Daniel Marbach, Jurriaan Brouer-Visser, Laura Brennan, Sabine Wilson, Iakov I Davydov, Nicolas Staedler, José Duarte, Iris Martinez Quetglas, Eveline Nüesch, Marta Cañamero, E. Chesne, George Au-Yeung, Erika Hamilton, Stephanie Lheureux, D. Richardson, Iben Spanggaard, Bruno Gomes, I. Franjkovic, M. DeMario, M. Kornacker, K. Lechner, ID ClinicalTrials.gov
{"title":"实体瘤的免疫调节：RO6870810（BET 抑制剂）和 Atezolizumab（PD-L1 抑制剂）的 1b 期研究","authors":"Daniel Marbach, Jurriaan Brouer-Visser, Laura Brennan, Sabine Wilson, Iakov I Davydov, Nicolas Staedler, José Duarte, Iris Martinez Quetglas, Eveline Nüesch, Marta Cañamero, E. Chesne, George Au-Yeung, Erika Hamilton, Stephanie Lheureux, D. Richardson, Iben Spanggaard, Bruno Gomes, I. Franjkovic, M. DeMario, M. Kornacker, K. Lechner, ID ClinicalTrials.gov","doi":"10.1101/2024.07.28.24309665","DOIUrl":null,"url":null,"abstract":"Purpose: 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. Patients and Methods: 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). Results: The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor 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 anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects. Conclusions: 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 anti-tumor effects.","PeriodicalId":506788,"journal":{"name":"medRxiv","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Immune Modulation in Solid Tumors: A Phase 1b Study of RO6870810 (BET Inhibitor) and Atezolizumab (PD-L1 Inhibitor)\",\"authors\":\"Daniel Marbach, Jurriaan Brouer-Visser, Laura Brennan, Sabine Wilson, Iakov I Davydov, Nicolas Staedler, José Duarte, Iris Martinez Quetglas, Eveline Nüesch, Marta Cañamero, E. Chesne, George Au-Yeung, Erika Hamilton, Stephanie Lheureux, D. Richardson, Iben Spanggaard, Bruno Gomes, I. Franjkovic, M. DeMario, M. Kornacker, K. Lechner, ID ClinicalTrials.gov\",\"doi\":\"10.1101/2024.07.28.24309665\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Purpose: 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. Patients and Methods: 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). Results: The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor 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 anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects. Conclusions: 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 anti-tumor effects.\",\"PeriodicalId\":506788,\"journal\":{\"name\":\"medRxiv\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.07.28.24309665\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.28.24309665","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目的：溴结构域和末端外结构域（BET）抑制剂（BETi）具有表观遗传调节能力，特别是在抑制致癌通路的转录方面。临床前试验表明，BETi 有可能减弱 PD1/PD-L1 免疫检查点轴，从而支持其与免疫调节药物联合使用。患者与方法：进行了一项 1b 期临床试验，以阐明 BET 抑制剂 RO6870810 作为单药和与 PD-L1 拮抗剂 atezolizumab 联用治疗晚期卵巢癌和三阴性乳腺癌 (TNBC) 患者的药代动力学和药效学特征。研究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（通过免疫组化和RNA-seq）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。研究结果由于接受RO6870810和atezolizumab联合治疗的患者出现了明显的免疫相关不良反应，研究提前结束。抗肿瘤活性仅限于2名患者（5.6%）出现部分反应。虽然血液和肿瘤样本中的既定 BETi 药效学标记物证实了靶点参与，但 BETi 未能显著降低肿瘤 PD-L1 的表达，并对抗肿瘤免疫产生抑制作用。只有阿特珠单抗联合用药时才能观察到肿瘤组织中免疫效应因子的激活，这与这种检查点抑制剂公认的生物效应相一致。结论BET抑制剂RO6870810与检查点抑制剂atezolizumab联合用药对卵巢癌和TNBC（三阴性乳腺癌）患者的风险-获益情况不利，因为会增加免疫反应增强或夸大的风险，但没有证据表明会产生协同抗肿瘤效应。
Immune Modulation in Solid Tumors: A Phase 1b Study of RO6870810 (BET Inhibitor) and Atezolizumab (PD-L1 Inhibitor)
Purpose: 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. Patients and Methods: 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). Results: The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor 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 anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects. Conclusions: 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 anti-tumor effects.
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