Clinical and biological efficacy of first line AI and palbociclib in ER+HER2-MBC with detectable circulating ESR1 mutation prior to treatment initiation

Background: In ER+ HER2- metastatic breast cancer (MBC), activating ESR1 mutations (ESR1mut) confer resistance to aromatase inhibitors (AI) when used as single agent. The impact of ESR1mut, when detected at baseline (prior to the initiation of therapy), on the efficacy of first line combined AI- CDK4/6 inhibitor therapy remains however unknown. Methods: The PADA-1 phase 3 trial (NCT03079011) aims at evaluating the utility of monitoring the onset of ESR1mut in cell-free DNA (cfDNA) from patients (pts) receiving AI-palbociclib, as a biomarker to trigger a switch from AI to fulvestrant. Main inclusion criteria were pts with no prior therapy for MBC and with no overt resistance to AI (i.e. no adjuvant AI or adjuvant AI completed \u003e12 months prior to the metastatic relapse). The present exploratory analysis evaluated the biological and clinical outcome of patients who tested positive for ESR1mut at baseline (before any treatment). Results: From 04/2017 to 01/2019, N=1017 ER+ HER2- MBC pts were included and had their cfDNA tested for ESR1mut at inclusion and during therapy (at 1 month and then every 2 months). N=33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), with a median allelic frequency (AF) of 2.5% (range: 0.1- 46%). First, we evaluated the kinetics of ESR1mut in the 33 ESR1mut-positive pts at inclusion. N=1 pt died after 1 month on treatment. In N=25/32 pts (78%), ESR1mut became undetectable (AF Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut observed in most patients following treatment initiation and the observed 17.5 months-long median PFS both suggest that the AI palbociclib combination retain clinical activity in ESR1mut-positive MBC. However, in most patients, these mutations were eventually detected again later during therapy and ESR1mut- positivity was associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. Funding: Pfizer Citation Format: Francois-Clement Bidard, Celine Callens, Florence Dalenc, Barbara Pistilli, Thibault de la Motte Rouge, Florian Clatot, Veronique D9Hondt, Luis Teixeira, Sibille Everhard, Helene Vegas, Jerome Lemonnier, Ivan Bieche, Anne Pradines, Jean-Francois Paitel, Dominique Spaeth, Jean-Luc Canon, Isabelle Moullet, Jean-Yves Pierga, Frederique Berger, Thomas Bachelot, Suzette Delaloge. Clinical and biological efficacy of first line AI and palbociclib in ER+ HER2- MBC with detectable circulating ESR1 mutation prior to treatment initiation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-22.