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7521 Background: ASPEN is a randomized, open-label, phase 3 study comparing ZANU, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi IBR in patients with WM. We present data with a median follow-up of 43 months. Methods: Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive ZANU 160 mg twice daily or IBR 420 mg once daily. Randomization was stratified by CXCR4 mutational status and lines of prior therapy (0 vs 1-3 vs > 3). Patients without MYD88 mutations were assigned to cohort 2 and received ZANU 160 mg twice daily. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Results: A total of 201 patients (ZANU arm, n = 102; IBR arm, n = 99) were enrolled in cohort 1 and 28 patients were enrolled in cohort 2. A larger proportion of patients in the ZANU arm of cohort 1 vs IBR had CXCR4 mutations by next-generation sequencing (32% vs 20%, or 33 of 98 vs 20 of 92 with data available) and were aged > 75 years (33% vs 22%). Median duration of treatment was 42 months (ZANU) and 41 months (IBR), with 67% and 58% remaining on treatment, respectively. The CR+VGPR rate by investigator was 36% with ZANU vs 22% with IBR ( p= 0.02) in cohort 1, and 31% in cohort 2. One patient achieved CR (cohort 2). In patients with wild type or mutant CXCR4 from cohort 1, CR+VGPR rates with ZANU vs IBR were 45% vs 28% ( p= 0.04) and 21% vs 5% ( p= 0.15) , respectively. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with ZANU vs IBR (Table). Exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension were lower with ZANU vs IBR (0.2 vs 0.8 and 0.5 vs 1.0 persons per 100 person-months, respectively; p< 0.05). Rate of neutropenia was higher and rate of grade ≥3 infection was lower with ZANU vs IBR. Safety outcomes of ZANU were similar between cohorts 1 and 2. Conclusions: ASPEN is the largest phase 3 trial with head-to-head BTKi comparison in WM. At a median follow-up of 43 months, ZANU was associated with higher CR+VGPR rate and demonstrated clinically meaningful advantages in long-term safety and tolerability vs IBR. Clinical trial information: NCT03053440. [Table: see text]

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

e20056 Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with WM harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations ( N Engl J Med. 2015;372:1430). The ASPEN trial evaluated zanubrutinib (ZANU), a potent and selective BTK inhibitor, in WM patients. Methods: In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 ( MYD88 mutation) or cohort 2 ( MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression. The objective was to assess the safety and efficacy of ZANU in patients with MYD88WT WM. Results: In total, 28 patients with 26 MYD88WT WM were enrolled into cohort 2. The median age was 72 years; 5 patients were treatment-naïve (TN) and 23 patients were relapsed/refractory (R/R; ≥1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With the median follow-up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. The overall response rate was 80.8%, with a major response rate of 50.0%, including a very good partial response (VGPR) rate of 26.9% (Table). Progression-free survival event-free rate at 12 months was 72.4%. The most frequently reported adverse events (AEs) were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient. There were no fatal AEs. Conclusions: ZANU showed clinically meaningful antitumor activity, including achieving major responses and durability of responses, and was considered well-tolerated with a low discontinuation rate due to AEs, in patients with MYD88WT WM. ZANU demonstrated efficacy regardless of MYD88 mutational status in WM. Clinical trial information: NCT03053440 . [Table: see text]

8007 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at ~12 months after last patient enrolled. Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, except in the ZANU arm there were more elderly patients (aged >75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events (AEs) leading to discontinuation or death were lower with ZANU. The rate of neutropenia was higher with ZANU (Table); however, grade ≥ 3 infection rates were similar (17.8% vs 19.4%). Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared to IBR. Clinical trial information: NCT03053440 . [Table: see text]

Background Findings from clinical trials of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. Methods In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. Results A total of 1204 patients were followed for a median of 19 months; the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was −0.21±2.62 in the evolocumab group and −0.29±2.81 in the placebo group (P