In findings of the SEQUOIA trial and updated results of the AU-003 trial,1,2 zanubrutinib, a Bruton’s tyrosine inhibitor (BTK), was shown to produce high overall response rates for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), even in the presence of high-risk cytogenetics. Results of the trials were presented at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition.
Constantine Tam, MBBS, MD
“Zanubrutinib is a next-generation BTK inhibitor with pharmacodynamic and pharmacokinetic advantages over ibrutinib,” said Constantine Tam, MBBS, MD, Peter MacCallum Cancer Centre, Melbourne, Australia, who presented the results of both studies. “The drug is approved by the U.S. Food and Drug Administration for relapsed or refractory mantle cell lymphoma and is being studied as front-line therapy in patients with CLL/SLL and Waldenström’s macroglobulinemia. With further experience, zanubrutinib monotherapy was found to be well tolerated and active in patients with CLL/SLL, irrespective of del(17p) status, with very high response rates.”
Response rates reported for zanubrutinib in the two trials ranged from 92.7% in patients with treatment-naive CLL/SLL and del(17p) (arm C) in the SEQUOIA trial to 100% in treatment-naive patients and 95% in the relapsed or refractory setting in the AU-003 trial.
Global Phase III Study: SEQUOIA
SEQUOIA is an open-label, global, multicenter, phase III study that includes a nonrandomized arm C, comprising treatment-naive patients with del(17p) CLL/SLL.1 At the ASH meeting, Dr. Tam reported the results of arm C. The study had two other arms randomizing patients without del(17p) to bendamustine/rituximab or zanubrutinib, the results of which are not yet available.
Arm C included 109 patients with centrally confirmed del(17p) who were treated with zanubrutinib at 160 mg twice daily. The median age of patients was 70 years (range, 42–86 years), 71.6% were male, and 12.8% had an Eastern Cooperative Oncology Group performance status of 2. A total of 91% of patients in arm C had CLL, and 9% had SLL. Almost two-thirds (61.5%) of these patients in arm C had unmutated IgHV, and 33.9% had concomitant del(11q), and 18.3% had trisomy 2; 38.5% had bulky disease.
“Due to the presence of del(17p), these patients were not suitable for fludarabine/cyclophosphamide/rituximab chemotherapy,” Dr. Tam said.
At a median follow-up of 10 months, the objective response rate was 92.7%; there were 2 complete responses (1.9%), 86 partial responses (78.9%), and 13 partial responses with lymphocytosis (11.9%). Responses were consistent across all subgroups.
“All groups had a high response rate, including all poor prognostic groups. The time to response was quick,” according to Dr. Tam. “Almost all patients (95%) had a duration of response lasting 6 months or more.”
The median follow-up for the safety analysis was also 10 months. One patient stopped treatment due to adverse events and four, due to progressive disease. At the time of the ASH meeting, 104 patients were continuing with zanubrutinib treatment.
“Adverse events were consistent with previous reports of zanubrutinib in a broader population. The most common adverse events were contusion and upper respiratory tract infection,” Dr. Tam reported.
Among patients in arm C, grade 3 or higher adverse events were reported in 36.7%; the most common grade 3 or higher adverse events were neutropenia (10.1%), pneumonia (3.7%), and hypertension (2.8%). Serious adverse events occurred in 23.9% of patients. One grade 5 case of pneumonia led to sepsis and death. Grade 3 or greater infections occurred in about 10% of patients, and major bleeding occurred in less than 4%. Grade 3 or greater atrial fibrillation occurred in 0.9%.
SEQUOIA is continuing to enroll patients on other arms. The phase III ALPINE study will compare zanubrutinib directly with ibrutinib in patients with relapsed or refractory CLL.
KEY POINTS
- Zanubrutinib, a highly selective inhibitor of BTK, showed activity in early trials of patients with CLL.
- The drug achieved high response rates and durable responses as upfront treatment and in the relapsed or refractory setting.
- Phase III trials of zanubrutinib in CLL are ongoing.
- If approved, zanubrutinib will join two other BTK inhibitors: ibrutinib and acalabrutinib.
Phase I/II AU-003 Study
Updated results of the phase I/II AU-003 trial showed that patients continued to have high response rates to zanubrutinib with longer follow-up.2 “Zanubrutinib monotherapy is well tolerated and active in CLL/SLL irrespective of del(17p),” Dr. Tam emphasized.
The study included 384 patients with various types of B-cell malignancy. Dr. Tam focused his presentation on 123 patients with CLL/SLL. The median age of patients in the CLL/SLL cohort was 67 years, and 17% were older than age 75; 22 had treatment-naive disease, and 101 had relapsed or refractory disease. Cytogenetic/molecular profile included 68.3% with unmutated IgHV and 16.2% with del(17p). A total of 38% had bulky disease.
Among the 22 patients treated in the front-line setting, the investigator-reported objective response rate was 100%, with 5 complete responses (22.7%) and 17 partial responses (77.3%). Among patients with relapsed or refractory disease, the investigator-reported objective response rate was 95%, with 15 complete responses (13.9%), 73 partial responses (72.3%), and 8 partial responses with lymphocytosis.
Among patients with del(17p), the objective response rate was 100% in treatment-naive patients (all partial responses); in patients with relapsed or refractory disease, the objective response rate was 92.3%, with one complete response (7.7%).
“At the time of assessment, all patients continued to respond,” Dr. Tam stated. “Responses continued to mature over time, with a gradual reduction in lymphocytosis and a gradual rise in the complete response rate,” Dr. Tam said.
The 12- and 24-month progression-free survival rates were 95% and 95%, respectively, in treatment-naive patients and 97% and 91%, respectively, in patients with relapsed or refractory disease.
At 2.5 years of follow-up, 100% of patients experienced any adverse event, and 61.8% had grade 3 or higher adverse events. Serious adverse events were reported in 47.2% of patients, with one death deemed unrelated to zanubrutinib.
The most common adverse events 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 or higher atrial fibrillation occurred in 1.6% of patients.
DISCLOSURE: Both studies were sponsored by BeiGene. Dr. Tam has received honoraria from AbbVie, BeiGene, Janssen-Cilag, Novartis, and Pharmacyclics and has received institutional research funding from AbbVie and Janssen-Cilag.
REFERENCES
1. Tam CS, Robak T, Ghia P, et al: Efficacy and safety of zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic leukemia with del(17p): Initial results from Arm C of the Sequoia (BGB-3111-304) trial. 2019 ASH Annual Meeting & Exposition. Abstract 499. Presented December 8, 2019.
2. Cull G, Simpson D, Opat S, et al: Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib demonstrates high overall response rates and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic leukemia: Updated results from a phase 1/2 trial. 2019 ASH Annual Meeting & Exposition. Abstract 500. Presented December 8, 2019.
