A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer

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 9on-target9 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.