SEQUOIA Trial: Zanubrutinib Compares Favorably with Bendamustine Plus Rituximab in CLL, SLL at Five Years

In the SEQUOIA phase 3, randomized, open-label trial, investigators compared zanubrutinib, a Bruton tyrosine kinase (BTK) inhibitor, with bendamustine plus rituximab combination therapy in patients who had untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without chromosome 17 short arm deletion (del(17p)).

Two prior analyses conducted in the trial at the median follow-up points of 26.2 months and 43.7 months revealed that zanubrutinib produced better progression-free survival (PFS) than the combination therapy. The results from an additional analysis, conducted at a median follow-up of 61.2 months, are consistent with these prior efficacy findings and prior favorable safety results for zanubrutinib. They have been presented in a study published in Journal of Clinical Oncology.

“Compared with BR [bendamustine plus rituximab], zanubrutinib provided greater PFS in treatment-naïve patients without del(17p) and was well tolerated over a median follow-up of 61.2 months. This extended SEQUOIA follow-up continued to support the use of zanubrutinib as a preferred first-line treatment for patients with CLL/SLL,” wrote study lead author Mazyar Shadman, MD, MPH, of Fred Hutchinson Cancer Center at University of Washington, Seattle, Washington, and colleagues.

The total cohort for SEQUOIA included 479 patients aged 65 years and older or 18 years and older with comorbidities. Following random assignment, 241 patients received oral zanubrutinib, 160 mg twice daily in 28-day cycles, and 238 patients received intravenous bendamustine plus rituximab for six cycles. The two treatment groups had similar baseline patient demographics and disease characteristics.

By a median follow-up of 61.2 months, 32.0% of patients who received zanubrutinib had discontinued treatment, most frequently because of adverse events (AEs) or progressive disease. Seventy-nine percent of patients who received the combination therapy had completed six cycles of treatment. Disease progression occurred in 12.4% of the zanubrutinib group and 41.2% of the combination therapy group.

Efficacy in SEQUOIA was assessed in the study’s randomized intention-to-treat population. Neither treatment group reached median overall survival (OS). The estimated 60-month OS rates in the zanubrutinib and combination therapy groups were 85.8% and 85.0%, respectively, and overall response rates were 97.5% and 88.7%, respectively. The investigator-assessed rate of complete response (CR) or CR with incomplete hematologic recovery was 20.7% in the zanubrutinib group and 23.5% in the combination therapy group.

Median PFS was not reached in the zanubrutinib group, and in the combination therapy group, median PFS was 44.1 months, with a hazard ratio (HR) of 0.29 (one-sided P=.0001). The 60-month estimated PFS was 76% in the zanubrutinib group and 40% in the combination therapy group. Zanubrutinib was found to result in prolonged PFS as compared with the combination therapy in patients with or without mutated IGHV genes, with HRs of 0.40 (one-sided P=.0003) and 0.21 (one-sided P<.0001), respectively.

“Although only a small number of samples were available for BTK mutation testing in this study, these data suggest that acquired mutations conferring resistance to BTK inhibitors are rare. Here, only two patients were found to have BTK inhibitor resistance mutations at disease progression among few primary progressors,” the study authors noted. Based on this, the investigators concluded that concerns about possible resistance mutations should not influence treatment decisions.

Safety in the SEQUOIA trial was assessed in all patients who had received at least one dose of treatment, and the analysis performed at the median 61.2-month follow-up detected no new safety signals from the prior analyses.

Regarding treatment-emergent or post-treatment AEs of interest (AEIs) in patients in the zanubrutinib and combination therapy groups, anemia occurred in 9.6% and 21.1%, any-grade infection in 79.6% and 65.6%, atrial fibrillation in 7.1% and 3.5%, bleeding in 52.1% and 13.2%, hypertension in 22.9% and 13.7%, neutropenia in 17.1% and 56.8%, and thrombocytopenia in 7.1% and 18.5% of patients, respectively. Regarding AEIs of grade 3 or worse severity in the zanubrutinib and combination therapy groups, anemia occurred in 0.8% and 2.6%, bleeding in 7.5% and 1.8%, infection in 30.0% and 22.5%, neutropenia in 12.5% and 51.1%, and thrombocytopenia in 2.5% and 8.4% of patients, respectively.

“AEs over time showed bleeding, cytopenias, and diarrhea to be highest in the first year and decrease thereafter, while hypertension increased over time,” the authors elaborated.

Second primary malignancies developed in 23.8% of patients who received zanubrutinib and 15.0% of patients who received the combination therapy, with skin cancers being the most common type in either group.

In each group, 34 deaths occurred. AEs were the most frequent cause of death, and the most common were COVID-19 infection, COVID-19 pneumonia, and pneumonia.

Reference

Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. Published online December 8, 2024. doi:10.1200/JCO-24-02265