Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitors for the Treatment of Hematological Malignancies and Solid Tumors: A Systematic Study of Clinical Trials

Abstract

Background: The upregulated expression of BET proteins is closely associated with the occurrence and development of hematological malignancies and solid tumors. Several BET inhibitors have been developed, and some have been in phase I/II of clinical trials. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated.Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes.Results: In the monotherapy of BET inhibitors, the most common and severe (grade ≥3) hematological adverse events (AEs) are thrombocytopenia, anemia, and neutropenia. The most common non-hematological syndromes are diarrhea, nausea, fatigue, dysgeusia, and decreased appetite, while the most severe AE is pneumonia. Additionally, Tmax of these BET inhibitors was between 0.5–6 h, but the range for T1/2 varied significantly. According to published data, the rates of SD, PD, CR and PR were 27.4%, 37.6%, 3.5%, and 5.7%, respectively, which is not very satisfactory. In addition to BRD4, oncogene MYC is another common target gene of these BET inhibitors. Ninety-seven signaling pathways may be regulated by BET inhibitors.Conclusion: All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application. Moreover, further efforts are necessary to explore the optimal dosing schemes and combinations to maximize the efficacy of BET inhibitors.

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

“…Among iBETs, BMS-986158 has notable pharmacodynamics profile with a longer half-life. [ 721 ]. RO6870810 (also termed RG6146 and TEN-0) is a novel iBET, resembling the JQ1 class.…”

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

“…In relation to this, sensitivity to treatment with the BET inhibitor JQ1 has been recently shown in two human erythroleukemia cell lines edited to incorporate a previously described homozygous STAG2 mutation (Antony et al, 2020). Both BRD4 and NIPBL are indispensable for the proper hematopoietic development (Dey et al, 2019;Mazzola et al, 2020) and both have been related with hematological defects: it has been detected an increased incidence of thrombocytopenia in CdLS patients (Lambert et al, 2011) and in clinical trials where BRD4 inhibitors have been essayed to treat diverse types of cancer, a prominent highly common toxic effect is thrombocytopenia (reviewed in (Sun et al, 2020)). In all these models where BRD4 and NIPBL functions converge in common regulatory processes, it might be interesting to investigate the effect of interfering with their interaction.…”

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

“…BET inhibitors also demonstrated antiangiogenic effects in FP-RMS xenograft models [116]. In adult clinical trials BET inhibitors have had limited efficacy and are not yet FDA-approved [117]. There is an ongoing trial evaluating the BET inhibitor BMS-986158 in children but results are not yet available (NCT03936465).…”