SOHO 2022: Zebrutinib has better ORR and PFS benefits than ibrutinib in patients with relapsed/refractory CLL/SLL disease

The results of the much-watched ALPINE study - zebrutinib versus ibrutinib in the treatment of previously treated patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have been released, which is also the second head-to-head comparative study of zebrutinib and ibrutinib after the ASPEN study
.

Results from a scheduled interim analysis of the Phase 3 ALPINE trial (NCT03734016), presented at the 10th Annual Meeting of the American Society of Hematology-Oncology (SOHO), showed that Brukinsa showed higher response rates and survival benefits
compared with ibruvica in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The ALPINE study is a randomized global phase III clinical trial, the second phase III clinical trial conducted by zebrutinib versus ibrutinib, which is designed to evaluate the efficacy and safety
of zebrutinib compared with ibrutinib in the treatment of previously treated R/R CLL/SLL patients.

Eligible patients included patients aged ≥18 years with relapsed/refractory CLL/SLL who had received at least one prior systemic therapy
.
Patients also need measurable lymphadenopathy by CT scan or MRI with an ECOG performance status of 0-2
.
Recurrent disease is defined as disease
that relapses and subsequently progresses within 6 months of last CLL/SLL therapy.
Refractory disease is defined as disease
that does not objectively remission or progress within 6 months of last CLL/SLL therapy.
Patients with current or previous Richter's transformation, prior treatment with a BTK inhibitor, or treatment with a vitamin K antagonist such as warfarin are not eligible
for enrollment.

A total of 652 patients with R/R CLL/SLL were randomized 1:1 to receive zebrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) until disease progression or unacceptable toxicity
.

The primary endpoint of the study was investigator-assessed objective response rate (ORR), first assessing non-inferiority and then efficacy
.
Key secondary endpoints included progression-free survival (PFS), duration to response, overall survival (OS), and incidence of
adverse events (AEs).

Key secondary endpoints included progression-free survival (PFS), defined as time from randomization to disease progression or death, and the presence of any grade of atrial fibrillation or atrial flutter
.
Other secondary endpoints included duration of response, overall survival (OS), incidence of PR with lymphocytosis or higher, and safety
.

The data cut-off date for this interim analysis was approximately 12 months
after randomization in 415 patients.
The data used in this analysis were for the first 415 patients
.

Demographics and disease characteristics were evenly
distributed across treatment groups.
Overall, the proportion of men at least 65 years old in the zebrutinib group was 62.
3% and 68.
6%, respectively, and 61.
5% and 75.
0%
in the ibrutinib group, respectively.
In addition, 7.
3% and 10.
1% of patients in the zebrutinib and ibrutinib groups, respectively, had received more than three prior lines of treatment
.
In addition, 58.
9% of patients in the zebrutinib group and 59.
6% of patients in the ibrutinib group had Ann Arbor stage I/II disease
.

Regarding the mutant status, 11.
6% of patients in the zebrutinib group and 12.
5% of patients in the ibrutinib group carried 17p deletions, and 14.
0% of patients in the zebrutinib group and 11.
5% of patients in the ibrutinib group carried TP53 mutations
.
In addition, 29.
5% and 26.
4% of patients in the zebrutinib and ibrutinib groups had 11q deletions
, respectively.
Overall, 51.
2% and 50.
5% of patients in the zebrutinib and ibrutinib groups had massive disease (defined as lesion size of at least 5 cm).

After a median follow-up of 15 months, the overall response rate (ORR) was 78.
3% (95% CI, 72.
0%~83.
7%) for patients treated with zebrutinib (n=208; bilateral P=0.
0006; prespecified α=0.
0099) for patients treated with ibrutinib, and 62.
5% (95%CI, 55.
5%~69.
1%)
for patients treated with ibrutinib 。 The rates of complete/complete response with bone marrow incomplete recovery (CR/CRi) were 1.
9%, partial response (PR) of 75.
8%, and nodular PR (nPR) of 0.
5% in the zebrutinib group, while the CR/CRi, PR, and nPR rates in the ibrutinib group were 1.
4%, 61.
1%, and 0
, respectively.
At a median follow-up of 15.
3 months (0.
1 to 23.
1) and 15.
4 months (0.
1 to 26.
0), 87.
4% and 75.
5% of patients in the zebrutinib and ibrutinib groups, respectively, were still receiving treatment
.

At a median follow-up of 14 months, investigators assessed PFS rates of 94.
9% and 84% at 12 months in the zebrutinib and ibrutinib groups, respectively (HR, 0.
40; 95% CI, 0.
23-0.
69; bilateral P = 0.
0007).

The 12-month OS rate was 97.
0% in the zebrutinib group and 92.
7% in the ibrutinib group (HR, 0.
54; 95% CI, 0.
23-1.
16; bilateral P=0.
1081).

Figure ALPINE study studies PFS data

In most patient subgroups, including age, sex, disease stage, number of lines of prior therapy, mutation status, and giant tumors, the ORR benefit of zebrutinib over ibrutinib was consistent
.
In the subgroup of patients with 17p deletion, ORRs were 83.
3% and 53.
8%
in the zebrutinib and ibrutinib groups, respectively.

In addition, the incidence of lymphocytosis PR, disease stabilization, and disease progression in the zebrutinib group was 10.
1%, 8.
2%, and 0.
5%,
respectively.
These rates were 18.
8%, 13.
5%, and 1.
0%
in the ibrutinib group, respectively.

The most common reason for discontinuation of treatment is AE.

Of the 11.
1% of patients who stopped treatment in the zebrutinib group, 1.
9% developed disease progression (PD), 1.
4% withdrew, and 7.
7% developed AE.

Among the 24.
0% of patients who discontinued treatment in the ibrutinib group, 6.
7% developed PD, 2.
9% withdrew, 13.
0% developed AE, 1.
0% were discontinued by investigator decision, and 1 patient was lost to follow-up
.
In addition, before the first ORR assessment, 2.
9% of patients in the zebrutinib group and 4.
3% of patients in the ibrutinib group discontinued treatment or started a new treatment
.

Regarding safety, 95.
6% and 99.
0% of patients in the zebrutinib and ibrutinib groups developed any grade of AE.

Grade 3 AEs
occurred in 55.
9% of patients in the zebrutinib group and 51.
2% of ≥patients in the ibrutinib group, respectively.
In addition, severe AEs occurred in 27.
5% and 32.
4% of patients in the zebrutinib and ibrutinib groups, and fatal AEs
occurred in 3.
9% and 5.
8% of patients, respectively.

Overall, 11.
3%, 39.
7%, and 7.
8% of patients with AEs resulting in dose reduction, dosing interruption, and treatment discontinuation occurred in the zebrutinib group, and 12.
1%, 40.
6%, and 13.
0%
in the ibrutinib group, respectively.

The most common AEs of any grade in the zebrutinib and ibrutinib groups were diarrhea (16.
7 versus 19.
3 percent), neutropenia (19.
6 versus 15.
5 percent), anemia (13.
2 versus 15.
0 percent), upper respiratory tract infections (21.
6 versus 14.
0 percent), arthralgias (9.
3 versus 14.
0 percent), hypertension (15.
7 versus 13.
0 percent), muscle cramps (2.
9 versus 11.
1 percent), and contusions (10.
3 percent vs.
10.
3 percent).
8.
7%), urinary tract infections (10.
8 versus 8.
2 percent), and cough (12.
7 versus 6.
3 percent).

AEs of particular concern in the zebrutinib and ibrutinib groups included heart organ disease (any grade, 13.
7 versus 25.
1 percent; ≥ grade 3, 2.
5% vs 6.
8%); bleeding (any grade, 35.
8 versus 2.
9 percent; ≥grade 3, 2.
9 versus 2.
9 percent), including major bleeding (any grade, 2.
9 versus 3.
9 percent; ≥ Level 3, 2.
9% vs 2.
9%); hypertension (any grade, 16.
7 versus 16.
4 percent; ≥ Level 3, 10.
8% vs 10.
6%); infection (any grade, 59.
8 versus 63.
3 percent; ≥ Level 3, 12.
7% vs 17.
9%); Neutropenia (any grade, 28.
4 versus 21.
7 percent; ≥ Level 3, 18.
6% vs 15.
0%); Thrombocytopenia (any grade, 9.
3 versus 12.
6 percent; ≥ Level 3, 3.
4% vs 3.
4%); Secondary primary malignancy (any grade, 8.
3 versus 6.
3 percent; ≥ grade 3, 4.
9 versus 1.
9 percent), including skin cancer (any grade, 3.
4 versus 4.
8 percent; ≥ Level 3, 1.
5% vs 1.
0%)
.

In addition, the incidence of atrial fibrillation and atrial flutter of any grade was consistently higher in the ibrutinib group, at 10.
1% and 2.
5%, respectively (bilateral P=0.
0014).

Grade 3 atrial fibrillation and atrial flutter
were observed in 1.
0% of patients in the zebrutinib group and ≥1.
9% of patients in the ibrutinib group.

"In recent years, the treatment of CLL/SLL has shifted with the emergence of effective inhibitors of B cell receptor signaling, such as the BTK inhibitor ibrutinib
.
" Lead investigator Professor Jennifer R.
Brown, director of the CLL Center at Dana-Farber Cancer Institute in the United States, and colleagues wrote
in a poster presentation of the data.

The clinical course of CLL often progresses to the disease, and patients with 17p deletion and TP53 mutation tend to have poor outcomes and poor remission with chemoimmunotherapy
.