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

Constantine S Tam; Stephen Opat; Shirley P D'Sa; Wojciech Jurczak; Hui-Peng Lee; Gavin Cull; Roger G Owen; Paula Marlton; Björn E Wahlin; Ramon Garcia-Sanz; Helen McCarthy; Stephen P Mulligan; Alessandra Tedeschi; Jorge J Castillo; Jaroslaw Czyz; Carlos Fernández de Larrea; David Belada; Edward N Libby; Jeffrey V Matous; Marina Motta; Tanya Siddiqi; Monica Tani; Marek Trněný; Monique C Minnema; Christian Buske; Véronique Leblond; Steven P Treon; Judith Trotman; Binghao Wu; Yiling Yu; Zhirong Shen; Wai Y Chan; Jingjing Schneider; Heather Allewelt; Aileen Cohen; Meletios-Athanasios A Dimopoulos

doi:10.1182/bloodadvances.2023010906

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

Constantine S Tam
, Stephen Opat
, Shirley P D'Sa
, Wojciech Jurczak
, Hui-Peng Lee
, Gavin Cull
, Roger G Owen
, Paula Marlton
, Björn E Wahlin
, Ramon Garcia-Sanz
, Helen McCarthy
, Stephen P Mulligan
, Alessandra Tedeschi
, Jorge J Castillo
, Jaroslaw Czyz
, Carlos Fernández de Larrea
, David Belada
, Edward N Libby
, Jeffrey V Matous
, Marina Motta

Tanya Siddiqi, Monica Tani, Marek Trněný, Monique C Minnema, Christian Buske, Véronique Leblond, Steven P Treon, Judith Trotman, Binghao Wu, Yiling Yu, Zhirong Shen, Wai Y Chan, Jingjing Schneider, Heather Allewelt, Aileen Cohen, Meletios-Athanasios A Dimopoulos

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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. TP53^MUT, ARID1A^MUT, and TERT^MUTwere associated with higher rates of CXCR4^MUT(P < .05). Patients with CXCR4^MUT(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 CXCR4^WTtreated with BTKis. CXCR4^NSwas 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 CXCR4^NStreated 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 TP53^MUT, 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 TP53^MUT, 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 CXCR4^MUTor TP53^MUThad worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Original language	English
Pages (from-to)	1639-1650
Number of pages	12
Journal	Blood Advances
Volume	8
Issue number	7
Early online date	5 Feb 2024
DOIs	https://doi.org/10.1182/bloodadvances.2023010906
Publication status	Published - 9 Apr 2024

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Tam, C. S., Opat, S., D'Sa, S. P., Jurczak, W., Lee, H.-P., Cull, G., Owen, R. G., Marlton, P., Wahlin, B. E., Garcia-Sanz, R., McCarthy, H., Mulligan, S. P., Tedeschi, A., Castillo, J. J., Czyz, J., Fernández de Larrea, C., Belada, D., Libby, E. N., Matous, J. V., ... Dimopoulos, M.-A. A. (2024). Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia. Blood Advances, 8(7), 1639-1650. https://doi.org/10.1182/bloodadvances.2023010906

@article{011a9661773d40908d4d152e403a7f5a,

title = "Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenstr{\"o}m macroglobulinemia",

abstract = "The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenstr{\"o}m 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 TERTMUTwere 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 CXCR4WTtreated with BTKis. CXCR4NSwas 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 CXCR4NStreated 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 CXCR4MUTor TP53MUThad worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.",

author = "Tam, \{Constantine S\} and Stephen Opat and D'Sa, \{Shirley P\} and Wojciech Jurczak and Hui-Peng Lee and Gavin Cull and Owen, \{Roger G\} and Paula Marlton and Wahlin, \{Bj{\"o}rn E\} and Ramon Garcia-Sanz and Helen McCarthy and Mulligan, \{Stephen P\} and Alessandra Tedeschi and Castillo, \{Jorge J\} and Jaroslaw Czyz and \{Fern{\'a}ndez de Larrea\}, Carlos and David Belada and Libby, \{Edward N\} and Matous, \{Jeffrey V\} and Marina Motta and Tanya Siddiqi and Monica Tani and Marek Trn{\v e}n{\'y} and Minnema, \{Monique C\} and Christian Buske and V{\'e}ronique Leblond and Treon, \{Steven P\} and Judith Trotman and Binghao Wu and Yiling Yu and Zhirong Shen and Chan, \{Wai Y\} and Jingjing Schneider and Heather Allewelt and Aileen Cohen and Dimopoulos, \{Meletios-Athanasios A\}",

year = "2024",

month = apr,

day = "9",

doi = "10.1182/bloodadvances.2023010906",

language = "English",

volume = "8",

pages = "1639--1650",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "7",

}

Tam, CS, Opat, S, D'Sa, SP, Jurczak, W, Lee, H-P, Cull, G, Owen, RG, Marlton, P, Wahlin, BE, Garcia-Sanz, R, McCarthy, H, Mulligan, SP, Tedeschi, A, Castillo, JJ, Czyz, J, Fernández de Larrea, C, Belada, D, Libby, EN, Matous, JV, Motta, M, Siddiqi, T, Tani, M, Trněný, M, Minnema, MC, Buske, C, Leblond, V, Treon, SP, Trotman, J, Wu, B, Yu, Y, Shen, Z, Chan, WY, Schneider, J, Allewelt, H, Cohen, A & Dimopoulos, M-AA 2024, 'Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia', Blood Advances, vol. 8, no. 7, pp. 1639-1650. https://doi.org/10.1182/bloodadvances.2023010906

TY - JOUR

T1 - Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia

AU - Tam, Constantine S

AU - Opat, Stephen

AU - D'Sa, Shirley P

AU - Jurczak, Wojciech

AU - Lee, Hui-Peng

AU - Cull, Gavin

AU - Owen, Roger G

AU - Marlton, Paula

AU - Wahlin, Björn E

AU - Garcia-Sanz, Ramon

AU - McCarthy, Helen

AU - Mulligan, Stephen P

AU - Tedeschi, Alessandra

AU - Castillo, Jorge J

AU - Czyz, Jaroslaw

AU - Fernández de Larrea, Carlos

AU - Belada, David

AU - Libby, Edward N

AU - Matous, Jeffrey V

AU - Motta, Marina

AU - Siddiqi, Tanya

AU - Tani, Monica

AU - Trněný, Marek

AU - Minnema, Monique C

AU - Buske, Christian

AU - Leblond, Véronique

AU - Treon, Steven P

AU - Trotman, Judith

AU - Wu, Binghao

AU - Yu, Yiling

AU - Shen, Zhirong

AU - Chan, Wai Y

AU - Schneider, Jingjing

AU - Allewelt, Heather

AU - Cohen, Aileen

AU - Dimopoulos, Meletios-Athanasios A

PY - 2024/4/9

Y1 - 2024/4/9

N2 - 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 TERTMUTwere 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 CXCR4WTtreated with BTKis. CXCR4NSwas 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 CXCR4NStreated 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 CXCR4MUTor TP53MUThad worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

AB - 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 TERTMUTwere 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 CXCR4WTtreated with BTKis. CXCR4NSwas 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 CXCR4NStreated 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 CXCR4MUTor TP53MUThad worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

UR - https://www.scopus.com/pages/publications/85189030305

U2 - 10.1182/bloodadvances.2023010906

DO - 10.1182/bloodadvances.2023010906

M3 - Article

C2 - 38315878

SN - 2473-9529

VL - 8

SP - 1639

EP - 1650

JO - Blood Advances

JF - Blood Advances

IS - 7

ER -

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

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