Lancet Haematol: Zebratinib is expected to be a new option for patients with B-cell malignancies who were previously intolerant to BTK

Zanubrutinib is an anticancer drug
independently developed by BeiGene, China.
As a locally developed highly selective second-generation potent BTK inhibitor, zebratinib can form complete and lasting precise inhibition
of BTK targets through molecular structure optimization.
Some researchers speculate that zebratinib may be a safe and effective treatment for cancer patients
who are intolerant to irutinib and/or acalabrutinib.

This is an ongoing, multicenter, open-label, single-arm Phase 2 clinical trial to evaluate whether zebratinib can prolong treatment in previously treated patients with B-cell malignancies by minimizing treatment-related toxicity and discontinuation
.

Patients with previously treated B-cell malignancies (chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulin blood leako, or marginal zone lymphoma) who were 18 years of age or older were recruited and given oral zebratinib 160 mg 2/day or 320 mg 1/day
.
The primary endpoint was relapse and change
in severity of irutinib and/or acalabrutinib intolerance events.
Secondary endpoints were overall survival, duration of remission, disease control rate, and progression-free survival
.

From 14 October 2019 to 8 September 2021, a total of 67 patients (36 males; Fifty-seven were intolerant to irutinib [cohort 1], and 10 were intolerant to acabrutinib or acalabrutinib and irutinib [cohort 2]).

With zebrutinib, most intolerance events did not recur (irutinib: 70%; Abrutinib: 83%)
.
Of the recurrent events, 7 of the 34 irutinib intolerance events (21%) and 2 of the 3 acalabrutinib intolerance events (67%) had constant severity at recurrence; Other recurrent irutinib intolerance events (79%) and acalabrutinib intolerance events (33%) were reduced
in severity.
No more severe intolerance events
occurred.
No grade 4 intolerance events occurred
.

Sixty-four of the 67 patients (96%) experienced ≥ 1 adverse event during treatment with zebrutinib, with the most common being bruising (22%), fatigue (21%), myalgia (15%), arthralgia (13%), and diarrhoea (13%)
.
Three patients developed atrial fibrillation (all grade 2).

Eight (12%) patients experienced serious adverse reactions (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reactions, trigeminal nerve disorders, urinary tract infection).

No treatment-related deaths
.

The median follow-up was 12.
0 months
.
Among the 64 patients with evaluable efficacy, the disease control rate was as high as 93.
8%, and the overall response rate was 64.
1%.

Median duration of response was not reached; The remission rate for 12-month asymptomatic duration was 95.
0%.

In addition, median progression-free survival was not reached; The 18-month progression-free survival rate was 83.
8%.

In summary, treatment options are limited
for patients who have previously been intolerant to BTK inhibitors.
The results suggest that zebratinib is a safe and viable treatment option for patients with B-cell malignancies and is expected to meet the needs
of those who are intolerant to irutinib or acartinib.

Original source:

Mazyar Shadman, et al.
Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.
The Lancet Haematology.
November 15, 2022.
https://doi.
org/10.
1016/S2352-3026(22)00320-9