Journal
FUTURE ONCOLOGY
Volume 18, Issue 15, Pages 1805-1816Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/fon-2021-1450
Keywords
apoptosis; BCL2; BCL-XL; BH3 mimetic; breast cancer; CDK4; 6 inhibitor; estrogen receptor; senescence; senolysis; venetoclax
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Funding
- AbbVie
- Pfizer
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The current standard treatment for estrogen receptor-positive, HER2-negative metastatic breast cancer is endocrine therapy with a CDK4/6 inhibitor. This study aims to investigate the potential benefits of adding the BCL2 inhibitor venetoclax to the treatment regimen. A phase 1 trial will be conducted to determine the optimal dosages for combination therapy.
Plain language summary The current 'gold standard' treatment for estrogen receptor-positive, HER2-negative metastatic breast cancer is endocrine therapy with a CDK4/6 inhibitor. This combination improves tumor response and patient outcomes, primarily by reducing tumor cell growth. Paradoxically, less killing of tumor cells is observed in the presence of a CDK4/6 inhibitor. The authors hypothesize that co-treatment with venetoclax, an inhibitor of the BCL2 survival protein, will help trigger tumor death, thereby further improving tumor responses and patient outcomes. As a first step, combination therapy comprising letrozole, palbociclib and venetoclax will be tested in a phase 1 trial to identify the recommended doses for subsequent studies. The addition of a CDK4/6 inhibitor to endocrine therapy improves progression-free and overall survival in women with metastatic estrogen receptor-positive breast cancer. In that setting, CDK4/6 inhibitors induce a potent cell-cycle arrest (which may be accompanied by tumor senescence) but fail to induce apoptotic cell death. Venetoclax is a potent inhibitor of BCL2, a pro-survival protein overexpressed in the majority of estrogen receptor-positive cancers. Pre-clinical findings indicate that venetoclax augments tumor response to the CDK4/6 inhibitor palbociclib by triggering apoptosis, including in senescent cells. The PALVEN phase 1b trial will further examine this finding. The primary objective is to identify the maximum tolerated dose and determine the recommended phase 2 dose for palbociclib, letrozole and venetoclax combination therapy.
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