Zanubrutinib Maintains PFS Benefit With Extended Follow-Up in Previously Untreated CLL/SLL

Extended follow-up from the phase 3 SEQUOIA trial (NCT03336333) demonstrated that zanubrutinib (Brukinsa) maintained a progression-free survival (PFS) benefit compared with bendamustine plus rituximab (Rituxan; BR) in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

Findings presented at the 17th Annual International Conference on Malignant Lymphoma showed that at a median follow-up of 43.7 months (range, 0-60.0) for the randomized cohort 1, patients without 17p deletions treated with zanubrutinib (n = 241) experienced a median PFS that was not evaluable (NE; 95% CI, NE-NE) compared with 42.2 months (95% CI, 38.4-49.8) for those administered BR (n = 238; HR, 0.30; 95% CI, 0.21-0.43; P < .0001).

The 42-month PFS rates were 82.4% for the zanubrutinib arm vs 50.0% for the BR arm.

Additionally, at a median follow-up of 47.9 months (range, 5.0-56.9) for the nonrandomized cohort 2, patients with 17p deletions treated with zanubrutinib (n = 110) achieved a 42-month PFS rate of 79.4% (95% CI, 70.4%-85.9%).

“Zanubrutinib remains an option for us [in the] first-line and relapsed treatment of [patients with] CLL and SLL,” lead study author Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center in Seattle, Washington, said in a presentation of the data.

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or SLL, based on previously reported data from SEQUOIA and the phase 3 ALPINE trial (NCT03734016).²

Prior findings from SEQUOIA at a median follow-up of 26.2 months demonstrated that zanubrutinib elicited a superior PFS vs BR in patients without 17p deletions (HR, 0.42; 95% CI, 0.28-0.63; P < .0001). Additionally, similar results were observed in patients with 17p deletions who were treated with zanubrutinib.³

SEQUOIA enrolled patients with previously untreated CLL or SLL who met the International Workshop on CLL criteria for treatment. Patients needed to be at least 65 years of age, or at least 18 years of age if they were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Anticoagulation and CYP3A inhibitors were allowed.

Patients without 17p deletions were enrolled to cohort 1, where they were randomly assigned 1:1 to receive 160 mg of oral zanubrutinib per day until progressive disease, unacceptable toxicity, or the end of study; or 6 cycles of BR consisting of 90 mg/m² of bendamustine on days 1 and 2 of each cycle, plus 375 mg/m² of rituximab on day 1 of cycle 1, then 500 mg/m² on day 1 of cycles 2 to 6.

Those in cohort 1 were stratified by age, Binet status, IGHV mutational status, and geographic region.

Those harboring 17p deletions were assigned to cohort 2, and all patients received 160 mg of zanubrutinib per day until they experienced progressive disease, intolerable toxicity, or reached the end of the study.

Investigator-assessed PFS in cohort 1 served as the trial’s primary end point. Secondary end points included overall survival (OS) in both cohorts, time to second progression, clinical outcomes correlated with baseline prognostic and predictive markers, and safety.

As of the October 31, 2022, data cutoff, 180 patients (74.7%) without 17p deletions were still receiving treatment with zanubrutinib, and 78 patients (70.3%) with 17p deletions were still receiving the BTK inhibitor. In the BR arm, 188 patients (79.0%) competed 6 cycles of treatment, and 86 patients (36.1%) experienced disease progression, irrespective of whether they received all 6 cycles. Forty-one patients (17.2%) crossed over to receive zanubrutinib following disease progression.

Within cohort 1, the median age was 70 years (range, 40-86) in the zanubrutinib arm and 70 years (range, 35-87) in the BR arm. The majority of patients in both arms were at least 65 years of age (82% for zanubrutinib and 82% for BR), were male (64% and 61%), were from Europe (72% and 72%), and had unmutated IGHV (53% and 52%).

Twenty-nine percent of patients in both arms had Binet stage C disease. Twenty-nine percent of patients in the zanubrutinib arm had bulky disease measuring at least 5 cm at baseline, 42% had cytopenia at baseline, and 18% had 11q deletions. Those rates were 31%, 46%, and 19%, respectively, in the BR arm. Six percent of patients in both arms harbored TP53 mutations, and 14% of patients in both arms had a complex karyotype with at least 3 abnormalities.

In cohort 2, the median age was 71 years (range, 42-87), 86% of patients were at least 65 years of age, 71% were male, and 47% were from Europe. Additionally, 35% had Binet stage C disease, 40% had bulky disease, 55% had cytopenia at baseline, 65% had unmutated IGHV, 33% had 11q deletions, 43% had TP53 mutations, and 38% had a complex karyotype.

Additional data showed that patients in cohort 1 without IGHV mutations treated with zanubrutinib (n = 125) experienced a median PFS of NE (95% CI, NE-NE) compared with 33.7 months (95% CI, 29.5-39.1) for those given BR (n = 121; HR, 0.23; 95% CI, 0.14-0.37; P < .0001).

For those with IGHV mutations in cohort 1, zanubrutinib (n = 109) elicited a median PFS of NE (95% CI, NE-NE) vs 49.4 months (95% CI, 44.4-NE) for BR (n = 110; HR, 0.35; 95% CI, 0.19-0.64; P < .00033).

Among all patients in cohort 1, the median OS was NE in the zanubrutinib arm and NE in the BR arm (HR, 0.87; 95% CI, 0.50-1.48; P = .5995). The 42-month OS rate was 89.4% for zanubrutinib and 88.3% for BR. “[The OS data were] not surprising given the availability of other [treatment] options and the crossover [permitted] in this study,” Shadman said.

In cohort 2, the 42-month OS rate was 89.5% (95% CI, 81.9%-94.1%).

Regarding safety, Shadman said no new signals were reported. Any-grade adverse effects (AEs) of interest included infections (72.9% for zanubrutinib in cohort 1; 62.6% for BR in cohort 1; 80.2% for zanubrutinib in cohort 2), bleeding (48.8%; 12.3%; 57.7%), other malignancies (18.8%; 12.3%; 24.3%), hypertension (17.5%; 13.7%; 13.5%), diarrhea (17.1%; 14.1%; 19.8%), neutropenia (16.7%; 56.8%; 18.9%), arthralgia (15.4%; 10.1%; 23.4%), anemia (7.1%; 20.7%; 6.3%), thrombocytopenia (6.3%; 18.1%; 8.1%), atrial fibrillation or flutter (5.0%; 2.6%; 6.3%), myalgia (3.8%; 1.8%; 7.2%), and opportunistic infection (2.5%; 1.8%; 0.9%).

The exposure-adjusted incidence rate (EAIR) for hypertension was similar between zanubrutinib in cohort 1 (0.49), BR in cohort 1 (0.45), and zanubrutinib in cohort 2 (0.35), and Shadman noted these EAIRs for hypertension were lower than previously reported. Data were also presented on EAIRs for atrial fibrillation or flutter (0.13 for zanubrutinib in cohort 1; 0.08 for BR; 0.15 for zanubrutinib in cohort 2), hemorrhage (2.02; 0.40; 2.73), and major hemorrhage (0.20; 0.05; 0.20).

Disclosures: Dr Shadman reported receiving consulting fees from AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, BeiGene, Bristol Myers Squibb, Morphosys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate Therapeutics, MEI Pharma, and Atara Biotherapeutics; and receiving research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, Genmab, Morphosys/Incyte, and Vincerx.

References

1. Shadman M, Munir T, Robak T, et al. Zanubrutinib vs bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 154.
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed June 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5