Interim results of the global phase 3 SEQUOIA trial were shared at the 2021 American Society of Hematology (ASH) Annual Meeting to highlight the feasibility of zanubrutinib as a selective next-generation Bruton tyrosine kinase (BTK) inhibitor versus bendamustine plus rituximab for treatment-naïve patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

“In a phase 1/2 study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes, and was associated with durable clinical responses in patients with CLL and SLL,” explained Constantine Tam, MBBS, MD, and co-researchers.

In all, 479 patients without del(17p) enrolled to the trial and were randomized to receive zanubrutinib 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m² on day 1 and 2 and rituximab 375 mg/m² in cycle 1, and 500 mg/m² in cycles 2 to 6 for 6 28-day cycles.

Patients met Internal Workshop on CLL (iwCLL) eligibility criteria for treatment if they were older than 65, and unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.

“The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) for zanubrutinib vs bendamustine plus rituximab. Secondary endpoints involved PFS by investigator assessment, overall response rate (ORR), overall survival (OS), and safety,” continued Dr Tam and co-authors.

Results showed the median follow-up time was 26.2 months. PFS by IRC was significantly prolonged with zanubrutinib vs bendamustine plus rituximab (HR 0.42, 95% CI, 0.28-0.63). Treatment benefit for zanubrutinib was observed across subgroups for age, Binet stage, bulky disease, and del(11q) status. Treatment was observed for patients with unmutated IGHV (HR 0.24) but not for mutated IGHV (HR 0.67).

Further, the estimated 24-mo PFS (IRC) for zanubrutinib vs bendamustine plus rituximab was 85.5 percent (95% CI, 80.1%-89.6%) vs 69.5 percent (95% CI, 62.4%-75.5%). ORR by IRC for zanubrutinib vs bendamustine plus rituximab was 94.6 percent (95% CI 91%-97.1%) vs 85.3 percent (95% CI, 80.1%-89.5%). Complete response rate was 6.6 percent with zanubrutinib and 15.1 percent with bendamustine plus rituximab. ORR by INV for zanubrutinib vs bendamustine plus rituximab was 97.5 percent (95% CI 94.7%-99.1%) vs 88.7 percent (95% CI, 83.9%-92.4%), respectively.

Reported adverse events (AEs) for zanubrutinib vs bendamustine plus rituximab included atrial fibrillation (3.3% vs 2.6%), bleeding (any grade/grade 3 or higher: 45%/11% vs 11%/1.8%), hypertension (14.2% vs 10.6%), infection (any grade/grade ≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any grade/grade ≥3: 15.8%/11.7% vs 56.8%/51.1%).

Of note, treatment discontinuation due to AEs occurred in 20 patients (8.3%) on the zanubrutinib treatment arm vs 31 patients (13.7%) receiving bendamustine plus rituximab. Most (85.5%) of patients receiving zanubrutinib remained on treatment. There were no sudden deaths reported.

“In the global registrational trial, zanubrutinib demonstrated statistically significant improvement in PFS compared to bendamustine plus rituximab as assessed by IRC. Superiority was also observed in PFS by investigator assessment as well as ORR by both IRC and INV. Zanubrutinib was generally well tolerated, with low rates of atrial fibrillation. These data support the potential utility of zanubrutinib in the frontline management of patients with TN CLL/SLL,” concluded Dr Tam, et al.—Alexa Stoia

Tam C, Giannopoulos K, Jurczak W, et al. SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 396.