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Biomarker analysis of the ASPEN study comparing zanubrutinib to ibrutinib in patients with Waldenström Macroglobulinemia.
Blood Advances 2024 Februrary 6
The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKi), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 zanubrutinib-treated and 92 ibrutinib-treated patients with mutated (MUT) MYD88 and 20 zanubrutinib-treated patients with wild-type (WT) MYD88. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P<0.05). Patients with CXCR4MUT (frameshift [FS] or nonsense [NS] mutations) had lower very good partial response and complete response rate (VGPR+CR) (17.0% vs 37.2%, P=0.020) and longer time to response (11.1 vs 8.4 months) than CXCR4WT BTKi-treated patients. CXCR4NS was associated with inferior progression-free survival (PFS; HR=3.39, P=0.017) in ibrutinib-treated, but not zanubrutinib-treated patients (HR=0.67, P=0.598), but VGPR+CR rates were similar between treatment groups (14.3% vs 15.4%). Compared to ibrutinib, zanubrutinib-treated patients with CXCR4NS had a favorable major response rate (MRR; 85.7% vs 53.8%, P=0.09) and PFS (HR=0.30, P=0.093). In patients with TP53MUT, significantly lower MRR was observed in ibrutinib- (63.6% vs 85.7%, P=0.04) but not zanubrutinib-treated patients (80.8% vs 81.9%, P=0.978). In TP53MUT, compared to ibrutinib, zanubrutinib-treated patients had higher VGPR+CR (34.6% vs 13.6%, P<0.05), numerically improved MRR (80.8% vs 63.6%, P=0.11), and longer PFS (not reached vs 44.2 months, HR=0.66, P=0.37). Collectively, WM patients with CXCR4MUT or TP53MUT had worse prognosis compared to patients with WT alleles and zanubrutinib led to better clinical outcomes.
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