Oral Presentation 31st Lorne Cancer Conference 2019

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 (#11)

Sheau Wen Lok 1 2 3 , James Whittle 2 3 4 5 , Francois Vaillant 1 5 , Charis Teh 1 5 , Louisa Lo 3 5 , Antonia Policheni 1 5 , Alice Bergin 2 3 4 , Jayesh Desai 2 3 , Sarah Ftouni 3 , Luke Gandolfo 4 5 , Danny Liew 5 6 , He K Liu 4 , Bruce Mann 2 3 5 7 , Kate Moodie 3 , Anand Murugasu 2 , Bhupinder Pal 4 5 8 , Andrew Roberts 2 3 4 , Mark Rosenthal 2 3 5 , Kylie Shackleton 1 2 , Maria Silva 1 , Zhen Siow 2 3 4 , Gordon Smyth 4 5 , Leanne Taylor 2 , Avraham Travers 2 3 4 , Belinda Yeo 8 9 , Miriam Yeung 3 , Andjelija Zivanovic Bujak 3 5 , Sarah-Jane Dawson 3 5 , Daniel Gray 4 5 , Jane Visvader 4 5 , Geoffrey Lindeman 2 3 4 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Royal Melbourne Hospital, Melbourne, VIC, Australia
  3. Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. The University of Melbourne, Parkville, VIC, Australia
  6. School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
  7. The Royal Women's Hospital, Parkville, VIC, Australia
  8. Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia
  9. Austin Health, Heidelberg, VIC, Australia

Background: BCL-2 is overexpressed in ~80% of ER+ breast cancer1. Venetoclax, a potent and selective inhibitor of the survival protein BCL-2 has yet to be evaluated in patients with solid tumours. Pre-clinical findings using patient-derived xenograft breast tumour models suggest that venetoclax synergises with endocrine therapy by increasing apoptosis2.

Methods: Using a phase 1b 3+3 dose escalation and expansion study design, 33 patients with ER and BCL-2 positive MBC were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). The primary endpoint was to determine the maximum tolerated dose (MTD), define dose-limiting toxicities (DLTs) and identify the recommended phase 2 dose (RP2D). In a dose expansion phase (at the RP2D), secondary endpoints including safety and tolerability, response at 24 wks (RECIST v1.1), clinical benefit rate (CBR) and progression-free survival (PFS) were studied.

Results: In the escalation phase (n=15), treatment was well tolerated with no DLTs or high-grade adverse events, apart from asymptomatic on-target lymphopenia. MTD was not reached and 800 mg was selected as the RP2D. For the 24 patients treated at the RP2D, the overall response rate was 54% (1 CR and 12 PR) and clinical benefit rate 75%. Median PFS was not reached at the time of data analysis (>51 weeks for the R2PD cohort). Clinical benefit was observed in 8/12 patients who had received >3 lines of therapy in the metastatic setting, including in 5/9 patients who progressed on tamoxifen. Treatment responses were pre-empted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumour DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations.

Conclusions: In the first clinical study to evaluate venetoclax in a solid tumour, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL-2+ MBC. These findings support further investigation of combination therapy for patients with BCL-2-positive tumours.

 

  1. 1. Merino D, Lok SW, Visvader JE, Lindeman GJ. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer. Oncogene 2016;35:1877-87.
  2. 2. Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME, et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 2013;24:120-9.