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":"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":"6 1","pages":""},"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}
引用次数: 0
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.
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