SEQUOIA study Chronic Lymphocytic Leukaemia (CLL)

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Study design

SEQUOIA is an international, phase 3, open-label, randomised study of BRUKINSA®▼ compared with bendamustine plus rituximab (BR) in patients with previously untreated CLL.1–3 The study comprises 3 cohorts, as shown in Figure 1.1–3

Cohorts 1 and 2 are complete, however Cohort 3 is ongoing.1–3

Figure 1. SEQUOIA study design.1–3

CLL, chronic lymphocytic leukaemia; SLL, small lymphocytic lymphoma. Treatment continued until disease progression or unacceptable toxicity.

Patients

Patients had previously untreated CLL/SLL, ≥65 years of age or <65 years of age and unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR).1,4

Stratification

In Cohort 1, randomisation was stratified by age (<65 years versus ≥65 years), Binet stage (C versus A or B), immunoglobulin variable region heavy chain (IGHV) mutational status (mutated versus unmutated), and geographic region (North America versus Europe versus Asia-Pacific).1,4

Key baseline characteristics

The key baseline characteristics for Cohort 1 are summarised below in Table 1.

Table 1. SEQUOIA: Key baseline characteristics for Cohort 1 (patients without del[17p]).1

BRUKINSA (n=241)Bendamustine +
rituximab
(n=238)
Median (IQR) age, years70 (66–75)70 (66–74)
<6545 (19%)46 (19%)
≥65*196 (81%)192 (81%)
Race or ethnicity, n (%)
White221 (92%)206 (87%)
Black4 (2%)4 (2%)
Asian or Pacific Islander5 (2%)9 (4%)
Not reported or unknown11 (5%)22 (9%)
Binet stage, n (%)
A/B171 (71%)168 (71%)
C70 (29%)70 (29%)
Bulky disease ≥5 cm , n (%)69 (29%)73 (31%)
Cytopenia at baseline, n (%)102 (42%)109 (46%)
del(17p)2 (1%)§0
del(11q)43 (18%)46 (19%)
del(13q)136 (56%)129 (54%)
Trisomy 1245 (19%)49 (21%)
Unmutated IGHV gene125/234 (53%)121/231 (52%)
No FISH abnormalities||56 (23%)59 (25%)
TP53 mutation15/232 (6%)13/223 (6%)
FISH, fluorescence in situ hybridisation; IQR, interquartile range. *Patients ≥75 years: 63 patients in the BRUKINSA group (26%) and 53 patients in bendamustine + rituximab group (22%). Patients with SLL had Binet stage calculated as if they had CLL. Defined as having anaemia (haemoglobin ≤110 g/L), thrombocytopenia (platelets ≤100 × 10⁹/L), or neutropenia (absolute neutrophil count ≤1.5 × 10⁹/L). §Two patients with del(17p) were misassigned to the randomly assigned cohort of patients without del(17p). These patients are included in the intention-to-treat analysis. ||Defined as the absence of del(17p), del(11q), del(13q), and trisomy 12. Adapted from Tam CS, et al. Lancet Oncol. 2022.1

Primary endpoint

In the SEQUOIA study, independent review committee (IRC)-assessed PFS in Cohort 1 (patients without del[17p]) was the primary endpoint and was met at the interim analysis.1,4 PFS was significantly longer with BRUKINSA compared with BR (Figure 2).1,4

At 24 months, the estimated PFS rate in Cohort 1 was 85.5% (95% CI: 80.1, 89.6) for BRUKINSA versus 69.5% (95% CI: 62.4, 75.5) for BR .1,4 After a median follow up of 26.2 months, the IRC determined that PFS was significantly improved with BRUKINSA versus BR (HR 0.42 [95% CI: 0.28 to 0.63]; two-sided p<0.0001; Figure 2).1,4

Figure 2. SEQUOIA: Kaplan-Meier estimates of IRC-assessed PFS for Cohort 1 (patients without del[17p]).1,4

CI, confidence interval; HR, hazard ratio; IRC, independent review committee; PFS, progression-free survival. Adapted from Tam CS, et al. Lancet Oncol. 2022.1

In Cohort 1, PFS was consistently longer with BRUKINSA compared with BR across almost all prespecified subgroup analyses, including patients with baseline high-risk disease status (Figure 3).1

Figure 3. SEQUOIA: IRC-assessed PFS across subgroups for BRUKINSA versus BR in Cohort 1 (patients without del[17p]).1

BR, bendamustine + rituximab; CI, confidence interval; IGHV, immunoglobulin heavy chain variable; IRC, independent review committee; PFS, progression-free survival. Adapted from Tam CS, et al. Lancet Oncol. 2022.1

Key secondary endpoints

Investigator-assessed (IA) PFS for Cohorts 1 and 2 was a key secondary endpoint in SEQUOIA and was found to be consistent with IRC-assessed PFS.1 An updated analysis was conducted after a median follow up of 43.7 months for Cohort 1.5 Median IA-PFS was not reached in the BRUKINSA group compared with 42.2 months in the BR group group.5 Estimated 42-month PFS rates were 82.4% for BRUKINSA and 50.0% for BR.5 IA-PFS was significantly improved with BRUKINSA versus BR with mutated IGHV (2-sided, p=0.00033) and unmutated IGHV (2-sided p=0.0001).5 The median follow up for Cohort 2 was 47.9 months.5 Median IA-PFS for Cohort 2 was not reached and the estimated 42 month rate was 79.4%.5

ORR for Cohorts 1 and 2 was a key secondary endpoint in the SEQUOIA study.1,4

In Cohort 1 (patients without del[17p]), IRC-assessed ORR, was 94.6% (228/241; 95% CI: 91.0, 97.1) in the BRUKINSA group, and 85.3% (203/238; 95% CI: 80.1, 89.6) in the BR group.1,4 In the BRUKINSA group, 16 (7%) of 241 patients had a complete response, as assessed by IRC, versus 36 (15%) of 238 patients in the BR group.1

For Cohort 2 (patients with del[17p]) IRC-assessed ORR was 90.0% (99/110; 95% CI: 82.8, 94.9).1

Safety

A total of 93% (224/240) of patients in the BRUKINSA group and 94% (214/227) of patients in the BR group experienced an adverse event.6

  • Serious adverse events occurred in 37% (88/240) of patients in the BRUKINSA group and 50% (113/227) of patients in the BR group1
  • The most common adverse events occurring in the BRUKINSA group were contusion (19%) and upper respiratory tract infection (17%)6

Adverse events, common adverse events, and adverse events of special interest are shown in
tables 4–6.

Table 4. SEQUOIA Cohort 1 adverse events (n, %).1,6

Any adverse eventBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-298 (41)37 (16)
Grade 387 (36)88 (39)
Grade 428 (12)81 (36)
Grade 511 (5)12 (5)‡
SeriousBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-216 (7)12 (5)
Grade 349 (20)70 (31)
Grade 412 (5)19 (8)
Grade 511 (5)12 (5)
All bleeding adverse events§BRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-299 (41)21 (9)
Grade 38 (3)3 (1)
Grade 401 (<1)
Grade 51 (<1)0
All cardiac adverse events§BRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-224 (10)13 (6)
Grade 310 (4)9 (4)
Grade 401 (<1)
Grade 52 (1)1 (<1)
Dose reduction due to AEsBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
All Grades20 (3)85 (37)
Discontinuation due to AEsBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
All Grades20 (8)31 (14)

*One patient in the BRUKINSA group did not receive BRUKINSA and is not included in the safety analysis.11 patients did not receive bendamustine + rituximab and are not included in the safety analysis. Includes one patient who had a Grade 5 event (confusion) that began prior to, but ended, after the data cutoff. §Grouped analyses. Adapted from Tam CS, et al. Lancet Oncol. 2022, and Supplemntary appendix.1,6

Table 5. SEQUOIA Cohort 1 common adverse events.1

ContusionBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-246 (19)8 (4)
Grade 300
Grade 400
Grade 500
Upper respiratory tract infectionBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-239 (16)25 (11)
Grade 32 (1)2 (1)
Grade 400
Grade 500
DiarrhoeaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-232 (13)26 (12)
Grade 32 (1)2 (1)
Grade 400
Grade 502 (1)
ArthralgiaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-230 (13)19 (8)
Grade 32 (1)1 (<1)
Grade 400
Grade 500
NeutropeniaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-210 (4)13 (6)
Grade 311 (5)50 (22)
Grade 416 (7)66 (29)
Grade 500
HypertensionBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-214 (6)9 (4)
Grade 315 (6)11 (5)
Grade 400
Grade 500
FatigueBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-225 (10)34 (15)
Grade 33 (1)2 (1)
Grade 400
Grade 500
CoughBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-227 (11)23 (10)
Grade 300
Grade 400
Grade 500
HeadacheBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-226 (11)17 (7)
Grade 300
Grade 400
Grade 500
RashBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-226 (11)38 (17)
Grade 306 (3)
Grade 400
Grade 500
ConstipationBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-223 (10)43 (19)
Grade 31 (<1)0
Grade 400
Grade 500
NauseaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-224 (10)71 (31)
Grade 303 (1)
Grade 400
Grade 500
Back painBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-221 (9)15 (7)
Grade 301 (<1)
Grade 400
Grade 500
PyrexiaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-217 (7)52 (23)
Grade 308 (4)
Grade 400
Grade 500
VomitingBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-217 (7)30 (13)
Grade 303 (1)
Grade 400
Grade 500
PneumoniaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-28 (3)9 (4)
Grade 34 (2)9 (4)
Grade 400
Grade 501 (<1)
AnaemiaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-210 (4)38 (17)
Grade 31 (<1)4 (2)
Grade 400
Grade 500
Basal cell carcinomaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-210 (4)3 (1)
Grade 31 (<1)0
Grade 400
Grade 500
ThrombocytopeniaBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-25 (2)14 (6)
Grade 33 (1)10 (4)
Grade 41 (<1)6 (3)
Grade 500
Infusion-related reactionBRUKINSA (n=240*)Bendamustine + rituximab (n=227)
Grade 1-21 (<1)37 (16)
Grade 305 (2)
Grade 401 (<1)
Grade 500
Grade 1–2 adverse events occurring in ≥10% of patients, or ≥Grade 3 in ≥5% of patients in any group. Patients who had more than one adverse event of the same type were counted once under the highest grade. Adverse events listed occurred during treatment or follow-up, excluding events that occurred after progression. The safety population included all patients who began the assigned treatment. *One patient in the BRUKINSA group did not receive BRUKINSA and is not included in the safety analysis. 11 patients did not receive bendamustine + rituximab and are not included in the safety analysis. Due to amphotericin B infusion. Adapted from Tam CS, et al. Lancet Oncol. 2022.1

Table 6. SEQUOIA Cohort 1 adverse events of interest.6

Patients without del(17p)
Any adverse event of InterestBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade207 (86.3)206 (90.7)
Grade ≥396 (40.0)156 (68.7)
AnaemiaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade11 (4.6)44 (19.4)
Grade ≥31 (0.4)4 (1.8)
ArthralgiaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade32 (13.3)20 (8.8)
Grade ≥32 (0.8)1 (0.4)
Atrial fibrillationBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade8 (3.3)6 (2.6)
Grade ≥31 (0.4)3 (1.3)
BleedingBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade108 (45.0)25 (11.0)
Grade ≥39 (3.8)4 (1.8)
BruisingBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade58 (24.2)9 (4.0)
Grade ≥300
Major BleedingBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade12 (5.0)4 (1.8)
Grade ≥39 (3.8)4 (1.8)
Minor BleedingBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade68 (28.3)15 (6.6)
Grade ≥300
PetechiaeBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade18 (7.5)0
Grade ≥31 (0.4)0
DiarrhoeaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade33 (13.8)31 (13.7)
Grade ≥32 (0.8)5 (2.2)
HypertensionBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade34 (14.2)24 (10.6)
Grade ≥315 (6.3)11 (4.8)
InfectionsBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade149 (62.1)127 (55.9)
Grade ≥339 (16.3)43 (18.9)
MyalgiaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade9 (3.8)3 (1.3)
Grade ≥300
NeutropeniaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade38 (15.8)129 (56.8)
Grade ≥328 (11.7)116 (51.1)
Other cancersBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade31 (12.9)20 (8.8)
Grade ≥317 (7.1)7 (3.1)
Dermatologic other cancersBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade16 (6.7)10 (4.4)
Grade ≥32 (0.8)2 (0.9)
ThrombocytopeniaBRUKINSA (n=240)Bendamustine + rituximab (n=227)
Any grade11 (4.6)40 (17.6)
Grade ≥35 (2.1)18 (7.9)
Adverse events listed occurred during treatment or follow-up, excluding events that occurred after progression. Patients with multiple events for any term in a grouped analysis were counted once. Safety population included all patients who began the assigned treatment. A subject may be counted in more than one row. Adapted from Tam CS, et al. Lancet Oncol. 2022. Supplementary appendix.6

Abbreviations: CLL, chronic lymphocytic leukaemia; HR, hazard ratio; IA-PFS, investigator-assessed progression-free survival.

Adverse events should be reported

United Kingdom (incl. Northern Ireland): Healthcare Professionals are asked to report any suspected adverse reactions via Yellow Card Scheme found at www.mhra.gov.uk/yellowcard.
Ireland: Healthcare Professionals are asked to report any suspected adverse reactions via HPRA.

All adverse events (UK and Ireland) should also be reported to BeiGene at [email protected]; (UK: 08009176799; Ireland: 1800812061).

For medical information, please contact: UK: 08004320266, Ireland: 1800946589 or email: [email protected]

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

September 2023 [0823-BRU-PRC-181]

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