As reported in The Lancet Oncology by Constantine S. Tam, MBBS, PhD, and colleagues, an interim analysis in the phase III SEQUOIA trial has shown significantly improved progression-free survival with first-line zanubrutinib vs bendamustine/rituximab in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without the high-risk del(17)(p13.1) abnormality.

Constantine S. Tam, MBBS, PhD

Study Details

Five hundred and ninety patients aged ≥ 65 years or ≥ 18 years with comorbidities from sites in 14 countries were enrolled in the open-label trial between October 2017 and July 2019. A total of 479 patients without del(17)(p13.1) were randomly assigned to receive zanubrutinib (n = 241) or bendamustine/rituximab (n = 238); 92% of patients in each group had CLL.

Treatment consisted of:

• Zanubrutinib at 160 mg twice daily
• Bendamustine at 90 mg/m² on days 1 and 2 for six cycles, plus rituximab at 375 mg/m² the day before or on day 1 of cycle 1 and at 500 mg/m² on day 1 of cycles 2 to 6.

Patients with del(17)(p13.1) received zanubrutinib (n = 111).

The primary endpoint was progression-free survival on independent review committee assessment in the intention-to-treat population in the randomly assigned zanubrutinib vs bendamustine/rituximab groups.

Progression-Free Survival

At interim analysis, with a median follow-up of 26.2 months (interquartile range = 23.7–29.6 months), progression-free survival events had occurred in 15% of patients in the zanubrutinib group vs 30% of the bendamustine/rituximab group; the improvement with zanubrutinib was significant, with a hazard ratio (HR) of 0.42 (95% confidence interval [CI] = 0.28–0.63, P < .0001). Median progression-free survival was not reached (95% CI = not estimable–not estimable) vs not reached (95% CI = 28.1 months–not estimable, with estimated 24-month rates of 85.5% vs 69.5%).

Death occurred in 7% vs 6% of patients (HR = 1.07, 95% CI = 0.51–2.22, P = .87). Median overall survival was not reached (95% CI = not estimable–not estimable) vs not reached (95% CI = 30.6 months–not estimable), with estimated 24-month rates of 94.3% vs 94.6%.

Initial findings in the group of patients with del(17)(p13.1) treated with zanubrutinib were previously reported. An updated analysis at median follow-up of 30.5 months showed that progression-free survival events on independent review committee assessment had occurred in 14% of patients. Median progression-free survival was not reached, with an estimated 24-month rate of 88.9%.

Adverse Events

In the randomly assigned population, grade 3 or 4 adverse events occurred in 48% of the zanubrutinib group vs 75% of the bendamustine/rituximab group, with the most common in both groups being neutropenia (11% vs 51%). Grade ≥ 3 infections occurred in 16% vs 19%. Serious adverse events occurred in 37% vs 50% of patients.

Zanubrutinib adverse events of interest included any grade atrial fibrillation in 3% of the zanubrutinib group, major bleeding events in 5% vs 2% of patients, and other cancers in 13% vs 9% of patients. Adverse events led to death in 11 patients (5%) in the zanubrutinib group and 12 patients (5%) in the bendamustine/rituximab group; the most common causes were COVID-19 in the zanubrutinib group (n = 5) and diarrhea (n = 2) and aspiration pneumonia (n = 2) in the bendamustine/rituximab group.

The investigators concluded, “Zanubrutinib significantly improved progression-free survival versus bendamustine/rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.”

Dr. Tam, of Peter MacCallum Cancer Centre, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by BeiGene. For full disclosures of the study authors, visit thelancet.com.