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

A, Kaplan–Meier survival curve for ER⁺BCL2⁺ PDX 315 (n = 6–10 mice per arm). Mice were treated with vehicle, tamoxifen, venetoclax, or the combination at indicated doses. Venetoclax oral gavage, 5 days per week. Tamoxifen was injected subcutaneously daily. Mice, which remained otherwise healthy, were sacrificed when tumor size reached the experimental ethical endpoint (>600 mm³). Log-rank (Mantel–Cox) P value for combination therapy with ABT-199 25 mg/kg versus combination with ABT-199 100 mg/kg: P = 0.01. Tumor growth curves for individual mice from the PDX model 315 are shown in Supplementary Fig. S2. B, Study design and consort flow diagram. Patients with metastatic ER⁺BCL2⁺ breast cancer (MBC) were treated with tamoxifen and venetoclax (in escalating doses) in a 3 + 3 phase I design continuously until progression, unacceptable toxicity, or death. Once the RP2D was determined, an additional 18 patients were enrolled as of the reporting date. Pharmacodynamic studies were performed on plasma and tumor tissue as well as metabolic studies using FDG-PET. C, Clinical trial consort diagram shows the number of subjects entering the study from enrollment. D, IHC evaluation of BCL2 staining intensity. 0, negative; 1, weak; 2, moderate; 3, strong. Scale bar, 50 μm. ctDNA, circulating tumor DNA; PBMC, peripheral blood mononuclear cell.