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

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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.

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