BeiGene Announces Results of Phase 3 ASPEN Trial of Zanubrutinib Compared to Ibrutinib for the Treatment of Patients with Waldenstr?m?s Macroglobulinemia
[caption id="attachment_9277" align="aligncenter" width="747"] Press Release[/caption]
December 16, 2019 at 7:00 AM EST
- Primary Endpoint of?Statistical Superiority Related to Deep Response (VGPR?or Better) Was Not Met;?However, Zanubrutinib Demonstrated More Frequent VGPRs (28.4% vs.19.2% in Overall Population)
- Zanubrutinib Demonstrated Advantages in Safety and Tolerability Compared to Ibrutinib
-?ASPEN?is the Largest Phase 3 Trial in Waldenstr?m?s Macroglobulinemia and the?First Comparative Trial Readout for BTK Inhibitors
- Company to Hold Investor Conference Call and Webcast Today at?8:30 AM ET
CAMBRIDGE, Mass.?and?BEIJING, China,?Dec. 16, 2019?(GLOBE NEWSWIRE) --?BeiGene, Ltd.(NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, today announced results from the Phase 3 ASPEN trial comparing its BTK inhibitor BRUKINSA? (zanubrutinib) to ibrutinib for the treatment of Waldenstr?m?s macroglobulinemia (WM). While the trial did not achieve statistical significance on its primary endpoint of superiority in complete response (CR) and very good partial response (VGPR) rates for zanubrutinib compared to ibrutinib, zanubrutinib demonstrated a higher VGPR rate as well as improvements in safety and tolerability in this first randomized comparative trial to read out within the BTK inhibitor class.
The?ASPEN?trial is a randomized Phase 3 trial in 229 patients with WM conducted in 61 centers in?Europe,?Australia, and?the United States. The study includes two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.
The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 treatment-na?ve (TN) patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).
Results from cohort 1 in the Phase 3 ASPEN trial, as of the data cutoff date of?August 31, 2019?with a median follow-up of 19.4 months, include:
?Our researchers sought to design a BTK inhibitor that would improve efficacy and decrease side effects in patients by maximizing BTK inhibition and minimizing off-target binding. We took a bold approach to our clinical development plan by evaluating zanubrutinib directly against ibrutinib in patients with WM and are encouraged by the improvements in VGPR rates and safety,? said?Jane Huang, M.D., Chief Medical Officer, Hematology at?BeiGene. ?The ASPEN trial, which was the largest prospective trial for patients with WM ever run, showed consistent safety advantages for patients treated with zanubrutinib compared to ibrutinib. While falling short of a statistically significant improvement in CR and VGPR, we believe the trial demonstrated that zanubrutinib is a highly potent BTK inhibitor that has clinical benefit and trends toward increased response quality.?
Dr. Huang continued, ?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. We plan to discuss our findings with regulatory authorities in the U.S. 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 3 ALPINE trial in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).?
?WM 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, M.D., 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 endpoint, 28.4% of zanubrutinib patients 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 BTKi therapy in the treatment of patients with WM.?
About the?ASPEN?trial
The Phase 3 randomized, open-label, multicenter?ASPEN?clinical trial (NCT03053440) evaluated BRUKINSA versus ibrutinib in people with relapsed/refractory (R/R) or treatment-na?ve (TN) Waldenstr?m?s macroglobulinemia. The primary objective was to establish superiority of BRUKINSA compared to ibrutinib as demonstrated by the proportion of people achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164).
Results of cohort 2 were previously presented at the 24th?Congress?of?European Hematology Association?(EHA) and showed an overall response rate (ORR) of 80.8%, a major response rate (MRR; partial response or better) of 53.8% and a VGPR rate of 23.1%.
The data from the study were masked and the results were first available for analysis this past week. The Company plans to submit the full?ASPEN?results for presentation to an upcoming medical congress.
BeiGene Conference Call and Webcast Information
Investors and analysts are invited to join the conference call on?Monday, December 16?at?8:30 a.m. ET?using the following dial-in information:
U.S. Toll-Free: +1 (844) 461-9930
Hong Kong: +852 5819-4851
China: +86 400-682-8609
Conference ID: 2885995
A live webcast of the conference call and the slides from the presentation can be accessed from the investors section of BeiGene?s website at?http://ir.beigene.com/?or?http://hkexir.beigene.com. An archived replay will be available two hours after the event for 90 days.
About the Zanubrutinib Clinical Trial Program
Clinical trials of zanubrutinib include:
- In R/R patients, the VGPR rate as assessed by independent review committee (IRC) was 28.9% in the zanubrutinib arm and 19.8% in the ibrutinib arm (no patients achieved a CR in either arm). The difference was not statistically significant (2-sided p=0.1160);
- In the overall patient population, the VGPR rate as assessed by IRC was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (no patients achieved a CR in either arm). The difference was not statistically significant (2-sided descriptive p=0.0921);
- In the R/R patient population, the major response rate (MRR), which is the rate of partial response (PR) or better, as assessed by IRC was 78.3% in the zanubrutinib arm and 80.2% in the ibrutinib arm; in the overall patient population, the MRR was 77.5% in the zanubrutinib arm and 77.8% in the ibrutinib arm;
- While the trial was not powered to detect a statistically significant improvement in progression free survival (PFS), and follow-up data for PFS is still short, early PFS and overall survival (OS) data for zanubrutinib were directionally consistent with the higher VGPR rates in the zanubrutinib arm: ??The 12-month PFS rate was 92.4% (83.8-96.5) in R/R patients and 89.7% (81.7-94.3) in all patients in the zanubrutinib arm, compared to 85.9% (75.9-91.9) in R/R patients and 87.2% (78.6-92.5) in all patients in the ibrutinib arm; and ? The 12-month OS rate was 98.8% (91.6-99.8) for R/R patients and 97.0% (90.9-99.0) for all patients in the zanubrutinib arm, compared to 92.5% (84.1-96.6) in R/R patients and 93.9% (86.8-97.2) in all patients in the ibrutinib arm;
- Grade >3 adverse events (AEs) were 58.4% in the zanubrutinib arm and 63.3% in the ibrutinib arm. In the zanubrutinib arm, four (4.0%) patients discontinued treatment due to AEs and there was one (1.0%) fatal adverse event; in the ibrutinib arm, nine patients (9.2%) discontinued due to AEs and there were four (4.1%) fatal adverse events;
- For AEs of special interest for BTK inhibitors, atrial fibrillation/flutter of any grade was 2.0% in the zanubrutinib arm and 15.3% in the ibrutinib arm; minor bleeding was 48.5% for zanubrutinib and 59.2% for ibrutinib; major hemorrhage was 5.9% for zanubrutinib and 9.2% for ibrutinib; and diarrhea was 20.8% for zanubrutinib and 31.6% for ibrutinib; and
- The rate of neutropenia was higher in the zanubrutinib arm (29.7%) as compared to the ibrutinib arm (13.3%).
R/R | Overall | ||||||
Efficacy | Zanubrutinib (N = 83) | Ibrutinib (N = 81) | Zanubrutinib (N = 102) | Ibrutinib (N = 99) | |||
VGPR + CR Rate | 28.9% | 19.8% | 28.4% | 19.2% | |||
PFS (12 month) (CI) | 92.4% (88.9 ? 98.8) | 85.9% (75.9 ? 91.9) | 89.7% (81.7 ? 94.3) | 87.2% (78.6 ? 92.5) | |||
OS (12 month) (CI) | 98.8% (91.6 ? 99.8) | 92.5% (84.1 ? 96.6) | 97.0% (90.9 ? 99.0) | 93.9% (86.8 ? 97.2) |
Zanubrutinib | Ibrutinib | ||
Safety | Overall (n = 101) | Overall (n = 98) | |
Grade >3 AEs | 58.4% | 63.3% | |
Treatment discontinuation due to AEs | 4 (4.0%) | 9 (9.2%) | |
Fatal AEs | 1 (1.0%) | 4 (4.1%) | |
Atrial fibrillation / flutter of any grade | 2.0% | 15.3% | |
Minor bleeding | 48.5% | 59.2% | |
Major hemorrhage | 5.9% | 9.2% | |
Diarrhea | 20.8% | 31.6% | |
Neutropenia | 29.7% | 13.3% |
- Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenstr?m?s macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;
- Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);
- Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);
- Phase 2 trial in combination with GAZYVA??(obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);
- Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);
- Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);
- Phase 2 ROSEWOOD trial (NCT03332017) in?China?comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;
- Completed Phase 2 trials in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918); and
- Completed enrollment in Phase 2 clinical trial in patients with WM (NCT03332173).