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

Marbach, D; Brouer-Visser, J; Brennan, L; Wilson, S; Davydov,, II; Staedler, N; Duarte, J; Martinez Quetglas, I; N&#252;esch, E; Ca&#241;amero, M; Chesn&#233;, E; Au-Yeung, G; Hamilton, E; Lheureux, S; Richardson, DL; Spanggaard, I; Gomes, B; Franjkovic, I; DeMario, M; Kornacker, M; Lechner, K

Author(s): Marbach, D; Brouer-Visser, J; Brennan, L; Wilson, S; Davydov,, II; Staedler, N; Duarte, J; Martinez Quetglas, I; Nüesch, E; Cañamero, M; Chesné, E; Au-Yeung, G; Hamilton, E; Lheureux, S; Richardson, DL; Spanggaard, I; Gomes, B; Franjkovic, I; DeMario, M; Kornacker, M; Lechner, K;
Details: Publication Year 2025-03-18,Volume 25,Issue #1,Page 500
Journal Title: BMC Cancer
Publication Type: Research article
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. 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. 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 antitumor effects. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03292172; Registration Date: 2017-09-25.
Publisher: BioMed Central
Keywords: Humans; *Antibodies, Monoclonal, Humanized/therapeutic; use/pharmacokinetics/pharmacology/adverse effects; Female; *Triple Negative Breast Neoplasms/drug therapy/immunology; Middle Aged; Aged; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects; *Ovarian Neoplasms/drug therapy/immunology; Immune Checkpoint Inhibitors/therapeutic use/adverse; effects/pharmacology/pharmacokinetics; B7-H1 Antigen/antagonists & inhibitors; Adult; Maximum Tolerated Dose; Bromodomain Containing Proteins; Proteins; BET inhibitor; Bromodomain; Immunotherapy; Ovarian cancer; Phase Ib solid tumors; Tnbc
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1186/s12885-025-13851-4
Open Access at Publisher's Site: https://doi.org/10.1186/s12885-025-13851-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-08 06:06:18

Last Modified: 2025-04-08 06:21:00