SEQUOIA Extended Follow-Up Supports Initial Findings in CLL/SLL

After five years of follow-up in the phase 3 SEQUOIA study, first-line zanubrutinib treatment continues to demonstrate an improvement in progression-free survival (PFS) versus bendamustine and rituximab (BR) for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

“This extended SEQUOIA follow-up continued to support the use of zanubrutinib as a preferred first-line treatment for patients with CLL/SLL,” wrote investigators led by Mazyar Shadman, MD, MPH, of Fred Hutchinson Cancer Center, Seattle, Washington, in a published paper.

Of 479 patients, 241 received zanubrutinib and 238 received BR; median follow-up for the analysis was 61.2 months (range, 0–78.0 months). The median age of patients evaluated was 70 years (range, 40–86 years) in the zanubrutinib arm and 70 years (range, 35–87 years) in the BR arm. In the zanubrutinib arm, 64% of the patients were male and 92% were White; in the BR arm, 61% were male and 87% were White. Most patients had a performance score (PS) of 0 or 1, with only 6% in the zanubrutinib arm and 8% in the BR arm showing a PS of 2. Ninety-two percent of patients in the zanubrutinib arm had CLL, as did 92% of the BR group. SLL was diagnosed in 85.8% of patients in the zanubrutinib arm and 85.0% of the BR arm.

The median PFS was 44.1 months in the BR arm, but the median PFS was not reached in the zanubrutinib arm (hazard ratio [HR], 0.29; one-sided P=.001). The PFS advantage of zanubrutinib versus BR was observed regardless of IGHV mutational status with an HR of 0.40 in the subgroup without mutations (one-sided P=.0003) and an HR of 0.21 in the subgroup with mutations (95% CI, 0.14-0.33; one-sided P<.0001).

Overall survival (OS) was not reached in either treatment arm; however, estimated OS rates at 60 months were 85.8% in the zanubrutinib arm and 85.0% in the BR arm.

All patients were evaluable for safety, and median treatment exposure was 5.5 months with zanubrutinib and 5.6 months with BR. Disease progression was observed in 12.4% of the zanubrutinib arm and 41.2% of the BR arm; 24.8% of those who experienced disease progression in the BR arm crossed over to the zanubrutinib arm.

Treatment-emergent adverse events (AEs) occurred in 95.4% of the zanubrutinib arm and 94.3% of the BR arm, and grade 3 or higher AEs occurred in 67.9% and 74.4%, respectively. The most common treatment-emergent and post-treatment AEs observed in the zanubrutinib and BR arms included any-grade infection (79.6% vs 65.6%, respectively), bleeding  (52.1% vs 13.2%), hypertension (22.9% vs 13.7%), neutropenia (17.1% vs 56.8%), anemia (9.6% vs 21.1%), thrombocytopenia (7.1% vs 18.5%), and atrial fibrillation or flutter (7.1% vs 3.5%).

Investigators concluded that in addition to continued efficacy, zanubrutinib was well tolerated by patients with treatment-naive CLL/SLL.

“Whether ongoing studies using either a time-limited approach as BTK inhibitor monotherapy or combination therapy will improve upon or equal efficacy without the AE burden of continuous BTK inhibitor monotherapy remains unclear,” wrote Shadman et al about the extended follow-up analysis.

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 ahead of print December 8, 2024. doi: 10.1200/JCO-24-02265