In cohort 1 of the phase III ASPEN trial, zanubrutinib demonstrated a higher very good partial response rate and a more tolerable safety profile compared with ibrutinib in patients with Waldenström macroglobulinemia. However, the study missed its primary end point of statistically significant superiority in complete response and VGPR rates, according to a press release from BeiGene, Ltd, developer of the BTK inhibitor.
Constantine S. Tam, MD
In cohort 1 of the phase III ASPEN trial, zanubrutinib (Brukinsa) demonstrated a higher very good partial response (VGPR) rate and a more tolerable safety profile compared with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia. However, the study missed its primary end point of statistically significant superiority in complete response (CR) and VGPR rates, according to a press release from BeiGene, Ltd, developer of the BTK inhibitor.
As of the data cutoff date August 31, 2019, patients in cohort 1, which included those who were treatment naïve (n = 19) and with relapsed or refractory disease (n = 83), had a median follow-up of 19.4 months. In the relapsed/refractory population, the VGPR rate was 28.9% in the zanubrutinib arm and 19.8% in the ibrutinib arm, per an independent review committee (IRC) assessment (2-sidedP= .1160). Overall, the VGPR rate was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (2-sided descriptive P= .0921). No patients achieved a CR by the data cutoff.
The major response rate, defined as the rate of partial response or better, in the relapsed/refractory group as assessed by IRC was 78.3% with zanubrutinib versus 80.2% with ibrutinib. In all patients in cohort 1, the major response rate was 77.5% with zanubrutinib and 77.8% with ibrutinib.
In patients who received zanubrutinib, the 12-month progression-free survival (PFS) rate was 92.4% in the relapsed/refractory group and 89.7% for all patients. In the ibrutinib arm, the 12-month PFS rate was 85.9% in the relapsed/refractory population and 87.2% in all patients.
The 12-month overall survival (OS) rate for all patients in the zanubrutinib group was 97.0% versus 93.9% with ibrutinib. For patients with relapsed or refractory disease, rates were 98.8% and 92.5%, respectively.
Grade >3 adverse events (AEs) occurred in 58.4% of patients in the zanubrutinib arm and 63.3% in the ibrutinib arm. Within the zanubrutinib arm, 4 patients discontinued treatment due to AEs, and 1 fatal AE occurred. In the ibrutinib arm, 9 patients discontinued due to AEs, and there were 4 fatal AEs.
For AEs of special interest normally observed with BTK inhibitors, investigators noted atrial fibrillation of any grade occurred in 2.0% of patients in the zanubrutinib versus 15.3% in the ibrutinib arms, minor bleeding occurred at rates of 48.5% versus 59.2%, major hemorrhage at 5.9% versus 9.2%, and diarrhea at 20.8% versus 31.6%, respectively. Additionally, neutropenia was seen in 29.7% of patients in the zanubrutinib arm versus 13.3% in the ibrutinib arm.
Overall, zanubrutinib had a more favorable profile, according to these findings.
“Waldenström macroglobulinemia is a devastating and incurable disease with significant morbidity. These meaningful results help us advance the understanding of the role of BTK specificity and off-target effects during treatment,” said Constantine S. Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia, and a member of the steering committee and principal investigator for the ASPEN trial. “Despite not reaching the primary end point, 28.4% of [patients receiving zanubrutinib] achieved VGPR as compared to 19.2% in the ibrutinib arm, and zanubrutinib had a more favorable safety profile, suggesting improved clinical benefit for zanubrutinib over standard BTK-inhibitor therapy in the treatment of patients with Waldenström macroglobulinemia.”
In the open-label, multicenter, randomized trial (NCT03053440), patients with Waldenström macroglobulinemia were enrolled across 61 cancer centers in the United States, Europe, and Australia. Patients were divided into 1 of 2 cohorts, which included 201 patients with anMYD88mutation (cohort 1) and a nonrandomized cohort of 28 patients with MYD88wild-type disease (cohort 2).
Patients in cohort 1 were randomized to receive either zanubrutinib at 160 mg twice daily or ibrutinib at 420 mg once daily. Patients in cohort 2 received 160 mg twice daily of the study drug. Patients in all arms of the trial received the study drug until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination by the sponsor.
The primary end point of the trial was the proportion of patients achieving either a CR or VGPR in cohort 1, while secondary end points included efficacy by major response rate, duration of response, and PFS. Safety and incidence of AEs of special interest were also included in the secondary end points of the trial, among others.
Patients had to have a clinically definitive histologic diagnosis of Waldenström macroglobulinemia to be included in the study, as well as measurable disease. For patients with no prior systemic therapy to be considered, they must be inappropriate candidates for standard chemoimmunotherapy. Patients had to have an ECOG performance status of ≤2, and have adequate bone marrow, renal, and hepatic function. If patients had prior exposure to a BTK inhibitor, evidence of disease transformation at the time of study entry, or a grade ≥2 AE from a prior anticancer therapy, they could not be enrolled in the ASPEN trial.
“Today’s results are consistent with what we know about zanubrutinib from our broad clinical development program that it is a more selective BTK inhibitor with beneficial pharmacokinetics designed to provide deep, meaningful responses for many patients,” said Jane Huang, MD, chief medical officer of Hematology at BeiGene. “We plan to discuss our findings with regulatory authorities in the US and Europe and plan to submit these data for presentation, with additional analysis, to an upcoming medical meeting. In addition, we will continue to evaluate zanubrutinib compared to ibrutinib in our ongoing Phase III ALPINE trial in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.”
BeiGene Announces Results of Phase 3 ASPEN Trial of Zanubrutinib Compared to Ibrutinib for the Treatment of Patients with Waldenström’s Macroglobulinemia [press release]. Cambridge, Massachusetts; BeiGene, Ltd; December 16, 2019.https://bit.ly/2trrcQB. Accessed December 17, 2019.