BeiGene presents results from SEQUOIA trial of Brukinsa + Venclexta in first-line chronic lymphocytic leukemia.

These data were reported in two oral presentations at the 63rd American Society for Hematology (ASH) Annual Meeting.

SEQUOIA Cohort 3 (Arm D): Brukinsa + Venetoclax in TN CLL Patients with del(17p) and/or TP53 Mutations:

Oral Presentation; Abstract #67: Cohort 3 of SEQUOIA was designed to examine the hypothesis that the addition of venetoclax to Brukinsa can drive tumors into deeper remission. Building on the demonstrated efficacy and safety of Brukinsa in Cohort 2, Cohort 3 is planned to enroll approximately 80 patients with TN CLL whose tumor exhibits del(17p) or TP53 mutations, with key endpoints being safety, overall response rate (ORR), PFS, and duration of response (DoR). These patients will receive Brukinsa treatment at 160 mg twice daily for three months, followed by combination treatment of Brukinsa at the same dosing and venetoclax with a ramp-up dosing to 400 mg once daily for 12 to 24 cycles until progressive disease, unacceptable toxicity, or confirmed undetectable measurable residual disease (uMRD).

“Unfavorable prognosis is often seen in CLL patients with del(17p) or pathogenic TP53 variants, even in the front-line setting. While the follow-up in Cohort 3 was relatively short, the high response rate and the deepened responses observed among those treated for longer periods suggested the potential of Brukinsa in combination with venetoclax in these high-risk CLL patients. The combination treatment also appeared generally well tolerated,” commented Alessandra Tedeschi, M.D., Grande Ospedale Metropolitano Niguarda in Italy, a principal investigator on the study. “We look forward to the continued evaluation of Brukinsa in combination with venetoclax in untreated CLL patients with del(17p) or TP53 mutations.”

At the data cutoff on September 7, 2021, 49 patients were enrolled in Cohort 3, including 46 patients (93.9%) with centrally confirmed positive del(17p) status and three patients (6.1%) with a pathogenic TP53 variant alone. Patients enrolled in Cohort 3 also exhibited other markers of high risk, including 87.8% with unmutated IGHV, 91.9% with concurrent TP53 mutation, and 83.3% with complex karyotype (at least three abnormalities).

With a short median follow-up of 12.0 months, a high ORR was observed in the 36 patients who had at least one post-baseline response evaluation by the data cutoff date. Preliminary efficacy results per investigator assessment included: i. Of the 14 patients who received combination treatment for more than 12 months, five patients (36%) achieved a confirmed complete response (CR) or CR with incomplete bone marrow recovery (CRi) in a bone marrow assessment and four additional patients met the criteria for CR or CRi but not confirmed in bone marrow assessment due to COVID-19 restrictions; and In all 36 patients evaluable for efficacy, the ORR was 97.2% (95% CI: 85.5, 99.9) and the CR/CRi rate was 13.9% (all CRs or CRis were in patients who received combination treatment for more than 12 months).

With a median follow-up of 7.9 months, safety results in all 49 enrolled patients included: i. 40 patients (81.6%) experienced at least one AE of any grade, with the most common (?12%) being infections (16.3%), neutropenia (14.3%), bruising (12.2%), diarrhea (12.2%), minor bleeding (12.2%), and nausea (12.2%); ii. 16 patients (32.7%) experienced at least one Grade greater than 3 AE and four patients (8.2%) experienced at least one serious AE; AEs leading to dose interruption, dose reduction, and treatment discontinuation occurred in 10 patients (20.4%), no patients (0.0%), and one patient (2.0%), respectively; and One patient (2.0%) experienced a fatal AE.

With a median follow-up of 13.5 months, safety results in the 34 patients who received combination treatment included; i. 29 patients (85.3%) experienced at least one AE of any grade, with the most common (?12%) being infections (23.5%), neutropenia (20.6%), diarrhea (14.7%), fatigue (14.7%), nausea (14.7%), and bruising (11.8%);13 patients (38.2%) experienced at least one Grade greater than 3 AE and three patients (8.8%) experienced at least one serious AE; and ii. AEs leading to dose interruption occurred in 10 patients (29.4%), with no AEs leading to dose reduction or treatment discontinuation.

About SEQUOIA: SEQUOIA is a randomized, multicenter, global Phase III trial (NCT03336333) designed to evaluate the efficacy and safety of Brukinsa compared to B+R in patients with TN CLL or SLL. The trial consists of three cohorts:Cohort 1 (n=479): randomized 1:1 to receive Brukinsa(n=241) or B+R (n=238) until disease progression or unacceptable toxicity, in patients not harboring del(17p); data from this group comprise the primary endpoint; Cohort 2 (n=110): patients with del(17p) receiving Brukinsa as a monotherapy; and Cohort 3 (enrollment ongoing): patients with del(17p) or pathogenic TP53 variant receiving Brukinsa in combination with venetoclax. Patients with del(17p) were not randomized to B+R, as they experience poor clinical outcomes and poor response to chemoimmunotherapy. The primary endpoint of the trial is IRC-assessed PFS. Secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed overall response rate (ORR), overall survival (OS), PFS and ORR in patients with del(17p), and safety. Cohort 2 (Arm C), representing high-risk patients treated with Brukinsa monotherapy, was previously presented at the American Society for Hematology (ASH) Annual Meeting in December 2020. This cohort of patients with del(17p) achieved significant efficacy with an 18-month PFS of 90.6%, as assessed by investigator.