Zanubrutinib Shows Benefits Over Bendamustine Plus Rituximab Across CLL/SLL Subgroups

The Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) demonstrated a superior progression-free survival (PFS) benefit compared with combination bendamustine and rituximab across biomarker subgroups of treatment-naive patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without deletion of the 17p chromosome, or del(17p).¹

The findings, which come from an analysis of the phase 3 SEQUOIA trial (NCT03336333), were presented at the 65th American Society of Hematology Annual Meeting and Exposition.

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In the SEQUOIA trial, fist-line zanubrutinib significantly improved PFS vs bendamustine plus rituximab in patients without del(17p), supporting the use of zanubrutinib in untreated CLL and SLL.² The new study evaluated PFS in subgroups of patients based on a range of biomarkers, including some known to be negative prognostic factors for CLL.¹

Blood samples from patients with CLL and bone marrow samples from patients with SLL collected at screening were assessed for chromosome abnormalities; underwent cytogenetic analysis for complex karyotype (CKT); were analyzed via next-generation sequencing (NGS) for immunoglobulin heavy chain variable (IGHV) gene mutations and expressed clones; and underwent ultrasensitive targeted NGS to analyze mutations across 106 genes.

Better PFS was seen with zanubrutinib vs combination treatment in patients with del(11q) (P < .001), del(13q) (P <.001), trisomy 12 (P < .01), or CKT of at least 3 (P < .01). Median PFS values were not yet reached in the zanubrutinib arm for these subgroups, compared with 29.2 months (P < .001), 40.8 months (P < .001), 40.7 months (P < .01), and 31.1 months (P < .01), respectively, in the combination arm subgroups. Patients without these alterations also showed better outcomes with zanubrutinib vs the combination regimen.

Treatment with zanubrutinib showed similar PFS benefits in patients with del(11q), which is a negative prognostic factor (P = .05), and in those with trisomy 12 (P = .40), which is an intermediate prognostic factor, compared with patients who did not have these these risk factors. The authors also noted that in the zanubrutinib arm, CKT of at least 3 was not associated with worse PFS (P = .18).

Among those with and without IGHV mutations (mIGVH and uIGVH, respectively), PFS was superior in the zanubrutinib arm, and PFS was not affected by IGVH mutation status in the zanubrutinib arm (P = .12). Patients who had uIGVH harboring IGVH1-69 clones—the most prevalent expressed clone in both arms—had significantly better PFS when treated with zanubrutinib vs combination therapy. 

Patients with mutations known to confer poor prognosis in CLL, including ATMi, NOTCH1, and SF3B1, showed significantly better PFS in the zanubrutinib arm vs the combination therapy arm, with similar PFS seen between patients with and without these mutations treated with zanubrutinib.

“Importantly, within the [zanubrutinib] treatment arm, patients with negative prognostic biomarkers showed comparable PFS benefit to patients without those markers,” the authors wrote. “Like with other BTK inhibitors, ibrutinib and acalabrutinib, IGHV mutational status did not affect PFS outcome. However, contrary to what has been reported for [treatment-naive] or relapsed/refractory patients treated with ibrutinib-based regimens, CKT of at least 3 was not associated with worse PFS in zanubrutinib-treated patients.”

References

1. Ramakrishnan V, Xu L, Paik JC, et al. Broad superiority of zanubrutinib (Zanu) over bendamustine + rituximab (BR) across multiple high-risk factors: biomarker subgroup analysis in the phase 3 SEQUOIA study in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without del(17p). Presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA. Abstract 1902. https://ash.confex.com/ash/2023/webprogram/Paper174543.html

2. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5