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Mini Oral - Breast cancer, metastatic

277MO - SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/ HER2- metastatic breast cancer (mBC): Biomarker analyses from a phase I/II study

Date

18 Sep 2020

Session

Mini Oral - Breast cancer, metastatic

Presenters

Sarat Chandarlapaty

Citation

Annals of Oncology (2020) 31 (suppl_4): S348-S395. 10.1016/annonc/annonc268

Authors

S. Chandarlapaty1, A. Bardia2, S. Lord3, H. Linden4, V. Pelekanou5, N. Ternes6, J. Ming7, V. Boutet8, E. Boitier8, A. Gosselin6, J. Sang Lee9, W. Dos-Santos Bele10, A. Protopopov9, M. Celanovic11, A. Bauchet8, M. Campone12

Author affiliations

  • 1 Medicine, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 2 Medical Oncology, Massachusetts General Hospital, Harvard Medical School, 02114 - Boston/US
  • 3 Department Of Oncology, University of Oxford, Churchill Hospital, Oxford/GB
  • 4 Department Of Medicine, University of Washington Medical Center, Seattle/US
  • 5 Clinical Precision Oncology-tranlsational Medicine Early Development, Sanofi, Cambridge/US
  • 6 Biostatistics And Programming, Sanofi, Paris/FR
  • 7 Oncology, Sanofi, Bridgewater/US
  • 8 Tmed & Biomarkers & Clinical Bioanalyses, Sanofi, Paris/FR
  • 9 Precision Oncology, Sanofi, Cambridge/US
  • 10 Molecular Profiling, Precision Oncology, Sanofi, Paris/FR
  • 11 Oncology-omd, Sanofi, Cambridge/US
  • 12 Medical Oncology, Institut de Cancérologie de l'Ouest, 44805 - Saint-Herblain/FR
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Resources

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Abstract 277MO

Background

SAR439859 has antitumor activity in patients (pts) with wild type (WT) and mutated ESR1 mBC. Here we describe tumor molecular features and evidence of on target activity in SAR439859-treated pts.

Methods

Plasma circulating cell-free DNA (cfDNA) and paired biopsies were collected at baseline (BL), on treatment (OT) and end of treatment (EOT: cfDNA only) from heavily pretreated postmenopausal pts with ER+/HER2- mBC who received SAR439859 monotherapy (Part A: dose range 20–600 mg QD; Part B: 400 mg QD) in a phase I/II study (NCT03284957). In cfDNA at BL and EOT, mutation (mut) analysis was performed on a next generation sequencing panel of 77 genes. ESR1 muts in cfDNA at BL and OT were assessed by droplet digital polymerase chain reaction (ddPCR). In tumor tissue, ER and progesterone receptor (PgR), Ki67 and Bcl-2 expression over time were assessed by immunohistochemistry; changes in ER signaling pathway activation were assessed by gene set variation analysis (RNA sequencing). Response was assessed in pts who received SAR439859 ≥150 mg QD.

Results

At BL, in cfDNA from 63 pts, 95% had ≥1 mut, 52% had ≥1 ESR1 mut, 92% had ≥1 non-ESR1 mut and 49% had concurrent ESR1 and other muts. Most prevalent BL non-ESR1 muts were in PIK3CA (44% of pts), EGFR (33%), TP53 (30%) and MET (25%). ESR1 muts most commonly detected at BL and EOT were D538G, Y537S and Y537N. ESR1 muts tended to decrease OT; of 14 pts with ESR1 muts at BL, 2 had WT ESR1 OT. In 8 paired biopsies (7 were highly proliferative luminal B tumors), ER, PgR and Ki67 decreased (median relative change from BL: -58%, -88% and -33%), while Bcl-2 increased (24%). ER activation score decreased in 3/5 paired biopsies tested (median change from BL -0.38). SAR439859 showed clinical benefit (complete response + partial response [PR] + stable disease ≥24 weeks) in 40% (12/30) of WT ESR1 pts and 32% (9/28) of mutated ESR1 pts, per ddPCR. Of the 5 pts with PRs, 4 had WT ESR1 and 1 had 2 ESR1 muts, at BL.

Conclusions

Common genomic alterations, including in ESR1 and PIK3CA, were detected in most mBC pts. SAR439859 showed clinical benefit irrespective of ESR1 mut status and resulted in ER degradation and pathway inhibition in heavily pretreated pts.

Clinical trial identification

NCT03284957.

Editorial acknowledgement

Editorial support was provided by Jade Drummond and Michelle Daniels of inScience Communications, funded by Sanofi.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

S. Chandarlapaty: Honoraria (self): Paige.ai; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Daiichi Sankyo. A. Bardia: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Daiichi/AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: PUMA; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Radius Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Immunomedics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Foundation Medicine; Licensing/Royalties: Up-To-Date. S. Lord: Honoraria (self): Eisai; Honoraria (self): Prosigna; Advisory/Consultancy: Shionogi; Research grant/Funding (self): CRUK; Research grant/Funding (self): Against Breast Cancer; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Synthon; Travel/Accommodation/Expenses: Piqur Therapeutics; Shareholder/Stockholder/Stock options: Mitox. V. Pelekanou: Full/Part-time employment: Sanofi. N. Ternes: Full/Part-time employment: Sanofi R&D . J. Ming: Shareholder/Stockholder/Stock options, Full/Part-time employment: Sanofi. V. Boutet: Full/Part-time employment: Sanofi. E. Boitier: Full/Part-time employment: Sanofi. A. Gosselin: Full/Part-time employment: Sanofi. J. Sang Lee: Full/Part-time employment: Sanofi. W. Dos-Santos Bele: Full/Part-time employment: Sanofi. A. Protopopov: Full/Part-time employment: Sanofi. M. Celanovic: Full/Part-time employment: Sanofi. A-L. Bauchet: Honoraria (self), Full/Part-time employment: Sanofi. M. Campone: Honoraria (self), Advisory/Consultancy: GT1; Honoraria (institution), Advisory/Consultancy: Sanofi; Honoraria (institution), Advisory/Consultancy: Pierre Fabre; Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Servier; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: AbbVie; Honoraria (institution), Advisory/Consultancy: Accord; Honoraria (institution), Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: Novartis-Lilly. All other authors have declared no conflicts of interest.

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