451PD - Phase I study of the PI3Kα inhibitor BYL719, as a single agent in patients with advanced solid tumors (aST)

Date 28 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Clinical Research
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Dejan Juric
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors D. Juric1, H. Burris2, M. Schuler3, J. Schellens4, J. Berlin5, R. Seggewiß-Bernhardt6, M. Gil-Martin7, A. Gupta8, J. Rodon9, J. Tabernero10, F. Janku11, H.S. Rugo12, D. Bootle13, C. Quadt14, C. Coughlin15, D. Demanse16, L. Blumenstein17, J. Baselga18
  • 1Department Of Hematology And Medical Oncology, Massachusetts General Hospital, 02114 - Boston/US
  • 2Dept. Drug Development, Sarah Cannon Research Institute, US-37203 - Nashville/US
  • 3Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Essen/DE
  • 4Clinical Pharmacology & Medical Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 5Dept. Medical Oncology, Vanderbilt Ingram Cancer Center, US-37232-6307 - Nashville/US
  • 6Oncology, CCC MF, Uni-Klinikum Würzburg, Wurzburg/DE
  • 7Medical Oncology, Catalan Institute of Oncology-IDIBELL, 08907 - Barcelona/ES
  • 8Medical Oncology, Churchill Hospital Cancer Centre, OX3 7LJ - Oxford/GB
  • 9Oncology, Vall d`Hebron Institute of Oncology, 08035 - Barcelona/ES
  • 10Medical Oncology Department, all d`Hebron Institute of Oncology, ES-08035 - Barcelona/ES
  • 11Investigational Cancer Therapeutics, MD Anderson Cancer Center, US-77030-4095 - Houston/US
  • 12Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, 94115 - San Francisco/US
  • 13Clinical Trials, Novartis Pharma AG, Basel/CH
  • 14Clinical Trials, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 15Oncology Translational Medicine, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 16Oncology Translational Medicine - Lead Statistician, Novartis Pharma AG, Basel/CH
  • 17Clinical Pharmacology, Novartis Pharma AG, Basel/CH
  • 18Hematology Oncology, Memorial Sloan-Kettering Cancer Center, 10128 - New York/US



BYL719 is a selective oral inhibitor of the Class l PI3K α-isoform. PI3Kα is encoded by PIK3CA, a frequently altered gene in human cancers. This was a Ph I, dose-escalation and -expansion, first-in-human study of BYL719 in pts with PIK3CA-altered aST, or PIK3CA-altered or wild-type (wt) ER+ breast cancer (BC) (NCT01219699).


Adult pts with advanced PIK3CA-altered (mutation or amplification) aST received oral BYL719 QD or BID (28-day cycles). Pts with PIK3CA wt ER+ BC were also enrolled into the dose expansion. A Bayesian logistic regression model with overdose control guided dose escalation. Primary objective was to determine MTD and/or RP2D of single-agent BYL719. Safety (CTCAE v4.0), tolerability, PK, preliminary efficacy (RECIST) were also assessed.


As of Mar 10, 2014, 132 pts received BYL719 QD (30–450 mg) or BID (120, 150, 200 mg). Median exposure was 11.9 (0.4–98) wks. DLTs were reported in: 4 pts (hyperglycemia x2, nausea x2) at 450 mg QD, 4 pts (hyperglycemia x4) at 200 mg BID, and 1 pt (hyperglycemia and hypophosphatemia) at 150 mg BID. BYL719 QD MTD is 400 mg (and was used for dose expansion); here, BYL719 BID MTD is declared as 150 mg. Most common (≥20%) suspected study drug-related all-Grade AEs at the MTDs were: BYL719 150 mg BID (n = 15) – hyperglycemia, nausea (both 53%), diarrhea, decreased appetite, fatigue, stomatitis (all 33%); and BYL719 400 mg QD (n = 63 including dose expansion) – hyperglycemia (51%), nausea (48%), diarrhea (41%), decreased appetite (38%), fatigue (32%), vomiting (30%), rash (20%). Overall, 15 of 131 evaluable pts had partial responses (PRs; incl. 2 [out of 24 pts] with PIK3CA-altered ER+ BC); 7 PRs were confirmed: 2 at 270 mg QD, 1 at 350 mg QD, 2 at 400 mg QD, 2 at 150 mg BID. Disease control rates (CR, PR, or SD) at MTDs were: BYL719 400 mg QD – 53%; and BYL719 150 mg BID – 67%. Median PFS at ≥270 mg in ER+ HER2– BC (n = 21) was 166 days. In pts with PIK3CA wt ER+ BC (n = 5) duration of exposure range was 7–61 days; no PRs were observed in wt pts.


BYL719 is the first α isoform-specific PI3K inhibitor to show single-agent responses in tumors with activating mutations. The safety profile was favorable with mostly on-target effects (i.e. hyperglycemia). Data comparing PIK3CA-altered and wt ER + /HER2– BC pts will be presented.


D. Juric: I have participated on scientific advisory board meetings for Novartis. No other conflicts of interest; M. Schuler: Ad Board/Consultant (Compensated): AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer Research grants: Boehringer Ingelheim, Novartis Honoraries for CME lectures: Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer; J. Berlin: Vanderbilt Cancer Center receives research support from Novartis for this trial. I personally do not receive funding; R. Seggewiß-Bernhardt: I have been on the Novartis' advisory board meeting "From bench to bed - Anforderungen an Translationale Konzepte", 5 & 6 March 2014 in Basel, Switzerland; J. Rodon: Attendance as consultant to a Novartis Advisory Board that was compensated; J. Tabernero: Consultant or advisory role: Amgen, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Roche, Sanofi, Celgene, Chugai and Taiho; F. Janku: I have research funding from Novartis; H.S. Rugo: I received Research Support on behalf of my university to conduct trials from Novartis. I have received travel support from Novartis; D. Bootle: I am an employee of Novartis, C. Quadt: I am employee of Novartis Oncology and own Novartis shares; C. Coughlin: I am an employee of Novartis; D. Demanse: I have an employment to disclose: Statistician at Novartis; L. Blumenstein: I am an employee of Novartis. All other authors have declared no conflicts of interest.