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.
Results from arms C and D of the phase 3 SEQUOIA trial demonstrated that zanubrutinib alone or in combination with venetoclax yields positive results in CLL/SLL subpopulations.
Zanubrutinib Demonstrates Promising Outcomes in Front-Line CLL/SLL with High-Risk Genetic Features
Recent data presented highlights the efficacy and safety of zanubrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) harboring high-risk genetic characteristics. Experts emphasize the significance of thes findings, particularly in the context of evolving treatment paradigms favoring fixed-duration therapies.
SEQUOIA Arm C: zanubrutinib Monotherapy in Del(17p) Patients
A total of 117 patients with del(17p) were enrolled in arm C of the SEQUOIA trial. Participants received zanubrutinib at 160 mg twice daily until unacceptable toxicity or study completion. Inclusion criteria required untreated CLL/SLL, measurable disease via CT/MRI, and unsuitability for fludarabine, cyclophosphamide, and rituximab. Primary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.
The patient population was largely comprised of individuals 65 years or older (85.6%), with good performance status (ECOG 0 or 1 in 87.3%). Key baseline characteristics included: 90.1% with CLL, 39.6% with bulky disease (longest diameter ≥5 cm), 52.3% with TP53 mutations, 99.1% with del(17p), and 42.3% with both del(17p) and TP53 mutations. Notably, 60.4% were IGHV unmutated, and 27.9% had three or more complex karyotype abnormalities.
Experts highlighted the compelling PFS and ORR rates observed in this arm. “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 [BTKi] monotherapy for this population,” stated Shadman. “This is a solid prospective data set that we, hopefully, continue to see long-term.”
Kipsy added, “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.”
Safety Profile
The safety profile of zanubrutinib in this population was manageable. 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). More serious 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 contributed to death in 6 patients (5.4%).
Shadman noted that patients on BTKis are generally “easier” to monitor, with routine visits every 3 months being sufficient.
Addressing patient anxieties, Shadman emphasized the importance of providing reassurance to those diagnosed with del(17p). “Many times, when you get the results of a study from a patient, and thay 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,
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