Zanubrutinib Significantly Prolongs PFS Over Chemoimmunotherapy in Treatment-Naïve CLL

Zanubrutinib resulted in a significant improvement in progression-free survival per independent review committee assessment vs bendamustine plus rituximab in treatment-naïve patients with chronic lymphocytic leukemia whose tumors did not exhibit the deletion of chromosome 17p13.1.

Zanubrutinib (Brukinsa) resulted in a significant improvement in progression-free survival (PFS) per independent review committee (IRC) assessment vs bendamustine plus rituximab (Rituxan) in treatment-naïve patients with chronic lymphocytic leukemia (CLL) whose tumors did not exhibit the deletion of chromosome 17p13.1 (del[17p]), meeting the primary end point of the phase 3 SEQUOIA trial (NCT03336333).1

At a median follow-up of 25.8 months, the BTK inhibitor was also found to result in a statistically significant improvement in PFS per investigator assessment, which serves as a secondary end point of the trial.

The safety data yielded thus far has proved to be consistent with the known toxicity profile of zanubrutinib, with the agent noted to be generally well tolerated.

“The combined clinical evidence from SEQUOIA, ALPINE, the 205 trial, and the AU-003 trial validates our confidence in [zanubrutinib] 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, Ltd., stated in a press release. “We are pleased to see that at the interim analysis of the SEQUOIA trial, [zanubrutinib] significantly prolonged PFS 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 [zanubrutinib] to date.”

The global, multicenter, phase 3 SEQUOIA trial enrolled patients with a confirmed diagnosis of CD20-positive CLL or small lymphocytic lymphoma (SLL) that required treatment, who were not eligible for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab.2 Patients needed to have measurable disease on imaging, an ECOG performance status of 0 to 2, a life expectancy of at least 6 months, acceptable bone marrow function, and adequate renal and hepatic function.

If they had received prior treatment for CLL or SLL, required ongoing treatment with corticosteroids, had a known prolymphocytic leukemia or a history of or suspected Richter’s transformation, clinically significant cardiovascular disease, a history of severe bleeding, a history of stroke or intracranial hemorrhage within 6 months of the first study dose, a severe or debilitating pulmonary disease, active infection requiring systemic treatment, or known central system involvement by leukemia or lymphoma, they were excluded.

The trial is comprised of 3 cohorts. Cohort 1 consists of 479 patients who were randomized 1:1 to receive either zanubrutinib (n = 241) or bendamustine plus rituximab (n = 238) in patients with CLL or SLL whose tumors did not harbor del(17p). Treatment was given until progressive disease or intolerable toxicity. Cohort 2 is comprised of 110 patients with del(17p) who are given single-agent zanubrutinib, and enrollment for cohort 3 is ongoing. In the third cohort, patients with del(17p) or a pathogenic TP53 variant will receive zanubrutinib plus venetoclax (Venclexta).

Notably, patients whose tumors harbor del(17p) were not randomized to bendamustine plus rituximab because they are known to have poor outcomes with this approach and to respond poorly to chemoimmunotherapy.

The primary end point of the trial is PFS per IRC assessment, and key secondary end points comprise investigator-assessed PFS, IRC- and investigator-assessed overall response rate (ORR), overall survival (OS), PFS, ORR in patients with del(17p), and safety.

Previously, data from cohort 2 were reported at the 2020 ASH Annual Meeting.3 At a data cutoff of April 15, 2020, and a median follow-up of 18.2 months (range, 5.0-26.3), the best ORR achieved with zanubrutinib in 109 patients was 94.5%; this included a complete response (CR) or CR with incomplete bone marrow recovery rate of 3.7%, a partial response (PR) rate of 87.2%, and a PR with lymphocytosis rate of 2.7%. Moreover, 4.6% of patients achieved stable disease with the BTK inhibitor and 0.9% experienced disease progression.

Additionally, the median PFS, duration of response, and OS had not yet been reached. The estimated 18-month PFS rate was 88.6% (95% CI, 79.0%-94.0%). The estimated DOR and OS at 18 months were 84.0% (95% CI, 67.5%-92.6%) and 95.1% (95% CI, 88.4%-97.9%), respectively.

Safety data from the analysis indicated that the adverse effects (AEs) reported in at least 10% of patients included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/decreased neutrophil count (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%).

Grade 3 toxicities that were experienced by more than 2% of participants comprised neutropenia/decreased neutrophil count (12.9%) and pneumonia (3.7%). AEs of interest with zanubrutinib were infections (64.2%), bleeding (47.7%), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Just under 10% (9.2%) of patients experienced skin tumors and 4.6% reported non-skin second malignancies. Three patients experienced atrial fibrillation or flutter, with 2 of the events occurring in the setting of sepsis.

Moreover, 3.7% of patients discontinued treatment with zanubrutinib because of toxicities; this was because of pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury. Two patients died of these effects, and 3 additional patients died because of progressive disease (n = 2) and sepsis following progression (n = 1).


  1. BeiGene announces positive topline results from phase 3 SEQUOIA trial comparing BRUKINSA (zanubrutinib) to bendamustine plus rituximab in patients with treatment-naïve chronic lymphocytic leukemia. News release. July 29, 2021. Accessed July 30, 2021.
  2. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). Updated April 29, 2021. Accessed July 30, 2021.
  3. Brown JR, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (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):11-12. doi:10.1182/blood-2020-134280