Marbach Daniel, Brouer-Visser Jurriaan, Brennan Laura, Wilson Sabine, Davydov Iakov I, Staedler Nicolas, Duarte José, Martinez Quetglas Iris, Nüesch Eveline, Cañamero Marta, Chesné Evelyne, Au-Yeung George, Hamilton Erika, Lheureux Stephanie, Richardson Debra L, Spanggaard Iben, Gomes Bruno, Franjkovic Izolda, DeMario Mark, Kornacker Martin, Lechner Katharina
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Roche Pharma Research and Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, New York, NY, USA.
BMC Cancer. 2025 Mar 18;25(1):500. doi: 10.1186/s12885-025-13851-4.
Bromodomain and extra-terminal domain (BET) inhibitors (BETi) have demonstrated epigenetic modulation capabilities, specifically in transcriptional repression of oncogenic pathways. Preclinical assays suggest that BETi potentially attenuates the PD1/PD-L1 immune checkpoint axis, supporting its combination with immunomodulatory agents.
A Phase 1b clinical trial was conducted to elucidate the pharmacokinetic and pharmacodynamic profiles of the BET inhibitor RO6870810 as monotherapy and in combination with the PD-L1 antagonist atezolizumab in patients with advanced ovarian carcinomas and triple-negative breast cancer (TNBC). Endpoints included maximum tolerated dosages, adverse event profiling, pharmacokinetic evaluations, and antitumor activity. Pharmacodynamic and immunomodulatory effects were assessed in tumor tissue (by immunohistochemistry and RNA-seq) and in peripheral blood (by flow cytometry and cytokine analysis).
The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Antitumor activity was limited to 2 patients (5.6%) showing partial response. Although target engagement was confirmed by established BETi pharmacodynamic markers in both blood and tumor samples, BETi failed to markedly decrease tumor PD-L1 expression and had a suppressive effect on antitumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects.
The combination of BET inhibitor RO6870810 with the checkpoint inhibitor atezolizumab presents an unfavorable risk-benefit profile for ovarian cancer and TNBC (triple-negative breast cancer) patients due to the increased risk of augmented or exaggerated immune reactions, without evidence for synergistic antitumor effects.
ClinicalTrials.gov ID NCT03292172; Registration Date: 2017-09-25.
溴结构域和额外末端结构域（BET）抑制剂（BETi）已显示出表观遗传调控能力，特别是在致癌途径的转录抑制方面。临床前试验表明，BETi可能会减弱PD1/PD-L1免疫检查点轴，支持其与免疫调节剂联合使用。
进行了一项1b期临床试验，以阐明BET抑制剂RO6870810作为单一疗法以及与PD-L1拮抗剂阿替利珠单抗联合用于晚期卵巢癌和三阴性乳腺癌（TNBC）患者时的药代动力学和药效学特征。终点包括最大耐受剂量、不良事件分析、药代动力学评估和抗肿瘤活性。在肿瘤组织（通过免疫组织化学和RNA测序）和外周血（通过流式细胞术和细胞因子分析）中评估药效学和免疫调节作用。
由于接受RO6870810和阿替利珠单抗联合治疗的患者中免疫相关不良反应的发生率较高，该研究提前终止。抗肿瘤活性仅限于2名患者（5.6%）出现部分缓解。尽管通过既定的BETi药效学标志物在血液和肿瘤样本中均证实了靶点结合，但BETi未能显著降低肿瘤PD-L1表达，且对抗肿瘤免疫有抑制作用。仅在阿替利珠单抗联合治疗中观察到肿瘤组织中的免疫效应激活，这与该检查点抑制剂公认的生物学效应一致。
BET抑制剂RO6870810与检查点抑制剂阿替利珠单抗联合使用，对卵巢癌和TNBC（三阴性乳腺癌）患者而言，风险效益比不佳，因为免疫反应增强或过度的风险增加，且无协同抗肿瘤作用的证据。
ClinicalTrials.gov标识符NCT03292172；注册日期：2017年9月25日。
