4-year follow-up data of zanubrutinib released!

Bruton's tyrosine kinase (BTK) is a key component of the B cell receptor signaling cascade
.

BTK inhibitors (BTKi) hold great promise in the treatment of B-cell malignancies (BCM)
.

Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor (BTKi), which is more targeted and has fewer adverse reactions than the first-generation BTKi
.

However, there are few clinical studies of zanubrutinib in Chinese R/R BCM patients, and it is unclear whether the recommended dose of zanubrutinib is applicable to Chinese R/R BCM patients
.

Therefore, some researchers conducted a single-arm, open-label, multicenter, phase I study to explore the safety and preliminary antitumor activity of zanubrutinib in the treatment of Chinese R/R BCM patients
.

Research Methods The study is mainly divided into two parts: the first part of the study included chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), follicular Lymphoma (FL) and marginal zone lymphoma (MZL)
.

The second part of the study included patients with FL and MZL
.

The main inclusion criteria were: (1) relapsed/refractory (R/R) disease after one or more therapies, as judged by the investigator to require treatment; (2) adequate blood and organ function
.

Exclusion criteria: patients with central nervous system lesions or disease transformation
.

The specific research design is shown in Figure 1
.

Antitumor activity assessments were performed every 12 weeks after the first dose and every 24 weeks thereafter
.

The first part of the study included 21 patients: CLL/SLL (n=9), WM (n=2) and non-Hodgkin lymphoma (NHL) (FL[n=6], MZL[n=2], MCL[n=2])
.

Of the 21 patients, 11 received zanubrutinib 160 mg twice a day (BID) and 10 received zanubrutinib 320 mg once a day (QD)
.

The second part of the study included 23 patients (FL[n=20], MZL[n=3])
.

The primary endpoint was the safety and tolerability of zanubrutinib in Chinese patients with BCM
.

Secondary endpoints were: single and multiple oral dose pharmacokinetics
.

Figure 1 Study Design Study Results Patient Baseline Characteristics A total of 44 patients were enrolled between July 5, 2016, and October 15, 2020
.

The overall median follow-up was 31.
5 months (range: 2.
3-49.
5 months)
.

In the first part of the study, the median follow-up time was 46.
1 months (range: 4.
6-48.
2 months) for the 160 mg BID dose group and 45.
8 months (range: 3.
0-49.
5 months) for the 320 mg QD dose group.

.

In the second part of the study, patients were followed for a median of 30.
0 months (range: 2.
3-36.
9 months)
.

The baseline characteristics of the patients are shown in Table 1
.

Table 1 Patient Baseline Characteristics Safety All patients received at least one dose of zanubrutinib
.

The median mean daily dose for both the 160 mg BID and 320 mg QD groups was 320 mg/day, and the median relative dose intensity was 100%
.

Overall, 29.
5% of patients took zanubrutinib for 2 years or more, and 42.
9% of patients
.

In the first part of the study, 42.
9% of patients took zanubrutinib for 3 years or more
.

The most frequently reported treatment-emergent adverse events (TEAEs) were decreased neutrophil count, anemia, and upper respiratory tract infection
.

The most commonly reported TEAEs were grade 3 or higher
.

Serious adverse reactions (AEs) were reported in 9 patients (20.
5%)
.

The most frequently reported adverse events of special interest (AESIs) were infections and neutropenia
.

All hemorrhagic events were grade 1 or 2
.

No second primary malignancy, tumor lysis syndrome, atrial fibrillation/flutter, or grade 3 or higher hypertension
.

AEs leading to treatment discontinuation occurred in 2 patients (4.
5%), AEs leading to treatment discontinuation occurred in 8 patients (18.
2%), and no AEs leading to treatment dose reduction
.

Six patients died: disease progression (n=3), unknown cause (n=2; both patients had disease progression and died 57 and 299 days after last zanubrutinib dose), and AE (n=1 ; toxic epidermal necrolysis)
.

Overall, the most common TEAEs in the zanubrutinib 160 mg BID and 320 mg QD groups were cytopenia and infection
.

Efficacy The overall response rate (ORR) was 52.
3% (95% confidence interval [CI]: 36.
7%-67.
5%), and the complete response rate (CRR) was 18.
2% (95% CI: 8.
2%-32.
7%)
.

The clinical benefit was most pronounced in CLL/SLL patients with an ORR of 100% (95% CI: 66.
4%-100%) and a CRR of 33.
3% (95% CI: 7.
5%-70.
1%)
.

The overall median time to response was 2.
8 months
.

The median progression-free survival (PFS) was 16.
4 months (95% CI: 8.
1%-21.
9%, Figure 2A)
.

The longest median PFS was 44.
3 months in patients with CLL/SLL (Figure 2B)
.

The median duration of response (DOR) was 13.
9 months (Figure 2C), and median overall survival was not reached among the overall patients
.

In the first part of the study, the ORR and partial response rates of patients in the 320mg QD group were higher than those in the 160mg BID group, and the CRR in the 160mg BID group was higher than that in the 320mg QD group
.

Figure 2.
Zanubrutinib efficacy correlation curve Pharmacokinetics 160mg and 320mg doses of zanubrutinib were rapidly absorbed and eliminated after oral administration, and peak drug concentration (Cmax) appeared 2 hours later
.

In the steady state on the first day of the second week, a representative plasma concentration-time distribution diagram is shown in Figure 3
.

At 320 mg QD, the mean steady state value (%CV) of the area under the curve (AUC0-8h) was 1148 (55.
5%) ng h/ml, approximately 2 times that of 160 mg BID (631.
3 [63.
2%] ng h/ml)
.

Figure 3 The plasma concentration-time distribution of zanubrutinib on the first day after 2 weeks of treatment.
Conclusion Zanubrutinib is well tolerated, and the clinical anti-tumor effect is significant when the 160 mg BID or 320 mg QD regimen is used
.

Pharmacokinetics, safety and efficacy data suggest that the recommended dosing regimen of zanubrutinib (160 mg BID or 320 mg QD) is suitable for Chinese patients
.

References Yuqin Song, Mingyuan Sun, Junyuan Qi, et al.
A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies.
Br J Haematol.
2022; 00: 1–11.
https://doi.
org/10.
1111/bjh.
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