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Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenstrom macroglobulinemia.

ABSTRACT:

Abstract

The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), 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 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. 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 < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

SUBMITTER: Tam CS

PROVIDER: S-EPMC11006814 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

Tam Constantine S CS Opat Stephen S D'Sa Shirley S Jurczak Wojciech W Lee Hui-Peng HP Cull Gavin G Owen Roger G RG Marlton Paula P Wahlin Björn E BE García-Sanz Ramón R McCarthy Helen H Mulligan Stephen S Tedeschi Alessandra A Castillo Jorge J JJ Czyż Jarosław J Fernández De Larrea Carlos C Belada David D Libby Edward E Matous Jeffrey J Motta Marina M Siddiqi Tanya T Tani Monica M Trněný Marek M Minnema Monique C MC Buske Christian C Leblond Véronique V Treon Steven P SP Trotman Judith J Wu Binghao B Yu Yiling Y Shen Zhirong Z Chan Wai Y WY Schneider Jingjing J Allewelt Heather H Cohen Aileen A Dimopoulos Meletios A MA

Blood advances 20240401 7

<h4>Abstract</h4>The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), 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 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 ge ...[more]

PMID: 38315878

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Project description:In Waldenström macroglobulinemia (WM), a lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M (IgM) gammopathy, aberrant Bruton tyrosine kinase (BTK) signaling has been identified as one mechanism of pathogenesis. For this reason, selective BTK inhibiting therapies have emerged as an attractive option for treatment within the therapeutic landscape also comprising chemotherapy, monoclonal antibodies, proteasome inhibitors, and B-cell lymphoma 2 (BCL2) inhibitors. The first BTK inhibiting therapy, ibrutinib, showed great efficacy in treating WM. However, response rates were dependent on whether patients had the CXCR4 mutation, a molecular aberration that may confer resistance to BTK inhibitors. Furthermore, ibrutinib's toxicities, most notably hypertension and atrial arrhythmia, led to dose reductions or discontinuation. The toxicity profile of ibrutinib can be attributed to the inhibition of additional kinases that are structurally related to BTK. Therefore, the next-generation highly selective zanubrutinib was developed to address the concerns regarding toxicity and tolerance related to ibrutinib therapy. Based on the results of the randomized, open-label Phase 3 ASPEN (NCT03053440) trial, the Food and Drug Administration (FDA) approved zanubrutinib for treating WM. This trial directly compared zanubrutinib to ibrutinib in patients with treatment-naïve or relapsed/refractory WM, and the results showed stronger responses with zanubrutinib. More importantly, patients responded strongly to zanubrutinib therapy regardless of CXCR4 mutation status. Additionally, zanubrutinib was associated with fewer grade 3 or higher toxicities and was generally better tolerated. Another Phase 1/2 study has been conducted with just zanubrutinib in WM showcasing high efficacy with few toxicities as well. Even though zanubrutinib has been the third and last BTK inhibitor to currently penetrate the market for B-cell lymphoproliferative malignancies, we highlight the emergence of zanubrutinib as a key player in the forefront of the therapeutic landscape in WM.