Orlando, FL—Zanubrutinib (Brukinsa), a novel Bruton tyrosine kinase (BTK) inhibitor—which was approved by the FDA in November 2019 for the treatment of mantle-cell lymphoma—achieved high overall response rate (ORR) and durable responses in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including those with high-risk cytogenetics, according to findings presented at ASH 2019.
The findings came from 2 clinical trials—the SEQUOIA study and updated results of the AU-013 study. In both studies, the response rates for zanubrutinib ranged from 92.7% in patients with treatment-naïve CLL or SLL and deletion 17p (del 17p) in the SEQUOIA study to 100% in treatment-naïve patients and 95% in the relapsed or refractory setting in the AU-013 study.
“Zanubrutinib is approved by the FDA for relapsed refractory mantle-cell lymphoma, and is being studied as front-line therapy in patients with del 17p. With further experience, zanubrutinib monotherapy was found to be well-tolerated and active in patients with CLL or SLL, irrespective of del 17p status, with very high response rates,” said lead investigator Constantine S. Tam, MBBS, MD, FRACP, FRCPA, Disease Group Lead, Low-Grade Lymphoma and Chronic Lymphocytic Leukemia, Peter MacCallum Cancer Centre, Melbourne, Australia, who presented these results.
Ibrutinib (Imbruvica) was the first BTK inhibitor approved by the FDA for CLL or SLL, followed by the approval of the second-generation BTK inhibitor, acalabrutinib (Calquence). Zanubrutinib is a next-generation BTK inhibitor, with pharmacodynamic and pharmacokinetic advantages over ibrutinib. All 3 drugs have impressive response rates.
The SEQUOIA Study: High-Risk Patients
The open-label, global, multicenter, phase 3 SEQUOIA clinical trial includes nonrandomized treatment-naïve patients with del 17p CLL or SLL (Arm C). Discussing response rates limited to patients in Arm C, Dr Tam said, “These are ultra-high-risk patients, who were unfit for fludarabine-cyclophosphamide-rituximab chemotherapy.”
Arm C included 109 patients with confirmed del 17p who received treatment with zanubrutinib 160 mg twice daily (median age, 70 years; range, 42-86 years). A total of 71.6% of the patients were male, and 12.8% had an Eastern Cooperative Oncology Group performance status of 2; 90% of the patients had CLL and 10% had SLL. Approximately 33% of the patients had IGHV mutation, 66.1% had del 13q, 33.9% had del 11q, 18.3% had Trisomy 2, and 38% had bulky disease.
At a median follow-up of 10 months, the ORR was 92.7%, including 2 (1.9%) complete responses, 86 (78.9%) partial responses, and 13 (11.9%) partial responses with lymphocytosis. The responses were consistent across all subgroups. Overall, 95% of the patients had a response lasting 6 months or longer.
“Time to response was rapid. All subgroups had high response rates, including poor prognostic groups,” Dr Tam told listeners.
“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 said.
“After 10 months, there were few events. One patient died, and 4 had progressive disease with 1 going on to Richter’s transformation,” Dr Tam noted. The median follow-up for the safety analysis was 6.3 months.
SEQUOIA is continuing to enroll patients in other arms. The phase 3 ALPINE study will compare head to head zanubrutinib and ibrutinib in the setting of relapsed or refractory CLL.
The AU-013 Study: Longer Follow-Up
With longer follow-up, patients enrolled in the phase 1/2 AU-013 clinical trial continue to have high and durable response rates with zanubrutinib therapy.
“Zanubrutinib monotherapy is well-tolerated and active in CLL or SLL, irrespective of del 17p,” Dr Tam emphasized.
Dr Tam presented response rates on a cohort of 123 patients with CLL or SLL enrolled in the AU-013 study. The patients’ median age is 67 years, and 21% were older than 75 years; 22 have treatment-naïve disease, and 101 have relapsed or refractory disease. Approximately 33% have IGHV mutation and 16.2% have del 17p; 38% have bulky disease.
The ORR (investigator-reported) was 100% among 11 patients who received front-line treatment with zanubrutinib, including 5 (22.7%) complete responses and 17 (77.3%) partial responses. The investigator-reported ORR was 95% in the relapsed or refractory setting, including 15 (13.9%) complete responses, 73 (72.3%) partial responses, and 8 partial responses with lymphocytosis.
“At the time of assessment, all patients continue to respond. Responses continue to mature over time, with a gradual reduction in lymphocytosis and a gradual rise in complete response rate,” Dr Tam said.
The 12- and 24-month progression-free survival rates were 95% and 97%, respectively, in treatment-naïve patients, and 97% and 91%, respectively, in those with relapsed or refractory disease.
At a median follow-up of 2.5 years, 100% of patients had an adverse event and 61.8% had grade ≥3 adverse events. Serious adverse events were reported in 47.2% of patients, and 1 death was 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 atrial fibrillation occurred in 1.6% of patients.