Abstract 336P
Background
Mutations in p110α (gene, PIK3CA) occur in ∼40% of HR+/HER2– BC. GDC-0077 is a potent p110α-isoform selective inhibitor that degrades mutant (mut) p110α and elicits anti-tumour activity in PIK3CAmut preclinical models alone and with endocrine therapy (ET). We present a preliminary co-analysis of PI3K pathway biomarkers and clinical outcomes from patients (pts) with PIK3CAmut HR+/HER2– BC in an ongoing open-label, phase I/Ib dose-escalation study of GDC-0077, with ET (letrozole/fulvestrant) +/– palbociclib (NCT03006172; data cut 1 Jan 2020).
Methods
Paired tumour samples were analysed by immunohistochemistry for Ki67 and phosphorylated AKT/S6 (pAKT/pS6). PIK3CAmut were detected from plasma circulating tumour DNA. Samples were collected at baseline (BL) and cycle 1 day 15 (C1D15). Depth of pharmacodynamic (PD) inhibition of Ki67, pAKT/pS6 and of PIK3CAmut allele frequency ratio between BL and C1D15 (MAFr15) were correlated with GDC-0077 dose, tumour responses (FDG-PET), best confirmed/unconfirmed overall response (RECIST v1.1) and time on treatment (TOT). Statistical analyses: Pearson correlations, continuous variables; Kruskal-Wallis and Mann-Whitney-Wilcoxon, group and pairwise comparisons, respectively.
Results
PD inhibition of Ki67 expression correlated significantly with pAKT/pS6 PD inhibition (p < 0.03). PD inhibition of these markers did not correlate with GDC-0077 dose or ET+/– palbociclib regimen, likely due to the limited range of doses explored and limited tumour pairs. PD inhibition of Ki67/pAKT correlated significantly with FDG-PET response (p < 0.03); Ki67/pS6 PD inhibition correlated with best overall response (p < 0.03); only PD inhibition of Ki67 correlated significantly with TOT (p < 0.05). Median MAFr15 was lowest in pts with partial response (median MAFr15 0.02, n = 14 pts) and highest in pts with disease progression (1.00, n = 12 pts).
Conclusions
These data demonstrate the feasibility of using tumour-/blood-based PI3K pathway biomarkers as surrogates of response in pts with PIK3CAmut HR+/HER2– BC treated with GDC-0077 alone or with ET +/– palbociclib. Further analyses of these markers by treatment regimen are pending a more mature clinical dataset.
Clinical trial identification
NCT03006172.
Editorial acknowledgement
Support for third-party editing assistance for this abstract, furnished by Daniel Clyde of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
V. Gambardella: Research grant/Funding (institution), Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Research grant/Funding (institution): Genentech, Inc. A. Cervantes: Research grant/Funding (institution), Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Research grant/Funding (institution): Genentech, Inc. P.L. Bedard: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Advisory/Consultancy, Research grant/Funding (institution): BMS; Leadership role, Executive Board: Breast International Group ; Leadership role, Past Chair, Investigational New Drug Committe: Canadian Clinical Trials Group; Leadership role, Executive Committee: AACR Project Genie; Leadership role, Adviser: Melanie's Way; Leadership role, Associate Editor: Journal of the National Cancer Institute Cancer Spectrum; Leadership role, Section Editor: The Oncologist; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Genentech, Inc.; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PTC Therapeutics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Servier; Research grant/Funding (institution): SignalChem Life Sciences; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Nektar; Leadership role, Cancer Research Institute/Canadian Clinical Trials Group Joint Scientific Leadership Committee: Canadian Clinical Trials Group. E.P. Hamilton: Research grant/Funding (institution), Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Genentech, Inc.; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Puma Biotechnology; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Mersana Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Silverback Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Black Diamond; Advisory/Consultancy: NanoString; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Hutchinson MediPharma; Research grant/Funding (institution): OncoMed; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): StemCentrx; Research grant/Funding (institution): Curis; Research grant/Funding (institution): Verastem; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Rgenix; Research grant/Funding (institution): Millenium; Research grant/Funding (institution): TapImmune; Research grant/Funding (institution): BerGenBio; Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): H3 Biomedicine; Research grant/Funding (institution): Radius Health; Research grant/Funding (institution): Acerta; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): FujiFilm; Research grant/Funding (institution): Effector; Research grant/Funding (institution): Merus; Research grant/Funding (institution): Nucana; Research grant/Funding (institution): Regeneros; Research grant/Funding (institution): Leap Therapeutics; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): ArQule; Research grant/Funding (institution): Syros; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Cytomx; Research grant/Funding (institution): InventisBio; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Unum Therapeutics; Research grant/Funding (institution): Sermonix Pharmaceutical; Research grant/Funding (institution): Sutro; Research grant/Funding (institution): Aravive; Research grant/Funding (institution): Zenith Epigenetics; Research grant/Funding (institution): Arvinas; Research grant/Funding (institution): Harpoon; Research grant/Funding (institution): Fochon; Research grant/Funding (institution): Orinove; Research grant/Funding (institution): Molecular Templates; Research grant/Funding (institution): Compugen; Research grant/Funding (institution): G1Therapeutics; Research grant/Funding (institution): Karyopharm Therapeutics; Research grant/Funding (institution): Torque Therapeutics. A. Italiano: Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution), Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Honoraria (self): Springworks; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Epizyme; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pharmamar. K. Jhaveri: Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Genentech, Inc.; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Lilly Pharmaceuticals; Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (institution): ADC Therapeutics; Advisory/Consultancy: Taiho Oncology; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: AbbVie; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Novita Pharmaceuticals; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Debio Pharmaceuticals; Research grant/Funding (institution): Clovis Oncology. D. Juric: Advisory/Consultancy: Novartis, Genentech, EMD Serono, Eisai, Ipsen, Syros, Vibliome Therapeutics, Relay Therapeutics, MapKure, Petra Pharma, Silverback Therapeutics; Research grant/Funding (institution): Novartis, Genentech, Eisai, EMD Serono, Pfizer, Syros, Takeda, Amgen, InventisBio, Dizal Pharma, Celgene, Infinity Pharmaceuticals; Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd. K. Kalinsky: Speaker Bureau/Expert testimony: Lilly; Research grant/Funding (institution): Immunomedics, Novartis, Incyte, Genentech/Roche, Eli-Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zentalis Pharmaceuticals, and CytomX Therapeutics; Travel/Accommodation/Expenses: Lilly, AstraZeneca; Spouse/Financial dependant, Spouse was previously employed by Novartis, Array Biopharma, and Pfizer. Currently employed: Novartis, Array Biopharma, Pfizer; Non-remunerated activity/ies, Third-party editing assistance: F. 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Hoffmann-La Roche Ltd; Honoraria (self), Research Grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research Grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research Grant/Funding (institution): Genentech, Inc.; Advisory/Consultancy, Research Grant/Funding (institution): GSK; Advisory/Consultancy, Research Grant/Funding (institution): PUMA Biotechnology; Advisory/Consultancy, Research Grant/Funding (institution): AstraZeneca; Research Grant/Funding (institution): Philips Healthcare; Research Grant/Funding (institution): Immunomedics; Research Grant/Funding (institution): Boehringer-Ingelheim; Research Grant/Funding (institution): Zenith Epigenetics; Travel/Accommodation/Expenses: Pierre-Fabre; Travel/Accommodation/Expenses: GP Pharma; Travel/Accommodation/Expenses: Grünenthal; Travel/Accommodation/Expenses: Eisai; Non-remunerated activity/ies, Executive Board of the SOLTI Breast Cancer Group. C. Saura: Advisory/Consultancy: AstraZeneca, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon, Sanofi Aventis; Research grant/Funding (institution): AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Inc., Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon, Zenith PharmaD; Travel/Accommodation/Expenses: AstraZeneca, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon, Sanofi Aventis; Non-remunerated activity/ies, Third-party editing assistance: Non-remunerated activity(ies), F. Hoffmann-La Roche Ltd – Third-party editing assistance. P. Schmid: Advisory/Consultancy: Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, Puma; Research grant/Funding (institution): Roche, Genentech, Oncogenex, Novartis; Spouse/Financial dependant, Consulting: Genentech, Roche; Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd. N. Turner: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharpe and Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno pharmaceuticals, Repare therapeutics; Advisory/Consultancy: AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharpe and Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno pharmaceuticals, Repare therapeutics; Research grant/Funding (institution): AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Merck Sharpe and Dohme, Guardant Health; Non-remunerated activity/ies, Non-remunerated activity(ies), F. Hoffmann-La Roche Ltd – Third-party editing assistance: F. Hoffmann-La Roche Ltd. A. Varga: Research grant/Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Travel/Accommodation/Expenses: Boehringer Ingelheim, AstraZeneca; Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd. B.P. Liu: Full/Part-time employment: Genentech, Inc.; Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd. J.W. Chen: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc. J. Aimi: Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Third-party editing assistance: F. Hoffmann-La Roche Ltd; Full/Part-time employment: Genentech, Inc./F. Hoffmann-La Roche Ltd. S. 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