Phase III ASPEN trial of Brukinsa did not reach statistical significance in Waldenström's macroglobulinemia.- BeiGene

BeiGene announced results from the Phase III ASPEN trial comparing its BTK inhibitor Brukinsa (zanubrutinib) to ibrutinib for the treatment of Waldenström'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 randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 treatment-naive (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 III ASPEN trial, as of the data cutoff date of August 31, 2019 with a median follow-up of 19.4 months, include the following. 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. 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.