Zanubrutinib improves outcomes in chronic lymphocytic leukemia, small lymphocytic lymphoma
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SALT LAKE CITY — Zanubrutinib improved outcomes compared with bendamustine/rituximab among adults with treatment-naive deletion 17p-negative chronic lymphocytic leukemia or small lymphocytic lymphoma, according to phase 3 study results.
Researchers reported significantly longer PFS and a higher overall response rate among patients who received zanubrutinib (Brukinsa, BeiGene).
The results — presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR — also showed zanubrutinib to be generally well-tolerated.
Rationale and methods
Zanubrutinib — a selective next-generation Bruton tyrosine kinase (BTK) inhibitor — is designed to have high specificity for BTK and minimize off-target effects.
A prior phase 1/phase 2 trial showed the agent had complete and sustained BTK occupancy and appeared associated with durable clinical responses, according to study background.
“CLL and small lymphocytic lymphoma are progressive B-cell malignancies that are characterized by progressive accumulation of leukemic cells in the peripheral blood, bone marrow and lymphoid tissue. In recent years, treatment of the two diseases has been transformed with the advent of effective inhibitors of B-cell receptor signaling,” Mazyar Shadman, MD, MPH, associate professor in the clinical research division at Fred Hutchinson Cancer Center, and colleagues wrote.
The randomized phase 3 SEQUOIA trial included 479 adults with treatment-naive deletion 17p-negative CLL or small lymphocytic lymphoma.
Researchers assigned 241 patients (median age, 70 years; 63.9% men) to 160 mg twice-daily zanubrutinib until disease progression. The other 238 patients (median age, 70 years; 60.5% men) received 90 mg/m² bendamustine on days 1 and 2 of 28-day cycles, plus rituximab (Rituxan; Genentech, Biogen) dosed at 375 mg/m² in cycle 1 and 500 mg/m² in cycles 2 to 6.
Researchers grouped patients according to age (< 65 years vs. 65 years), Binet stage, immunoglobulin heavy chain gene mutational status and geographic region.
PFS assessed by independent review committee served as the primary endpoint. Secondary endpoints included PFS by investigator, ORR, OS and safety.
Key findings
Median follow-up was 26.2 months.
Results showed significant PFS improvement with zanubrutinib compared with bendamustine plus rituximab per independent committee review (HR = 0.42; 95% CI, 0.28-0.63) and investigator assessment (HR = 0.42; 95% CI, 0.27-0.66).
Researchers observed benefit with zanubrutinib across subgroups based on age, Binet stage, bulky disease status and deletion 11q status. They also observed benefit with zanubrutinib among patients with unmutated immunoglobulin heavy-chain variable region gene (HR = 0.24; P < .0001) but not among patients with mutated immunoglobulin heavy-chain variable region gene.
Independent review committee assessment showed improved estimated 2-year PFS (85.5% vs. 69.5%) and ORR (94.6% vs. 85.3%) with zanubrutinib.
Investigator assessment showed a higher ORR with zanubrutinib (97.5% vs. 88.7%); however, more patients treated with bendamustine/rituximab achieved complete response (15.1% vs. 6.6%).
Adverse events of interest that occurred more frequently with zanubrutinib included atrial fibrillation (any grade, 3.3% vs. 2.6%), bleeding (any grade, 45% vs. 11%; grade 3 or higher, 3.8% vs. 1.8%), hypertension (any grade, 14.2% vs. 10.6%) and infection (any grade, 62.1% vs. 55.9%; grade 3 or higher, 16.3% vs. 18.9%). Neutropenia occurred more frequently among in the bendamustine/rituximab group (any grade, 56.8% vs. 15.8%; grade 3 or higher, 51.1% vs. 11.7%).
A comparable percentage of patients assigned zanubrutinib and bendamustine/rituximab experienced adverse events that led to death (4.6% vs. 4.8%). Researchers reported no sudden deaths.
A higher percentage of patients treated with bendamustine/rituximab discontinued treatment due to adverse events (13.7% vs. 8.3%). Most patients (85.5%) assigned zanubrutinib remained on treatment at data cutoff.
“These data support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL or small lymphocytic lymphoma,” Shadman and colleagues wrote.
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Shadman M, et al. Abstract LBA5. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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