Tumor cells harboring select genetic abnormalities (eg, BRD3/4-NUT) have shown sensitivity to BET inhibition. BMS-986158, a potent, selective and orally bioavailable BET inhibitor (BETi) was active in several established and pt-derived tumor xenograft models (Gavai AV, et al. AACR 2018; Wee S, et al. AACR 2018). Here we present initial data for BMS-986158 monotherapy from a phase 1/2a trial in previously treated pts with advanced cancer (NCT02419417).
During dose escalation, pts received BMS-986158 (0.75, 1.25, 2.0, 3.0, or 4.5 mg) once daily across 3 schedules: A (5 days on/2 days off), B (14 days on/7 days off), or C (7 days on/14 days off). Pharmacokinetics (PK), pharmacodynamics, and safety were evaluated.
As of March 20, 2018, 68 pts (median age, 59) received BMS-986158 (A [n = 31], B [n = 8], or C [n = 29]); 43% of pts had ≥ 4 prior therapies. Initial PK analysis of BMS-986158 showed dose-proportional and linear increase in exposure, with fast absorption (Tmax 2-4 h), long half-life (T1/2 33-82 h), and dose-dependent AUC. Treatment(tx)-related AEs (TRAEs) occurred in 63% of pts (Gr 3-4, 22%). TRAEs (any Gr; Gr 3-4) reported in ≥ 15% of pts were mild diarrhea (34%; 0%), thrombocytopenia (28%; 15%), and fatigue (16%; 1.5%). No tx-related deaths or discontinuations due to a TRAE occurred. The dose-limiting toxicity (DLT) was Gr 3-4 thrombocytopenia. Effects of BMS-986158 on gene transcription for biomarkers of BET activity (eg, CCR2 and HEXIM1) in peripheral blood cells were dose dependent and reversible with the 4.5-mg dose resulting in the highest change in gene expression. Of 4 pts with NUT midline carcinoma, an aggressive and fatal disease, 1 pt with a BRD3-NUT fusion received BMS-986158 (2.0 mg, schedule A) for 279 days, with best overall response of stable disease and 16% reduction in tumor burden, providing further evidence of target-mediated effects.
BMS-986158 was well tolerated, with reversible thrombocytopenia as the only DLT. This safety profile together with initial PK findings and effect on target gene expression support the ongoing evaluation of BMS-986158 in pts with select advanced cancers.
Clinical trial identification
Legal entity responsible for the study
Writing and editorial assistance was provided by Kathy Covino, PhD of Chrysalis Medical Communications, Inc., funded by Bristol-Myers Squibb.
J. Hilton: Advisory board: Bristol-Myers Squibb, AstraZeneca, Novartis, Pfizer, Eli-Lilly. A. Gavai, S. Wee, N. Srivastava, A. Klippel, D. Jackson, A. Apfel, S.D. Chasalow, D. Williams, M. Donovan, B. Fischer, S. Khaldoyanidi: Employment: Bristol-Myers Squibb; Stock ownership: Bristol-Myers Squibb. J.R. Diamond: Grants: Bristol-Myers Squibb, Bayer, Millennium Takeda, Immunomedics, Merck, Taiho, Rexahn. All other authors have declared no conflicts of interest.