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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


Lok, SW; Whittle, JR; Vaillant, F; Teh, CE; Lo, LL; Policheni, AN; Bergin, ART; Desai, J; Ftouni, S; Gandolfo, LC; Liew, D; Liu, HK; Mann, GB; Moodie, K; Murugasu, A; Pal, B; Roberts, AW; Rosenthal, MA; Shackleton, K; Silva, MJ; Siow, ZR; Smyth, GK; Taylor, L; Travers, A; Yeo, B; Yeung, MM; Zivanovic Bujak, A; Dawson, SJ; Gray, DHD; Visvader, JE; Lindeman, GJ
2019-12-05
Cancer Discovery
Journal Article
9
3
354-369
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.
AACR
Systems Biology and Personalised Medicine; Stem Cells and Cancer; Molecular Genetics of Cancer; Immunology; Bioinformatics; Cancer and Haematology
10.1158/2159-8290.CD-18-1151
30518523
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2020-03-05 09:24:31 Last Modified 2020-03-05 09:26:42