Dataset Information

Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial.

ABSTRACT: 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.

SUBMITTER: Dimopoulos M

PROVIDER: S-EPMC7724905 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.

Dimopoulos Meletios M Sanz Ramon Garcia RG Lee Hui-Peng HP Trneny Marek M Varettoni Marzia M Opat Stephen S D'Sa Shirley S Owen Roger G RG Cull Gavin G Mulligan Stephen S Czyz Jaroslaw J Castillo Jorge J JJ Motta Marina M Siddiqi Tanya T Gironella Mesa Mercedes M Granell Gorrochategui Miquel M Talaulikar Dipti D Zinzani Pier Luigi PL Askari Elham E Grosicki Sebastian S Oriol Albert A Rule Simon S Kloczko Janusz J Tedeschi Alessandra A Buske Christian C Leblond Veronique V Trotman Judith J Chan Wai Y WY Michel Jan J Schneider Jingjing J Tan Ziwen Z Cohen Aileen A Huang Jane J Tam Constantine S CS

Blood advances 20201201 23

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 W ...[more]

PMID: 33284944

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Project description:AbstractThe 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.

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.

Dataset Information

Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial.

Publications

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.

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