361P - PALVEN: A phase Ib study of palbociclib, letrozole and venetoclax in ER and BCL2-positive metastatic breast cancer

Background

The addition of a CDK4/6 inhibitor to endocrine therapy improves progression-free and overall survival in women with metastatic ER-positive (ER+) breast cancer. 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 prosurvival protein overexpressed in most ER+ cancers. Preclinical findings indicate that venetoclax augments tumor response to the CDK4/6 inhibitor palbociclib by triggering apoptosis in proliferating and senescent cells.

Methods

In a phase 1b study using a standard 3+3 design, we evaluated the safety of triplet therapy with palbociclib, venetoclax (both commenced at 100mg daily (d) and administered orally on d1-21 in a 28d cycle) and letrozole (2.5mg oral d) in post-menopausal women with ER+, HER2 non-amplified and BCL2+ metastatic breast cancer who had received ≤2 prior lines of systemic therapy. The primary objectives were to identify the maximum tolerated dose (MTD) and determine the recommended phase II dose (RP2D) of triplet therapy.

Results

A total of 15 patients (pts) were deemed evaluable for dose limiting toxicity (DLT), having received 21d of palbociclib, letrozole and venetoclax. Four dose levels were investigated. Two DLTs were observed in dose level 1, both grade 3 ALT elevation; one DLT comprising uncomplicated grade 4 neutropenia that did not recover in 7 days, occurred in dose level 1b (venetoclax 400mg d1-21, palbociclib 75mg d1-21, letrozole 2.5mg d1-28) in a pt who received recent radiotherapy. A total of six pts were treated at dose level 1b with no further DLTs observed. Dose level 1b was confirmed as the MTD and selected as the RP2D.

Conclusions

Triplet therapy with palbociclib, letrozole and venetoclax in ER+ and BCL2+ metastatic breast cancer is safe and well tolerated at the MTD. Efficacy and outcome data will be analysed at prespecified time points. PALVEN is the first trial combining a BCL2 and CDK4/6 inhibitor. Findings will provide insights into whether BCL2 inhibitors could trigger apoptosis and improve responses to CDK4/6 inhibitor therapy. (IIS funded by NHMRC, NBCF, Cancer Australia, BCRF, BCT, VCCC, with support from AbbVie & Pfizer; NCT03900884).

Clinical trial identification

NCT03900884.

Editorial acknowledgement

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

IIS funded by NHMRC, NBCF, Cancer Australia, BCRF, BCT, VCCC, with support from AbbVie & Pfizer.

Disclosure

C. Muttiah: Other, Institutional, Other, Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. I have received benefits related to those payments: The Walter and Eliza Hall Institute of Medical Research. J. Desai: Financial Interests, Personal, Invited Speaker: Pierre Fabre, Merck KGaA, Novartis; Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Roche/Genentech, Pfizer, Amgen, pierre fabre, BeiGene, Axelia, Ellipses; Financial Interests, Coordinating PI: Roche/Genentech, BeiGene; Financial Interests, Local PI: Amgen, AstraZeneca, GSK, Novartis; Financial Interests, Steering Committee Member: Pfizer; Non-Financial Interests, Principal Investigator: BeiGene, Roche/Genentech, Amgen, Pfizer, Novartis, Boehringer, MapCure, Springworks, AstraZeneca, Vivace, Incyte; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Leadership Role: Australia New Zealand Sarcoma Association; Other, Not-for-profit. Director-uncompensated: Cancer Trials Australia. A. Travers: Financial Interests, Personal, Research Funding, Not relevant to or at the time of contribution to this study.: AstraZeneca. J. Visvader: Financial Interests, Institutional, Other, The Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. I have received benefits related to those payments: Walter and Eliza Hall Institute of Medical Research. J.R. Whittle: Financial Interests, Personal, Advisory Board, Research: AnHeart Therapeitics ; Financial Interests, Personal, Advisory Board: Servier Therapeutics ; Financial Interests, Advisory Board: Merck, Roche. G. Lindeman: Financial Interests, Personal, Advisory Board, and Consulting role: AbbVie; Financial Interests, Personal, Advisory Board, and Consulting, and Honoraria: Pfizer; Financial Interests, Institutional, Research Funding: Amgen, AbbVie, Genentech (Roche), Pfizer, Cooperative Research Centre (CRC) for Cancer Therapeutics (CTx); Other, Institutional, Other, I am an employee of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax. Employees are entitled to receive benefits related to these payments.: Walter and Eliza Hall Institute of Medical Research. All other authors have declared no conflicts of interest.