Meeting
2019 ASCO Annual Meeting
Exploratory analysis of the effect of taselisib on downstream pathway modulation and correlation with tumor response in ER-positive/HER2-negative early-stage breast cancer from the LORELEI trial.
Authors
Paolo Nuciforo
Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Paolo Nuciforo , Dominik Hlauschek , Cristina Saura , Evandro de Azambuja , Roberta Fasani , Patricia Villagrasa , Karoline Muehlbacher , Christos Sotiriou , Aleix Prat , Georg Pfeiler , Florentine Hilbers , Timothy R. Wilson , Junko Aimi , Thomas Stout , Vicente Valero , Christian Fesl , Jose Baselga , Michael Gnant , Martine Piccart , Fabrice Andre
Organizations
Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, ABCSG, Wien, Austria, Vall d’Hebron University Hospital, Barcelona, Spain, Institut Jules Bordet, Brussels, Belgium, SOLTI Breast Cancer Research Group, Barcelona, Spain, ABCSG, Vienna, Austria, Department of Medical Oncology, Hospital Clinic, Barcelona, Spain, Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Breast International Group, Brussels, Belgium, Genentech, Inc., San Francisco, CA, Genentech, South San Francisco, CA, Genentech, Inc., South San Francisco, CA, University of Texas MD Anderson Cancer Center, Houston, TX, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Memorial Sloan Kettering Cancer Center, New York, NY, Medical University of Vienna, Vienna, Austria, Institut Gustave Roussy, Villejuif, France
Research Funding
Pharmaceutical/Biotech Company
Background: Taselisib (T) is an oral, potent, selective inhibitor of Class I PI3-kinase with enhanced activity against PIK3CA mutant cancer cells. Results from the LORELEI trial have demonstrated a significant improvement in ORR (objective response rate) by centrally assessed magnetic resonance imaging in all randomized patients as well as in the PIK3CA mutant (MT) cohort treated with neoadjuvant T plus letrozole (L) compared to placebo (P) plus L. Here we present the results of exploratory analyses of selected pathway-related phosphoproteins. Methods: Baseline (BL) and week3 (W3) tumor biopsies were obtained from 334 patients enrolled in the trial. Phosphoproteins (pAKT, pPRAS40 and pS6) were analyzed by IHC. BL levels as well as changes from BL to W3 were correlated with response assessed either by ORR or cell cycle arrest (Ki67 at W3 < 2.7%). Results: In the overall population, BL phosphoproteins levels were similar between the T and P arms. Higher pAKT (p < 0.001) and pPRAS40 (p = 0.004) levels were observed in MT vs wild-type (WT), whereas the opposite result was found for pS6 (p = 0.03). Treatment-induced absolute changes of phosphoproteins adjusted for BL levels were not significantly different between the T and P arms in the overall population, except for pPRAS40 with higher decrease in the T arm (p = 0.014). After stratification for PIK3CA genotype, a significantly greater decrease in expression levels was observed for pPRAS40 (p < 0.001) and pS6 (p = 0.020) in MT tumors treated with T. The treatment effects were not significantly different in the WT population. A trend for an association between decrease in pS6 levels at W3 and improved ORR was observed in the MT (p = 0.08) and T (p = 0.09) subgroups. The magnitude of pS6 suppression at W3 was higher in tumors achieving a cell cycle arrest in the MT/T subgroup (biserial correlation = -0.473). Conclusions: Exploratory analyses of phosphoproteins showed bioactivity of taselisib as indicated by downstream pathway suppression. Translational research aiming to integrate these results with additional exploratory biomarkers data is currently ongoing. Clinical trial information: NCT02273973
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Abstract Details
Session Type
Poster Session
Session Title
Breast Cancer—Metastatic
Track
Breast Cancer
Sub Track
Hormone Receptor-Positive
Clinical Trial Registration Number
NCT02273973
Citation
J Clin Oncol 37, 2019 (suppl; abstr 1050)
DOI
10.1200/JCO.2019.37.15_suppl.1050
Abstract #
1050
Poster Bd #
131
Abstract Disclosures
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