J Clin Oncol: Zebrutinib versus irutinib for relapsed/refractory chronic lymphocytic leukemia

Zanubrutinib is a potent and irreversible second-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupation and minimize off-target kinase inhibition
.
Researchers such as Peter Hillmen hypothesize that complete/sustained BTK occupancy may improve efficacy outcomes, enhance BTK specificity, or reduce toxicity
associated with off-target inhibition.

The ALPINE trial is a global, randomized, open-label, Phase 3 clinical study comparing the efficacy and safety
of zebratinib with irutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
The primary endpoint was the overall response rate
.
The scheduled interim analysis is 12 months after
the first 415 patients were enrolled.

Progression-free survival (A) and overall survival (B) in the two groups and progression-free survival (C) in different subgroups

From 1 November 2018 to 14 December 2020, a total of 652 patients
were enrolled.
This article reports the results
of an interim analysis of the first 415 patients randomized to zebrutinib (n=207) or ilrutinib (n=208).
At a median follow-up of 15 months, the overall response rate was significantly higher in the zebrutinib group than in the irutinib group (78.
3 versus 62.
5 percent; p<0.
001).

Overall response rates were also higher in the zebrutinib group than in the ilrutinib group in the following subgroups: del(16p)/TP53 mutations (80.
5% vs 50.
0%) and del(11q) (83.
6% vs 69.
1%)
.
The 12-month progression-free survival rate in the total population in the zebratinib and irutinib groups was 94.
4% versus 84.
0% (HR 0.
40),
respectively.

The cumulative incidence of cardiovascular events (A) and atrial fibrillation (B) in both groups

The incidence of atrial fibrillation was significantly lower in the zebrutinib group than in the irutinib group (2.
5 versus 10.
1 percent; p=0.
001）
。 The incidence of cardiovascular events, major bleeding, and adverse events leading to treatment termination/death was lower
in the zebratinib group than in the ilrutinib group.

In summary, compared with irutinib, zebratinib significantly improves the overall remission rate in patients with relapsed/refractory chronic lymphocytic leukemia, while reducing the incidence of atrial fibrillation, improving progression-free survival, and improving overall cardiovascular safety
.

Original source:

Peter Hillmen, et al.
Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial.
Journal of Clinical Oncology.
November, 2022.
https://ascopubs.
org/doi/full/10.
1200/JCO.
22.
00510