Zanubrutinib Favored Over Bendamustine/Rituximab Combination Across Biomarker Subgroups in CLL/SLL Without del(17p)

Treatment with the BTK inhibitor zanubrutinib (Brukinsa) conferred a progression-free survival (PFS) benefit compared with bendamustine plus rituximab (Rituxan) across most biomarker subgroups of patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without del(17p), according to findings from the phase 3 SEQUOIA trial (NCT03336333) presented as a poster during the 2023 ASH Annual Meeting.¹

At the October 31, 2022, data cutoff, zanubrutinib was found to be superior to bendamustine plus rituximab regardless of evaluated cytogenetic abnormalities. Patients with del(11q), del(13q), trisomy 12, and CKT of at least 3 all experienced a PFS benefit with zanubrutinib vs the combination; the median PFS values were not yet reached (NR) vs 29.2 months (P < .001), NR vs 40.8 months (P < .001), NR vs 40.7 months (P < .01), and NR vs 31.1 months (P < .01), respectively. Moreover, patients without these alterations also experienced a PFS benefit with zanubrutinib over the combination, with respective median values of NR vs 50.3 months (P = .05), NR vs 44.9 months (P = .77), NR vs 40.8 months (P = .40), and NR vs 45.4 months (P = .18), respectively.

In patients with IGHV mutations, the median PFS was NR in the zanubrutinib arm compared with NR in the combination arm (P < .01). The median PFS was NR vs 34.6 months, respectively, among those without IGHV mutations (P < .0001). In patients with unmutated IGHV1-69, the median PFS was NR vs 34.6 months with zanubrutinib and the combination, respectively (HR, 0.23; 95% CI, 0.1-0.57; P = .00048).

“PFS in zanubrutinib-treated patients was favorable to that of bendamustine/rituximab-treated patients in most biomarker subgroups analyzed, including for known negative prognostic markers in CLL,” investigators wrote in the poster. “In the zanubrutinib treatment arm, comparable PFS benefit was observed for patients with or without most negative prognostic biomarkers analyzed.”

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL or SLL. The regulatory decision was supported by previously reported data from SEQUOIA and the phase 3 ALPINE trial (NCT03734016).²

SEQUOIA was an open-label, global study that enrolled patients with previously untreated CLL or SLL who were deemed unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Patients also needed to have CD20-positive disease, measurable disease by imaging, an ECOG performance status of 2 or less, a life expectancy of at least 6 months, and adequate bone marrow, renal, and hepatic function.³

Patients were divided into 3 cohorts: those without del(17p) (cohort 1) and patients with del(17p) (cohorts 2 and 3). Patients in cohort 1 were randomly assigned 1:1 to receive oral zanubrutinib 80 mg twice daily (n = 241) or intravenous bendamustine 90 mg/m² on days 1 and 2 of each cycle for 6 cycles plus intravenous rituximab 375 mg/m² on day 0 of cycle 1 and 500 mg/m² on day 1 of cycles 2 through 6 (n = 238).

The primary end point in cohort 1 was PFS by independent central review. Secondary end points in cohort 1 included overall response rate, overall survival, duration of response, investigator-assessed PFS, and patient-reported outcomes.

In the biomarker subgroup analysis, investigators examined patients with del(11q), del(13q), trisomy 12, CKT of 3 or above, mutated IGHV, unmutated IGHV, mutated ATM single nucleotide variant, mutated BRAF single nucleotide variant, mutated NOTCH1 single nucleotide variant, and mutated SF3B1 single nucleotide variant. In the zanubrutinib and combination arms, the number of patients with/without these alterations were 41 vs 46, 149 vs 142, 45 vs 49, 23 vs 22, 107 vs 103, 126 vs 127, 24 vs 35, 24 vs 14, 45 vs 43, and 39 vs 46, respectively. Additionally, the most prevalent gene utilized in patients with unmutated IGHV was IGHV1-69, which was present in both the zanubrutinib (n = 31) and combination arms (n = 39).

Additional findings from the biomarker subgroup analysis demonstrated that in patients with ATM mutations, the median PFS in the zanubrutinib arm was NR compared with 40.1 months in the combination arm (P = .02). Patients with wild-type ATM experienced a median PFS of NR vs 40.8 months, respectively (P = .58).

In patients with mutated BRAF, the median PFS was NR compared with 33 months in the zanubrutinib and combination arms, respectively (P = .01). In patients with wild-type BRAF the respective median PFS values were NR vs 43.2 months (P = .02).

Patients with NOTCH1 mutations achieved a median PFS of NR in the zanubrutinib arm compared with 34.5 months in the combination arm (P < .001). Patients without NOTCH1 mutations achieved a median PFS of NR vs 45.4 months, respectively (P = .38).

Finally, patients with mutated SF3B1 experienced a median PFS of NR in the investigational arm compared with 40.1 months in the combination arm (P < .001). Among those with wild-type SF3B1, the median PFS was NR vs 43.2 months, respectively (P = .39).

Median PFS values favored treatment with zanubrutinib over bendamustine plus rituximab across the del(11q), del(13q), trisomy 12, CKT of 3 or above, mutated IGHV, unmutated IGHV, mutated ATM single nucleotide variant, mutated BRAF single nucleotide variant, mutated NOTCH1 single nucleotide variant, and mutated SF3B1 single nucleotide variant biomarker subgroups. The respective PFS hazard ratios of zanubrutinib vs bendamustine plus rituximab were 0.26 (95% CI, 0.13-0.51; P < .001), 0.29 (95% CI, 0.18-0.46; P < .001), 0.36 (95% CI, 0.17-0.76; P < .01), 0.26 (95% CI, 0.10-0.67; P < .01), 0.37 (95% CI, 0.20-0.70; P < .01), 0.25 (95% CI, 0.16-0.39; P < .0001), 0.31 (95% CI, 0.11-0.85; P = .02), 0.27 (95% CI, 0.10-0.72; P = .01), 0.26 (95% CI, 0.12-0.56; P < .001), and 0.17 (95% CI, 0.06-0.44; P < .001).

Study authors concluded that their study “provides further evidence that zanubrutinib is a potentially best-in-class BTK inhibitor with promising efficacy for the frontline treatment of patients with CLL/SLL.”

References

1. Ramakrishnan V, Xu L, Paik JC, et al. Broad superiority of zanubrutinib (zanu) over bendamustine + rituximab (br) across multiple high-risk factors: biomarker subgroup analysis in the phase 3 SEQUOIA study in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without del(17p). Blood. 2023;142(suppl 1):1902. doi:10.1182/blood-2023-174543
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed December 14, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). ClinicalTrials.gov. Updated November 9, 2023. Accessed December 14, 2023. https://clinicaltrials.gov/study/NCT03336333