Immune modulation in solid tumors: a phase 1b study of RO6870810 (BET inhibitor) and atezolizumab (PD-L1 inhibitor)

被引：0

作者：

Marbach, Daniel ^{[1
]}

Brouer-Visser, Jurriaan ^{[2
]}

Brennan, Laura ^{[2
]}

Wilson, Sabine ^{[1
]}

Davydov, Iakov I. ^{[1
]}

Staedler, Nicolas ^{[1
]}

Duarte, Jose ^{[1
]}

Quetglas, Iris Martinez ^{[1
]}

Nueesch, Eveline ^{[3
]}

Canamero, Marta ^{[4
]}

Chesne, Evelyne ^{[1
]}

Au-Yeung, George ^{[5
,6
]}

Hamilton, Erika ^{[7
]}

Lheureux, Stephanie ^{[8
]}

Richardson, Debra L. ^{[9
]}

Spanggaard, Iben ^{[10
]}

Gomes, Bruno ^{[1
]}

Franjkovic, Izolda ^{[4
]}

Demario, Mark ^{[2
]}

Kornacker, Martin ^{[1
]}

Lechner, Katharina ^{[4
]}

机构：

[1] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Roche Pharm Res & Early Dev, Basel, Switzerland

[2] F Hoffmann La Roche Ltd, Roche Innovat Ctr New York, Roche Pharm Res & Early Dev, New York, NY USA

[3] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Prod Dev, Data Sci, Basel, Switzerland

[4] F Hoffmann La Roche Ltd, Roche Innovat Ctr Munich, Roche Pharm Res & Early Dev, Penzberg, Germany

[5] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[6] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia

[7] Sarah Cannon Res Inst, Nashville, TN USA

[8] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada

[9] Univ Oklahoma Hlth Sci Ctr, Stephenson Canc Ctr, Div Gynecol Oncol, Oklahoma City, OK USA

[10] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark

来源：

BMC CANCER | 2025年 / 25卷 / 01期

关键词：

Bromodomain; BET inhibitor; Immunotherapy; Phase Ib solid tumors; TNBC; Ovarian cancer; SELECTIVE-INHIBITION; THERAPEUTIC TARGET; PROTEIN; BRD4;

D O I：

10.1186/s12885-025-13851-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PurposeBromodomain 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 methodsA 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).ResultsThe 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.ConclusionsThe 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.Trial registrationClinicalTrials.gov ID NCT03292172; Registration Date: 2017-09-25.

引用

页数：13

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