BeiGene (NASDAQ: BGNE), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, today announced results from a planned interim analysis of the Phase 3 SEQUOIA trial in patients with treatment-naïve (TN) chronic lymBeiGene (NASDAQ:BGNE), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, today announced results from a planned interim analysis of the Phase 3 SEQUOIA trial in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL), including the randomized Cohort 1 comparing BRUKINSA to bendamustine plus rituximab (B+R) and Cohort 3 (Arm D) of BRUKINSA in combination with venetoclax in patients with deletion of chromosome 17p (del[17p]) and/or pathogenic TP53 variants. These data were reported in two oral presentations at the 63rd American Society for Hematology (ASH) Annual Meeting.
“In the positive SEQUOIA trial, BRUKINSA delivered the therapeutic promise of a selective BTK inhibitor as a frontline treatment for CLL patients, with demonstrated superiority over chemoimmunotherapy. These robust data, along with the results from our previously reported Phase 3 ALPINE trial, strengthen our belief that BRUKINSA could become an important new treatment option for patients with CLL,” remarked Jane Huang, M.D., Chief Medical Officer of Hematology at BeiGene. “In addition, BRUKINSA achieved favorable safety advantages in both trials such as lower rates of atrial fibrillation.”
“Compared to chemoimmunotherapy, BRUKINSA demonstrated superior PFS benefit for CLL patients receiving frontline treatment, including those harboring high-risk characteristics, such as unmutated IGHV status and del(11q),” said Constantine Tam, MBBS, M.D., Peter MacCallum Cancer Center, and a principal investigator of the study. “Safety findings in SEQUOIA were similar to what has been reported in other BRUKINSA clinical trials, with consistently low rates of atrial fibrillation. Based on these results, BRUKINSA, as a highly selective BTK inhibitor, can potentially provide a chemo-free treatment option for CLL patients.”
For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH Annual Meeting at http://www.beigenevirtualexperience.com.
SEQUOIA Cohort 1: BRUKINSA vs. B+R in TN CLL Patients Without del (17p)
Oral Presentation; Abstract #396; Plain language summary available at https://www.beigene.com/pls/ash2021/sequoia
A total of 479 patients with TN CLL whose tumor did not exhibit del(17p) were enrolled in Cohort 1 of the SEQUOIA trial, with 241 patients randomized to receive BRUKINSA (Arm A) and 238 patients randomized to receive B+R (Arm B). Patient characteristics were balanced between the two arms, with more than 50% with unmutated IGHV gene and 18% with del(11q) in each. Patients with del(17p) typically have poor response to chemoimmunotherapy and were assigned to receive BRUKINSA treatment in Cohort 2. Results from Cohort 2 were previously presented at the 2020 ASH Annual Meeting.
The primary endpoint of the SEQUOIA trial is progression-free survival (PFS) per independent review committee (IRC) assessment in the randomized Cohort 1.
At the interim analysis, with a median follow-up of 26.15 months, BRUKINSA demonstrated superiority in PFS over B+R, as assessed by IRC. Results included:
The 24-month PFS rate was 85.5% (95% CI: 80.1, 89.6) in Arm A, compared to 69.5% (95% CI: 62.4, 75.5) in Arm B, with a hazard ratio (HR) of 0.42 (95% CI: 0.27, 0.63), p < 0.0001;
PFS benefit was consistently observed across key patient subgroups, including patients with del(11q), unmutated IGHV status, Binet stage C, and bulky disease; and
Overall survival (OS) results were early, and at 24 months, OS probability was similar between two arms, with 94.3% (95% CI: 90.4, 96.7) in Arm A and 94.6% (95% CI: 90.6, 96.9) in Arm B.
Safety analysis was based on 240 patients in Arm A and 227 patients in Arm B who received at least one dose of respective treatment. BRUKINSA was generally well tolerated with a safety profile consistent with its broad clinical program, including a low rate of atrial fibrillation. Results included:
224 patients (93.3%) in Arm A experienced at least one adverse event (AE) of any grade, with the most common (≥12%) being contusion (19.2%), upper respiratory tract infection (17.1%), neutropenia (15.4%), diarrhea (13.8%), and arthralgia (13.3%);
In comparison, 218 patients (96.0%) in Arm B experienced at least one AE of any grade, with the most common (≥12%) being neutropenia (56.8%), nausea (32.6%), pyrexia (26.4%), rash (19.4%), anemia (18.9%), constipation (18.9%), infusion-related reaction (18.9%), fatigue (15.9%), vomiting (14.5%), thrombocytopenia (13.7%), and diarrhea (13.2%);
126 patients (52.5%) in Arm A experienced at least one Grade ≥3 AE, compared to 181 patients (79.7%) in Arm B, with the most common in both arms being neutropenia (11.3% in Arm A vs. 51.1% in Arm B) and thrombocytopenia (1.7% in Arm A vs. 7.0% in Arm B);
88 patients (36.7%) in Arm A experienced at least one serious AE, compared to 113 patients (49.8%) in Arm B;
AEs leading to dose reduction, interruption or delay, and discontinuation occurred in 18 patients (7.5%), 111 patients (46.3%), and 20 patients (8.3%), respectively, in Arm A, compared to 84 patients (37.4%), 154 patients (67.8%), and 31 patients (13.7%), respectively, in Arm B;
Fatal AEs were reported in 11 patients (4.6%) in Arm A, compared to 11 patients (4.8%) in Arm B;
AEs of interest of any grade included anemia (Arm A vs. Arm B: 4.6% vs. 19.4%), arthralgia (13.3% vs. 8.8%), atrial fibrillation (3.3% vs. 2.6%), bleeding (45.0% vs. 11.0%), diarrhea (13.8% vs. 13.7%), hypertension (14.2% vs. 10.6%), infections (62.1% vs. 55.9%), myalgia (3.8% vs. 1.3%), neutropenia (15.8% vs. 56.8%), other cancers (12.9% vs. 8.8%), and thrombocytopenia (4.6% vs. 17.6%).
In addition, efficacy results with an extended follow-up from Cohort 2 (Arm C) of BRUKINSA as a monotherapy in patients with del(17p) were reported at ASH. With a median follow-up of 30.5 months, the 24-month PFS rate was 88.9% (95% CI: 81.3, 93.6).
Summary of SEQUOIA Cohort 1 Interim Analysis
SEQUOIA Cohort 1
Summary
BRUKINSA
(n=241)
Bendamustine + Rituximab
(n=238)
Efficacy Results
IRC-Assessed
24-month PFS (Primary Endpoint)
85.5%
(95% CI: 80.1, 89.6)
69.5%
(95% CI: 62.4, 75.5)
Hazard Ratio=0.42 (95%CI: 0.27, 0.63)
2-sided p <0.0001
Overall Safety Results
AEs of any grade
93.3%
96.0%
Grade ≥3 AEs
52.5%
79.7%
Serious AEs
36.7%
49.8%
AEs leading to dose reduction
7.5%
37.4%
AEs leading to dose interruption or delay
46.3%
67.8%
AEs leading to treatment discontinuation
8.3%
13.7%
Fatal AEs
4.6%
4.8%
Adverse Events of Interest (Any Grade)
Anemia
4.6%
19.4%
Neutropenia
15.8%
56.8%
Thrombocytopenia
4.6%
17.6%
Arthralgia
13.3%
8.8%
Atrial fibrillation
3.3%
2.6%
Bleeding
45.0%
11.0%
Diarrhea
13.8%
13.7%
Hypertension
14.2%
10.6%
Infections
62.1%
55.9%
Myalgia
3.8%
1.3%
Other cancers
12.9%
8.8%
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:
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:
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%);
16 patients (32.7%) experienced at least one Grade ≥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:
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 ≥3 AE and three patients (8.8%) experienced at least one serious AE; and
AEs leading to dose interruption occurred in 10 patients (29.4%), with no AEs leading to dose reduction or treatment discontinuation.
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