Phase III ASPEN trial of Brukinsa in Waldenström’s macroglobulinemia shows positive follow-up data.- BeiGene

BeiGene announced follow-up data from the Phase III ASPEN trial comparing BRUKINSA (zanubrutinib) to ibrutinib for the treatment of Waldenström’s macroglobulinemia. Data presented from the Phase III ASPEN trial (NCT03053440) include the 201 patients in the randomized cohort of patients with WM and a MYD88 mutation. While the ASPEN 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 numerically higher VGPR rate, as well as clinically meaningful improvements in safety and tolerability compared to ibrutinib. Additional five-month investigator-assessed follow-up data in the overall patient population reinforced the trend toward higher VGPR rates for zanubrutinib and advantages in safety.

At data cutoff of August 31, 2019, with 19.4 months median follow-up the combined CR+VGPR rate as assessed by independent review committee (IRC) for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (2-sided descriptive p=0.0921). The combined CR+VGPR rate as assessed by investigators for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 17.2% in the ibrutinib arm (2-sided descriptive p=0.0437). Most common grade of at least 3 adverse events (at least 5% in either arm) for zanubrutinib compared to ibrutinib included hypertension (6% vs. 11%), neutropenia (16% vs. 8%), pneumonia (1% vs. 7%), anemia (5% vs. 5%), and thrombocytopenia (5% vs. 3%). Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (2.0% vs. 15.3%), bleeding of any grade (48.5% vs. 59.2%), major hemorrhage (5.9% vs. 9.2%), diarrhea (20.8% vs. 31.6%), hypertension (10.9% vs. 17.3%); neutropenia (29.7% vs. 13.3%), infection (66.3% vs. 67.3%), and second malignancy (11.9% vs. 11.2%). Despite higher rates of grade at least 3 neutropenia among AEs of interest in the zanubrutinib arm (19.8% vs. 8.2% for ibrutinib), rates of infection were similar in patients taking zanubrutinib and ibrutinib (all grades: 66.3% vs. 67.3%; grade at least 3: 17.8% vs. 19.4%); and in the zanubrutinib arm, four (4.0%) patients discontinued treatment due to AEs and one (1.0%) patient had an adverse event leading to death; in the ibrutinib arm, nine patients (9.2%) discontinued due to AEs and four (4.1%) patients had an adverse event leading to death.

After an additional five-months of follow-up with a data cutoff of January 31, 2020, with 24.2 months median follow-up, CR+VGPR as assessed by investigator for zanubrutinib was 30.4% compared to 18.2% for ibrutinib (exploratory analysis; 2-sided descriptive p=0.0302). Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (3.0% vs. 18.4%), bleeding of any grade (50.5% vs. 60.2%), major hemorrhage (5.9% vs. 10.2%), diarrhea (21.8% vs. 32.7%), hypertension (12.9% vs. 20.4%); and neutropenia (31.7% vs. 15.3%). Despite higher rates of grade at least 3 neutropenia in the zanubrutinib arm (22.8% vs. 8.2% for ibrutinib), rates of infection remained similar in patients taking zanubrutinib and ibrutinib (all grade: 69.3% vs. 71.4%; grade of at least 3: 18.8% vs. 23.5%); and no additional patients discontinued treatment due to AEs in the zanubrutinib arm, compared to an additional five patients in the ibrutinib arm (4% vs 14.3%). No additional patients had an adverse event leading to death in both arms (1.0% vs. 4.1%).