Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

FIG 1.

PFS and OS in zanubrutinib- and BR-treated patients (ITT). HRs and 95% CIs were based on a stratified Cox regression model with the BR arm as the reference group; stratification factors were age (<65 years v ≥65 years), Binet stage (C v A or B), and IGHV gene mutational status (mutated v unmutated). All P values were one-sided and descriptive. (A) PFS in the overall population; (B) PFS in patients with mutated and unmutated IGHV genes; (C) PFS in the overall population adjusted for COVID-19; (D) OS in the overall population; (E) OS in the overall population adjusted for COVID-19. BR, bendamustine plus rituximab; HR, hazard ratio; IGHV, immunoglobulin heavy-chain variable region; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival.

FIG 2.

Treatment-emergent and post-treatment AEIs^a over time, any grade and grade ≥3. ^aCumulative prevalence is reported, so ongoing events may be counted in >1 period. AEI, adverse event of interest; BR, bendamustine plus rituximab.

FIG A1.

CONSORT diagram. ^aBecause of thrombocytopenia and anemia after random assignment but before first dose. ^bBecause of thrombocytopenia after random assignment but before first dose. ^cOne patient discontinued after extended dose hold for an AE, one patient elected to discontinue treatment after multiple AEs, and one patient did not want to continue treatment. AE, adverse event; BR, bendamustine plus rituximab.

FIG A2.

Forest plot of the hazard ratio for PFS assessed by the investigator (ITT set). ^aThe hazard ratio and 95% CI were assessed using a stratified (for all patients) or unstratified (for subgroup) Cox regression model with the BR arm as the reference arm. ^bCytopenia: anemia (hemoglobin ≤110 g/L), thrombocytopenia (platelet count ≤100 × 10⁹/L), or neutropenia (absolute neutrophil count ≤1.5 × 10⁹/L). ^cOn the basis of monosomy 13q mutation results. BR, bendamustine plus rituximab; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IGHV, immunoglobulin heavy-chain variable region; ITT, intention-to-treat; LDH, lactate dehydrogenase; LDi, longest diameter; PFS, progression-free survival; SLL, small lymphocytic lymphoma; TP53, tumor protein 53; ULN, upper limit of normal; VAF, variant allele frequency.