ALPINE study Chronic Lymphocytic Leukaemia (CLL)

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Study design

ALPINE was a phase 3, randomised study of BRUKINSA®▼ compared with ibrutinib in patients with relapsed/refractory (R/R) CLL (Figure 1).1

Figure 1. ALPINE: Study design.1

Treatment continued until disease progression or unacceptable toxicity.

Patients

The ALPINE study enrolled patients with R/R CLL after at least one prior systemic therapy.1,2

Stratification

Randomisation was stratified by age (<65 years versus ≥65 years), geographic region (China versus non-China), refractory status (yes or no), and del(17p)/TP53 mutation status (present or absent).1,2

Key baseline characteristics

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

Table 1. ALPINE: key baseline characteristics (ITT population).1*

CharacteristicBRUKINSA (n=327)Ibrutinib
(n=325)
Median age, years (range)
≥75 yr
67 (35–90)
74 (22.6)
68 (35–89)
69 (21.2)
Male, n (%)213 (65.1)232 (71.4)
Disease stage, n (%)
Binet stage A/B or Ann Arbor stage I/II
Binet stage C or Ann Arbor stage III/IV

182 (55.7)
145 (44.3)

189 (58.2)
135 (41.5)
ECOG performance status, n (%) ≥1198 (60.6)203 (62.5)
Median prior lines of therapy (range)
≥3 prior lines, n (%)
1 (1–6)
24 (7.3)
1 (1–12)
30 (9.2)
Prior chemoimmunotherapy, n (%)260 (79.5)247 (76.0)
Bulky disease (≥5 cm), n (%)145 (44.3)149 (45.8)
del(17p) and/or mutated TP53, n (%)
TP53 mutated, n (%)
45 (13.8)
30 (9.2)
50 (15.4)
25 (7.7)
del(11q), n (%)91 (27.8)88 (27.1)
IGHV mutation
Mutated
Unmutated

79 (24.2)
239 (73.1)

70 (21.5)
239 (73.5)
Complex karyotype§56 (17.1)70 (21.5)
ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain variable; ITT, intention-to-treat. *The ITT population consisted of all the patients who underwent randomisation. Percentages may not sum to 100 due to rounding. ECOG performance-status scores are assessed on a 0-to-5-point scale, with higher scores indicating greater disability. Bulky disease was defined as a tumour that was 5 cm or larger in the greatest dimension. §A complex karyotype is defined as three or more abnormalities. Adapted from Brown JR, et al. N Engl J Med. 2023.1

Primary endpoint

The primary endpoint in the ALPINE study was the investigator assessed ORR, defined as complete response (CR) or partial response (PR), which was met at the interim analysis.1,3

A pre-planned interim analysis of the first 415 enrolled patients was conducted after a median follow up of 15.3 months.2,3 ORR (partial or complete response) was significantly higher with BRUKINSA (78.3%; 95% CI: 72.0, 83.7) versus ibrutinib (62.5%; 95% CI: 55.5, 69.1), demonstrating non-inferiority (one-sided p<0.0001) and superiority (two-sided p=0.0006) of BRUKINSA to ibrutinib.2,3 A consistent benefit in favour of BRUKINSA was observed across all pre-specified patient subgroups.3

Investigator-assessed ORR continued to be higher in the BRUKINSA group compared with the ibrutinib group in subsequent analyses; 79.5% (95% CI: 74.7, 83.8) versus 71.1% (95% CI: 65.8, 75.9) at 24 months (descriptive p=0.0133) and 83.5% (95% CI: 79.0, 87.3) and 74.2% (95% CI: 69.0, 78.8) in the final analysis, respectively.2,4 Similar results were observed when ORR was assessed by an independent review committee.1–3

Secondary endpoint

Investigator-assessed PFS was a key secondary endpoint in the ALPINE study.1 At a median
follow-up of 29.6 months, BRUKINSA was superior to ibrutinib for PFS (hazard ratio for disease progression or death was 0.65 (95% CI: 0.49, 0.86; p=0.002; Figure 2).1

Figure 2. ALPINE: investigator-assessed PFS for BRUKINSA versus ibrutinib.1

Tick marks represent censored data, and the shaded areas 95% confidence intervals. Adapted from Brown JR, et al.
N Engl J Med. 2023.1

Safety

The overall median treatment duration was 28.4 months in the BRUKINSA group and 24.3 months in the ibrutinib group.1

A total of 98.1% (318/324) of patients in the BRUKINSA group and 99.1% (321/324) of patients in the ibrutinib group experienced an adverse event.1 Serious adverse events occurred in 42.0% (136/324) of patients in the BRUKINSA group and 50.0% (162/324) of patients in the ibrutinib group.1

The most common adverse events of any grade that occurred in at least 20% of patients in either group included diarrhoea, hypertension, neutropenia, COVID-19, and upper respiratory tract infection.1

Atrial fibrillation and flutter (any grade; a key secondary endpoint) occurred in 5.2% (17/324) of patients in the BRUKINSA group and 13.3% (43/324) of patients in the ibrutinib group.1

Adverse events, and adverse events of special interest are summarised in Tables 2 and 3.

Table 2. ALPINE: summary of adverse events.1

Adverse EventBRUKINSA (n=324)Ibrutinib
(n=324)
≥1 adverse event318 (98.1)321 (99.1)
Grade ≥3 adverse events218 (67.3)228 (70.4)
All serious adverse events136 (42.0)162 (50.0)
Events leading to dose reduction40 (12.3)55 (17.0)
Events leading to dose interruption162 (50.0)184 (56.8)
Events leading to treatment discontinuation50 (15.4)72 (22.2)
Events leading to death33 (10.2)36 (11.1)
Grade ≥3 adverse events reported in >2% of the patients in either trial group
Neutropenia52 (16.0)45 (13.9)
Hypertension48 (14.8)36 (11.1)
COVID-19–related pneumonia23 (7.1)13 (4.0)
COVID-1922 (6.8)16 (4.9)
Pneumonia19 (5.9)26 (8.0)
Decreased neutrophil count17 (5.2)14 (4.3)
Syncope9 (2.8)4 (1.2)
Thrombocytopenia9 (2.8)12 (3.7)
Anaemia7 (2.2)8 (2.5)
Atrial fibrillation6 (1.9)12 (3.7)
Increased blood pressure4 (1.2)10 (3.1)
*The safety population consisted of all the patients who received at least one dose of a trial drug. Shown are all adverse events with an onset from the time of the first dose of trial drug up to 30 days after the last dose of trial drug or to the day before initiation of a new therapy for CLL/SLL, whichever occurred first. COVID-19 denotes coronavirus disease 2019. Adapted from Brown JR, et al. N Engl J Med. 2023.1

Table 3. ALPINE: adverse events of special interest.4

≥1 Adverse event of special InterestBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade 294 (90.7)300 (92.6)
Grade ≥3186 (57.4)184 (56.8)
AnaemiaBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade50 (15.4)53 (16.4)
Grade ≥37 (2.2)8 (2.5)
Atrial fibrillation and flutterBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade17 (5.2)43 (13.3)
Grade ≥38 (2.5)13 (4.0)
HaemorrhageBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade137 (42.3)134 (41.4)
Grade ≥311 (3.4)12 (3.7)
Major haemorrhageBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade12 (3.7)14 (4.3)
Grade ≥311 (3.4)12 (3.7)
HypertensionBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade76 (23.5)74 (22.8)
Grade ≥349 (15.1)44 (13.6)
InfectionsBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade231 (71.3)237 (73.1)
Grade ≥386 (26.5)91 (28.1)
Opportunistic infectionBRUKINSA (n=324)Ibrutinib
(n=324)
Any Grade7 (2.2)10 (3.1)
Grade ≥35 (1.5)5 (1.5)
NeutropeniaBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade95 (29.3)79 (24.4)
Grade ≥368 (21.0)59 (18.2)
Secondary primary malignanciesBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade40 (12.3)43 (13.3)
Grade ≥322 (6.8)17 (5.2)
Skin cancersBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade21 (6.5)28 (8.6)
Grade ≥37 (2.2)4 (1.2)
ThrombocytopeniaBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade42 (13.0)50 (15.4)
Grade ≥311 (3.4)17 (5.2)
Tumour lysis syndromeBRUKINSA (n=324)Ibrutinib
(n=324)
Any grade1 (0.3)0
Grade ≥31 (0.3)0
*Specific related MedDRA preferred terms were pooled for each AESI category and summarised. Febrile neutropenia was reported in 4 (1.2%) vs 3 (0.9%) patients treated with BRUKINSA and ibrutinib, respectively. Adapted from Brown JR, et al. N Engl J Med. 2023. Supplementary appendix.4

Patient-reported outcomes (PROs)

Health-related Quality of life (HRQoL) outcomes were assessed in the ALPINE study using the patient-reported outcome measures EORTC QLQ-C30 and EQ-5D-5L.5,6

Treatment with BRUKINSA resulted in clinically meaningful improvements in HRQoL, including EORTC QLQ-C30 GHS and functioning scales and symptom scales.6 These improvements were maintained over time.6 No significant differences were observed between the two treatment arms, however, it should be noted that HRQoL was generally good at baseline6

Abbreviations: CLL, chronic lymphocytic leukaemia.

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-182]

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