Zanubrutinib versus ibrutinib in R/R CLL/SLL: final ALPINE results

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is characterized by repeated relapses which result in poor response to therapy and eventually affect survival. The advent of Bruton’s tyrosine kinase (BTK) inhibitors has transformed the treatment of patients with relapsed/refractory (R/R) CLL/SLL, prolonging progression-free survival (PFS) and overall survival (OS) in patients who otherwise have limited treatment options.

Ibrutinib, a first-in-class irreversible BTK inhibitor, is efficacious; however, it is associated with off-target effects due to non-specific kinase inhibition and interference with anti-CD20 monoclonal antibodies. Zanubrutinib, a second-generation BTK inhibitor which is highly selective, was designed to minimize off-target inhibition.^1,2

ALPINE (NCT03734016) is a global, phase III, randomized trial of zanubrutinib vs ibrutinib in patients with previously treated CLL/SLL. Interim results of the trial, previously reported by the Lymphoma Hub, found that zanubrutinib met the primary endpoint of non-inferior objective response rate (ORR). The final analysis of the ALPINE trial was presented by Brown at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2022² and has concurrently been published in New England Journal of Medicine.³ Below, we summarize the key findings.  

Study design

Patients with R/R CLL/SLL with ≥1 prior treatment and measurable lymphadenopathy were eligible. Patients were randomized 1:1 to receive either zanubrutinib 160 mg twice daily or ibrutinib 420 mg three times a day. Patients were stratified by age, geographic region, refractory status, and del(17p)/TP53 mutation (mut) status. The design of the final analysis is summarized in Figure 1. ORR non-inferiority and superiority were demonstrated in the ORR interim and final analyses; PFS was tested for non-inferiority under hierarchical testing when 205 events had occurred.

DCO, data cut-off; IRC, independent review committee; INV, investigator; ORR, objective response rate; PFS, prolonging progression-free survival.
*Adapted from Brown, et al.²

 The primary endpoint was ORR non-inferiority and superiority (by investigator assessment). The key secondary efficacy endpoint was PFS, with other secondary endpoints including OS, ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter.

Results

Baseline characteristics

Overall, 652 patients from 15 countries were randomized to receive zanubrutinib (n = 327) or ibrutinib (n = 325). The data cut-off was August 8, 2022. Baseline demographics and disease characteristics were well-balanced across both the zanubrutinib and ibrutinib treatment arms (Table 1).

Table 1. Baseline demographics and disease characteristics*

ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain variable; mut, mutated. *Adapted from Brown et al.2 †Complex karyotype is defined as having ≥3 abnormalities.
Characteristic, % (unless otherwise stated)	Zanubrutinib arm (n = 327)	Ibrutinib arm (n = 325)
Median (range) age, years	67 (35–90)	68 (35–89)
≥65 years	61.5	61.5
Male	65.1	71.4
ECOG Performance Status ≥1	60.6	62.5
Median prior lines of therapy (range), n	1	1
>3 prior lines	7.3	9.2
del(17p) and/or TP53mut	22.9	23.1
>del(17p)	13.8	15.4
TP53mut without del(17p)	9.2	7.7
del(11q)	27.8	27.1
IGHV mutational status
Mutated	24.2	21.5
Unmutated	73.1	73.5
Complex karyotype†	17.1	21.5
Bulky disease (≥5 cm)	44.3	45.8

Efficacy

With a median follow-up of 29.6 months, PFS was significantly superior in the zanubrutinib arm vs ibrutinib arm assessed by independent review committee (IRC; p = 0.0024; Figure 2). PFS favored zanubrutinib across all subgroups including prior lines of therapy, del(17p)/TP53^mut status, IGHV mutational status, and complex karyotype regardless of IRC or investigator assessment.

ITT, intent-to-treat; PFS, progression-free survival.
*Adapted from Brown, et al.²

 Higher ORR was observed in the zanubrutinib arm vs ibrutinib arm (86.2% vs 75.7%; p = 0.007) when assessed by IRC (Figure 3), with a rate of PR-L or better of 91.7% vs 83.1% (p = 0.001). A lower number of deaths were reported in the zanubrutinib arm vs ibrutinib arm (60 patients vs 48 patients).

CR, complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; ORR, overall response rate; PD, progressive disease; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease.
*Adapted from Brown, et al.²

Safety

• The overall safety profile favored zanubrutinib (Table 2).
• The most common adverse events (AEs) included neutropenia, COVID-19-related AEs, hypertension, upper respiratory tract infection, diarrhea, anemia, and arthralgia
• Numerically lower rates of cardiac AEs were reported in the zanubrutinib arm vs ibrutinib arm
  • atrial fibrillation/flutter: 5.2% vs 13.3%, respectively.
  • fetal cardiac events: 0 vs 6 patients, respectively.
  • serious cardiac AEs: 1.9% vs 7.7%, respectively.

Table 2. Safety and tolerability of the zanubrutinib arm vs ibrutinib arm*

AE, adverse event. *Adapted from Brown et al.2
Characteristic, % (unless otherwise stated)	Zanubrutinib arm (n = 324)	Ibrutinib arm (n = 324)
Median treatment duration, months	28.4	24.3
Any grade AE	98.1	99.1
Grade 3–5	67.3	70.4
Grade 5	10.2	11.1
Serious AEs	42.0	50.0
AEs leading to
Dose reduction	12.3	17.0
Dose interruption	50.0	56.8
Treatment discontinuation	15.4	22.2

Conclusion

The presenter concluded that in patients with R/R CLL/SLL, PFS was significantly longer among patients who received zanubrutinib compared with ibrutinib; this was consistent across all subgroups, including the high-risk patients with del(17p)/TP53^mut. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death.