A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2-positive metastatic breast cancer
Publication Year 2019-12-05,Volume 9,Issue #3,Page 354-369
Journal Title
Cancer Discovery
Publication Type
Journal Article
Venetoclax, a potent and selective BCL-2 inhibitor, synergizes with endocrine therapy in pre-clinical models of ER-positive breast cancer. Using a phase 1b 3+3 dose escalation and expansion study design, 33 patients with ER and BCL-2-positive metastatic disease (mean prior regimens, 2; range 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated 'on-target' lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase 2 dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and clinical benefit rate 75%. Treatment responses were pre-empted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations.
WEHI Research Division(s)
Systems Biology And Personalised Medicine; Stem Cells And Cancer; Molecular Genetics Of Cancer; Immunology; Bioinformatics; Cancer And Haematology
PubMed ID
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Creation Date: 2020-03-05 09:24:31
Last Modified: 2020-03-05 09:26:42
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