Zanubrutinib Highly Effective in CLL/SLL, Despite Presence of High-Risk Cytogenetics

Constantine S. Tam, MBBS, MD

Constantine S. Tam, MBBS, MD

In the SEQUOIA trial, zanubrutinib (Brukinsa), a Bruton’s tyrosine kinase inhibitor, showed continued high overall response rates (ORR) for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), regardless of deletion 17p status, according to findings presented at the American Society of Hematology (ASH) Annual Meeting and Exposition.

In arm C of the phase III SEQUOIA trial,1 the ORR with zanubrutinib was 92.7% (95% CI, 86%-96.8%) for treatment-naive patients with del(17p) CLL/SLL. After 29.5 months of follow-up in the AU-003 trial,2 the ORR was 100% in treatment-naive patients with CLL/SLL. In the relapsed/refractory setting, zanubrutinib elicited an ORR of 95%.  

"With further follow-up and experience, zanubrutinib monotherapy was found to be well-tolerated and active in patients with CLL/SLL, irrespective of del(17p) status," Constantine S. Tam, MBBS, MD, from the Peter MacCallum Cancer Centre, said while presenting the results from both studies. "The complete response rate [in AU-003] was 16% and continues to mature over time."  

Interim SEQUOIA Data  

Arm C of the SEQUOIA trial included 109 patients with del(17p) CLL/SLL. The median age of patients was 70 years, and 12.8% had an ECOG performance status of 2. The median number of months since diagnosis was 21.62. In addition to del(17p), 66.1% of patients also harbored del(13q), 33.9% had del(11.q), 18.3% had Trisomy 12, and 61.5% had unmutated IGHV.  

At a median follow-up of 10.0 months, there were 2 complete responses (CR; 1.9%), 86 partial responses (PR; 78.9%), and 13 PRs with lymphocytosis (11.9%). Overall, 95% of patients had a duration of response lasting 6 months or longer, and similar response rates were seen across all patient subgroups.  

Overall, 36.7% of patients experienced a grade ≥3 adverse event (AE), with the most common events being neutropenia (10.1%), pneumonia (3.7%), and hypertension (2.8%). Serious AEs were experienced by 23.9% of patients. There was 1 grade 5 case of pneumonia that led to sepsis and eventually death for the patient. Grade ≥3 infection occurred in approximately 10% of patients and major bleeding was seen in nearly 4% of individuals. Grade ≥3 atrial fibrillation was experienced by 0.9% of patients.  

Updated AU-003 Findings

"In this very large cohort of de novo del(17p) patients treated with frontline zanubrutinib, the overall response rate was high at 92.7%. The drug was well tolerated, and the toxicity profile was consistent with what is already published for zanubrutinib," said Tam.AU-003 was the first study to explore zanubrutinib in humans and provides the longest available follow up for the BTK inhibitor. At this point, 384 patients have been enrolled in the trial, including 123 with CLL/SLL. The median age of patients with CLL/SLL was 67 years, with 22 having treatment-naive disease and 101 have relapsed or refractory CLL/SLL. The most common molecular risk factor was unmutated IGHV (68.3%) and 16.2% of patients had del(17p).  

Responses in the treatment-naive group consisted of 5 CRs (22.7%) and 17 PRs (77.3%). In this group, 95.2% of patients continued to respond at the time of the assessment. In the relapsed/refractory cohort, responses consisted of 14 CRs (13.9%), 73 PRs (72.3%), and 8 PRs with lymphocytosis (7.9%). Responses continued for 97.6% of patients. Across both groups combined, the ORR was 95.9% and the CR rate was 15.4%. 

In patients with del(17p) CLL/SLL, the ORR was 100% in the treatment naive group, which were all PRs (n = 3). In the relapsed/refractory del(17p) group, the ORR was 92.3%, with 1 CR (7.7%). All patients continued to respond at the time of the assessment.  

In the treatment-naive group, the 12-month and 24-month progression-free survival (PFS) rates were 95% and 97%, respectively. For the relapsed/refractory group, the 12-month and 24-month PFS rates were 97% and 91%, respectively.  

Across the study, grade ≥3 AEs of any cause were seen in 61.8% of patients receiving zanubrutinib, with AEs leading to discontinuation for 4.1% of patients. Serious AEs were experienced by 47.2% of patients, with one fatal adverse event that was deemed unrelated to study drug. The most common AEs were contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%). Grade ≥3 atrial fibrillation occurred in 1.6% of patients.  

"If you break down when these adverse events happen, you see that the most troublesome adverse events, including neutropenia, atrial fibrillation, opportunistic infection, and pneumonia, all tend to occur early with a reduced risk in the third year of treatment," said Tam. "There is a constant approximately 10% risk of grade 3 infection year-by-year, which actually seems high at first glance but is in fact totally consistent with other BTK inhibitors in this same population."  

Other arms of the phase III SEQUOIA trial continue to enroll, including an arm comparing zanubrutinib with bendamustine plus rituximab for treatment-naive CLL/SLL (NCT03336333). Additionally, the phase III ALPINE study is currently recruiting to explore zanubrutinib compared with ibrutinib for patients with relapsed/refractory CLL. The primary completion date for this trial is February 2021 (NCT03734016).  

References

1. Tam CS, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): initial results from arm C of the Sequoia (BGB-3111-304) trial. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 499. bit.ly/2rkuTqP. 
2. Cull G, Simpson D, Opat S, et al. Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): updated results from a phase 1/2 trial. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019;  Orlando, FL. Abstract bit.ly/355AShI.