442O - PI3K kinase inhibitor GSK2126458 (GSK458): clinical activity in select patient (pt) populations defined by predictive markers (study P3K112826)

Date 29 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Clinical research
Basic Scientific Principles
Presenter Pamela Munster
Authors P. Munster1, J. Specht2, T.L. Werner3, E..C. Dees4, A. Tan5, J. Schellens6, M.P. Lolkema7, D.A. Smith8, S.R. Morris8, R. Kurzrock9
  • 1University of California, San Francisco, San Francisco/US
  • 2University Of Washington Division Of Medical Oncology, Fred Hutchinson Cancer Research Center, Seattle/US
  • 3Dept. Of Internal Medicine, Oncology Division, University of Utah School of Medicine, Salt Lake City/US
  • 4Developmental Therapeutics Working Group Chair, UNC Lineberger Cancer Comprehensive Cancer Center, Chapel Hill/US
  • 5Breast Medical Oncology And Phase I Program, The Cancer Institute of New Jersey, New Brunswick/US
  • 6Medical Oncology, The Netherlands Cancer Institute, Amsterdam/NL
  • 7Dept Of Medical Oncology, University Medical Center Utrecht, Utrecht/NL
  • 8Research And Development, Oncology, GlaxoSmithKline, Research Triangle Park/US
  • 9Department Of Investigational Cancer Therapeutics, UT MD Anderson Cancer Center, Houston/US




GSK458 is an oral, potent inhibitor of PI3K (α, �, γ, &dgr;), mTORC1, and mTORC2. Cell lines with activation of the PI3K pathway are more likely to be sensitive to GSK458.


Pts with advanced solid tumors received GSK458 until disease progression or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID) was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type [WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer, and KRAS-WT metastatic endometrial cancer) were evaluated.


170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from 0.1 to 3 mg, the MTD for both QD and BID was 2.5 mg. The median (range) time above the target plasma concentration (20 ng/mL) was longer in BID versus QD dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response relationship between GSK458 plasma concentrations and increases in serum insulin levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none had responses per RECIST. Objective responses were seen in bladder cancer (1/3 PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months, 1PR), but no responses were seen in PIK3CA-mutant breast cancer (1/10: stable for >6 months) or KRAS-WT endometrial cancer (1/12: stable disease for > 6 months).


Based on its superior pharmacokinetic profile, BID is the recommended schedule for GSK458 monotherapy. Surrogate PD markers (insulin) indicate on target activity. GSK458 showed promising activity in PIK3CA mutant bladder cancer and RCC.


P. Munster: Phase I Research: GSK

J. Specht: Corporate-sponsored research: Pfizer, BMS, Genentech, BiPar Sciences, Boehringer Ingelheim

E.C. Dees: Corporate-sponsored research: GSK, Novartis, Genentech/Roche, Millennium

A. Tan: Corporate-sponsored research: GSK

A. Daud: Membership on an advisory board or board of directors: Oncosec; Corporate-sponsored research: GSK, Pfizer, Merck, Oncosec, Exelixis

G. Falchook: Corporate-sponsored research: GSK; GSK Travel reimbursement for ESMO 2010

J. F. Kleha: Stock ownership: GSK; GSK Employee

M. Durante: Stock ownership: GSK; GSK Employee

D.A. Smith: Stock ownership: GSK; GSK Employee

L. Adams: Stock ownership: GSK; GSK Employee

J. Greshock: Stock ownership: GSK; GSK Employee

S.R. Morris: Stock ownership: GSK; GSK Employee

All other authors have declared no conflicts of interest.