SEQUOIA Trial Meets Primary PFS End Point Improvement With Frontline Zanubrutinib for CLL

The SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab for patients with treatment-naïve chronic lymphocytic leukemia demonstrated superior progression-free survival results with the BTK inhibitor.

The phase 3 SEQUOIA trial (NCT03336333) comparing zanubrutinib (Brukinsa) with bendamustine (Bendeka) plus rituximab (Rituxan) met its primary end point of progression-free survival (PFS) superiority for patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to a press release from the manufacturer of the Bruton tyrosine kinase inhibitor, BeiGene.1

At the median follow-up was 25.8 months, independent review committee (IRC) and found that zanubrutinib achieved highly statistically significant improvement in PFS compared with control therapy coupled with a manageable safety profile.

“The combined clinical evidence from SEQUOIA, ALPINE [NCT03734016], the 205 trials, and the AU-003 trial [NCT02343120] validates our confidence in Brukinsa as a regimen which can offer improvements in treatment outcomes for hundreds of thousands of patients living with CLL,” Jane Huang, MD, Chief Medical Officer of Hematology at BeiGene, said in a press release.

Patients were broken up into 3 cohorts in this randomized trial. In cohort 1 (n = 479), patients were randomized in a 1:1 fashion with 241 assigned to zanubrutinib and 238 to bendamustine plus rituximab until disease progression or unacceptable toxicity. In cohort 2, 110 patients with del(17p) received zanubrutinib as a monotherapy. Cohort 3 continues to enroll patients with deletion 17p (del[17p]) or the pathogenic TP53 received zanubrutinib with venetoclax (Venclexta).

All patients who received zanubrutinib were received oral administration twice a day with by 2 80-mg capsules. Patients in cohorts receiving control therapy had intravenous bendamustine at 90 mg/m2/day on the first 2 days of each cycle for 6 cycles, and rituximab intravenously at 375 mg/m2 on day 0 of cycle 1 and then 500 mg/m2 on day 1 of cycles 2 and 6.

Patients who have del(17p) were not randomized to receive bendamustine plus rituximab because of historically poor clinical outcomes and responses to chemoimmunotherapy. 

Secondary end points of the trial includ investigator-assessed PFS, IRC and investigator-assessed overall response rate (ORR), overall survival, and PFS and ORR in patients with del(17p) and safety.

The cohort 2 findings were previously presented at the 2020 American Society for Hematology Annual Meeting, where those with del(17p) had an 18-month PFS rate of 90.6% by investigator assessment.2

Zanubrutinib has previously showed promising results in patients with relapsed/refractory CLL in a phase 2 trial (NCT03206981). In this population, an ORR of 87.9% per the IRC was observed in a total cohort of 91 patients, with 6.6% achieving complete response and 69.2% achieving a partial response.

“We are pleased to see that at the interim analysis of the SEQUOIA trial, Brukinsa significantly prolonged progression-free survival for treatment-naïve [patients with CLL], and that the demonstrated safety profile was consistent with what we have observed in its global development program with more than 2300 patients treated with Brukinsa to date,” concluded Huang.


1. BeiGene announces positive topline results from phase 3 SEQUOIA trial comparing brukinsa to bendamustine plus rituximab in patients with treatment-naïve chronic lymphocytic leukemia. News Release. BeiGene. July 29, 2021. Accessed July 30, 2021.

2. Brown J, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial. Blood. 2020;136(suppl 1):11-13. doi:10.1182/blood-2020-134280

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