Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma

药效学 医学 生物标志物 淋巴瘤 临床试验 T细胞 肿瘤科 流式细胞术 活检 免疫学 内科学 免疫系统 癌症研究 药理学 药代动力学 生物 生物化学
作者
Ann‐Marie Bröske,Koorosh Korfi,Anton Belousov,Sabine Wilson,Chia-Huey Ooi,Christopher R. Bolen,Marta Cañamero,Enrique Gómez Alcaide,Ian James,Emily Piccione,David Carlile,Natalie Dimier,Pablo Umaña,Marina Bacac,Maja Weisser,Michael Dickinson
出处
期刊:Blood Advances [Elsevier BV]
卷期号:6 (3): 1025-1037 被引量:52
标识
DOI:10.1182/bloodadvances.2021005954
摘要

Abstract Glofitamab, a novel CD20xCD3, T-cell–engaging bispecific antibody, exhibited single-agent activity in Study NP30179, a first-in-human, phase 1 trial in relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that glofitamab leads to T-cell activation, proliferation, and tumor cell killing upon binding to CD20 on malignant cells. Here, we provide evidence of glofitamab’s clinical activity, including pharmacodynamic profile, mode of action, and factors associated with clinical response, by evaluating biomarkers in patient samples from the dose-escalation part of this trial. Patients enrolled in Study NP30179 received single-dose obinutuzumab pretreatment (1000 mg) 7 days before IV glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12 cycles once every 2 or 3 weeks. Blood samples were collected at predefined time points per the clinical protocol; T-cell populations were evaluated centrally by flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and genomic biomarker analyses were performed on tumor biopsy samples. Pharmacodynamic modulation was observed with glofitamab treatment, including dose-dependent induction of cytokines, and T-cell margination, proliferation, and activation in peripheral blood. Gene expression analysis of pretreatment tumor biopsy samples indicated that tumor cell intrinsic factors such as TP53 signaling are associated with resistance to glofitamab, but they may also be interlinked with a diminished effector T-cell profile in resistant tumors and thus represent a poor prognostic factor per se. This integrative biomarker data analysis provides clinical evidence regarding glofitamab’s mode of action, supports optimal biological dose selection, and will further guide clinical development. This trial was registered at www.clinicaltrials.gov as #NCT03075696.
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