52.3% were TP53-mutated, 99.1% had del(17p), and 42.3% had both del(17p) and TP53 mutations; notably, 60.4% were IGHV unmutated, and 27.9% had 3 or more 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, zanabrutinib as a BTKi continued to be well-tolerated as a monotherapy,” Kipsy said.

Regarding safety, grade 1 and 2 treatment-emergent adverse events (TEAEs) of special interest included hemorrhage (n = 54), infection (n = 49), second primary malignancy (n = 23), and skin cancers (n = 22). Grade 3 or higher TEAEs of special interest included infections (n = 33), neutropenia (n = 16), hypertension (n = 8), and second primary malignancy (n = 7). AEs also led to death in 6 patients (5.4%).

Furthermore, when prompted by Kipsy about how to monitor AEs while a patient is on a BTKi, Shadman said that these are generally “easier” patients to see, and that he generally sees them every 3 months.

Overall, on this data, Shadman said, “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.”

Discussing Arm D

With a median follow-up of 31.2 months in all patients, the median PFS was not reached, and the 24-month PFS was 92% (95% CI, 85%-96%). The ORR and CR/CRi rates were 97.4% and 48.3%, respectively. Among patients with del(17p) and/or TP53 mutations, with a median follow-up of 38.7 months, the median PFS was not reached, and the 24-month and 36-month PFS were 94% (95% CI, 85%-98%) and 88% (95% CI, 75%-94%), respectively. The ORR and CR/CRi rates were 98.5% and 47%. Among those without del(17p) and/or TP53 mutations, with a median follow-up of 29.6 months, the median PFS was not reached, and the 24-month PFS was 89% (95% CI, 76%-95%). The ORR and CR/CRi rates were 95.7% and 48.9%.

The undetectable MRD rate was 58.8% among all patients, 59.1% in patients with del(17p) and/or TP53 mutations, and 59.6% in those without del(17p) and/or TP53 mutations. The best peripheral blood-undetected MRD rates by cycle 16 and cycle 28 were 21% and 49%, respectively, 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,” said Kipsy. “For that particular subgroup, what is deepening responses and making [the data] look more compelling may involve the way the study was designed, with the adaptation of needing to get to a CR…and MRD activity before coming off venetoclax and getting at least the 27th cycle of zanubrutinib.”

Among the 114 patients enrolled in arm D, 66 had del(17p) and/or a TP53 mutation, and 47 did not have del(17p). All received zanubrutinib plus venetoclax. The dosing schedule was: cycles 1 to 3, zanubrutinib monotherapy at 160 mg twice daily for 3 months; cycles 4 to 28, zanubrutinib plus venetoclax ramp-up; and cycles 28 and beyond, continuous zanubrutinib monotherapy until disease progression, undetectable MRD-guided stopping criteria were met, or unacceptable toxicity. During cycles 4 to 28, patients may have discontinued venetoclax for undetectable MRD starting at cycle 16.

“As expected, in the high-risk cohort, there were more patients with unmutated IGHV and unstable, complex karyotypes,” said Shadman.

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); of grade 3 or higher, the most common were neutropenia (n = 23), infections (n = 12), hypertension (n = 10), and second primary malignancies (n = 5). Notably, no deaths were related 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,” concluded Shadman.

References

1. Tam CS, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naïve CLL/SLL. J Clin Oncol. 2025:43(suppl_16):7011. doi:10.1200/JCO.2025.43.16_suppl.7011
2. Shadman M, Munir T, Ma S, et al. Combination of zanubrutinib plus venetoclax for treatment-naïve CLL/SLL: results in SEQUOIA arm D. J Clin Oncol. 2025;43(suppl 16):7009. doi:10.1200/JCO.2025.43.16_suppl.7009