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Title: A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer.
Austin Authors: Lok, Sheau W;Whittle, James R;Vaillant, François;Teh, Charis E;Lo, Louisa L;Policheni, Antonia N;Bergin, Alice R T;Desai, Jayesh;Ftouni, Sarah;Gandolfo, Luke C;Liew, Danny;Liu, He K;Mann, G Bruce;Moodie, Kate;Murugasu, Anand;Pal, Bhupinder;Roberts, Andrew W;Rosenthal, Mark A;Shackleton, Kylie;Silva, Maria João;Siow, Zhen R;Smyth, Gordon K;Taylor, Leanne;Travers, Avraham;Yeo, Belinda ;Yeung, Miriam M;Bujak, Andjelija Zivanovic;Dawson, Sarah-Jane;Gray, Daniel H D;Visvader, Jane E;Lindeman, Geoffrey J
Affiliation: Austin Health, Heidelberg, Victoria, Australia
The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
The Royal Melbourne Hospital, Melbourne, Victoria, Australia
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
The University of Melbourne, Melbourne, Victoria, Australia
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
The Royal Women's Hospital, Melbourne, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: Mar-2019 2018-12-05
Publication information: Cancer discovery 2019; 9(3): 354-369
Abstract: Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-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 II 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 the clinical benefit rate was 75%. Treatment responses were preempted 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. SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.See related commentary by Drago et al., p. 323.This article is highlighted in the In This Issue feature, p. 305.
DOI: 10.1158/2159-8290.CD-18-1151
ORCID: 0000-0003-3229-3760
Journal: Cancer discovery
PubMed URL: 30518523
Type: Journal Article
Appears in Collections:Journal articles

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