Zanubrutinib Improves PFS in Treatment-Naïve CLL/SLL

Constantine S. Tam, MD

Zanubrutinib (Brukinsa) elicited a statistically significant improvement in progression-free survival (PFS) vs the combination of bendamustine and rituximab (Rituxan; BR) in patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to interim findings from cohort 1 of the phase 3 SEQUOIA trial (NCT03336333) that were presented at the 2021 ASH Annual Meeting and Exposition.

At median follow-up of 26.2 months, zanubrutinib led to a significant improvement in independent review committee (IRC)–assessed PFS vs BR (HR, 0.42; 95% CI, 0.27-0.63; 2-sided P < .0001). A similar improvement in PFS was reported according to investigator assessment ([INV] HR, 0.42; 95% CI, 0.27-0.66; 1-sided P < .0001, 2-sided P = .0001).

The estimated 24-month IRC-assessed PFS rate was 85.5% (95% CI, 80.1%-89.5%) with zanubrutinib vs 69.5% (95% CI, 62.4%-75.5%) with BR.

“These data demonstrate that a chemotherapy-free treatment using a potent and selective BTK inhibitor is safe and effective for patients with treatment-naïve CLL/SLL,” lead study author Constantine S. Tam, MD, an associate professor at Peter MacCallum Cancer Centre, said in a virtual presentation of the data.

Zanubrutinib is a selective next-generation BTK inhibitor with increased specificity for BTK and reduced off-target effects that is under study in the global phase 3 SEQUOIA study.

In cohort 1 of the study, patients with treatment-naïve CLL/SLL without del(17p) were randomized to receive 160 mg of zanubrutinib twice daily until progressive disease or unacceptable toxicity, or 90 mg/m² of bendamustine on day 1 and 2 plus 375 mg/m² of rituximab in cycle 1 and 500 mg/m² in cycles 2 through 6 for 6, 28-day cycles.

In cohort 2, patients with del(17p) received zanubrutinib, and in cohort 3, patients with del(17p) and TP53 mutations received zanubrutinib plus venetoclax (Venclexta).

Patients had to have been at least 65 years of age or unfit for treatment with fludarabine, cyclophosphamide, and rituximab to be eligible for enrollment.

Central verification of del(17p) status by fluorescence in situ hybridization was required.

Between October 31, 2017, and July 22, 2019, 479 patients without del(17p) were randomized to zanubrutinib (n = 241) and BR (n = 238). A total of 240 and 227 patients received treatment and were included in the safety analysis, respectively.

The median age was 70.0 years in both arms. Most patients had unmutated IGHV in the zanubrutinib and BR arms, at 53.4% (n = 125/234) vs 52.4% (n = 121/231), respectively. Additionally, 17.8% of patients in the zanubrutinib arm vs 19.3% of patients in the BR arm had del(11q).

Patients were stratified by age (<65 vs ≥65), Binet Stage (C vs A/B), IGHV mutational status, and geographic region.

The primary end point was IRC-assessed PFS. Secondary end points included INV-assessed PFS, IRC- and INV-assessed overall response rate (ORR), overall survival (OS), and safety.

Additional results showed that the IRC-assessed ORR was 94.6% (95% CI, 91.0%-97.1%) with zanubrutinib vs 85.3% (95% CI, 80.1%-89.5%) with BR. The complete response rate was 6.6% with zanubrutinib vs 15.1% with BR.

The INV-assessed ORR was 97.5% (95% CI, 94.7%-99.1%) with zanubrutinib vs 88.7% (95% CI, 83.9%-92.4%) with BR. The estimated 24-month OS rate was 94.3% (95% CI, 90.4%-96.7%) with zanubrutinib vs 94.6% (95% CI, 90.6%-96.9%) with BR.

Notably, the PFS benefit with zanubrutinib was seen across subgroups for age, Binet stage, bulky disease, and del(11q) status. Treatment benefit was also observed for patients with unmutated IGHV (HR, 0.24), but not for mutated IGHV (HR, 0.67).

At the time of data cutoff, 206 patients in the zanubrutinib arm were still receiving treatment; 188 patients in the BR arm had completed treatment, and 15 patients had crossed over to receive zanubrutinib after centrally confirmed progression.

Regarding safety, any-grade adverse effects (AEs) of interest with zanubrutinib vs BR, respectively, included atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%).

Grade 3 or greater AEs with zanubrutinib vs BR, respectively, included bleeding (3.8% vs 1.8%), infection (16.3% vs 18.9%), and neutropenia (11.7% vs 51.1%).

Treatment discontinuation due to AEs occurred in 20 patients (8.3%) receiving zanubrutinib vs 31 patients (13.7%) receiving BR; 85.5% of patients receiving zanubrutinib remain on treatment.

AEs leading to death occurred in 11 patients (4.6%) receiving zanubrutinib vs 12 pts (5.3%) receiving BR. No sudden deaths were reported.

“Consistent with other zanubrutinib studies, zanubrutinib appeared well tolerated with no new safety signals identified; the rate of atrial fibrillation was also low,” Tam concluded.

Reference

Tam CS, 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: 2021 ASH Annual Meeting and Exposition; December 9-14, 2021; Atlanta, GA. Abstract 396.