1675P - Preclinical and preliminary clinical activity of NVP-BKM120, an oral pan-class I PI3K inhibitor, in the brain

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Clinical research
Basic Scientific Principles
Presenter Michel Maira
Authors M. Maira1, C. Schnell1, P. Lollini2, C. Chouaid3, P. Schmid4, P. Nanni5, D. Lam6, E. Di Tomaso7, C. Massacesi8, J. Rodon9
  • 1Oncology, Novatis Institute for Biomedical Research, 4002 - Basel/CH
  • 2Department Of Hematology And Oncological Sciences, University of Bologna, Bologna/IT
  • 3Pneumologie, Hopital Saint-Antoine, 75012 - Paris/FR
  • 4Medical Oncology, Brighton and Sussex Medical School, BN1 9PX - Brighton/UK
  • 5Department Of Experimental Pathology, University of Bologna, Bologna/IT
  • 6Oncology, Novartis, NJ - Florham Park/US
  • 7Institutes For Biomedical Research, Novartis, MA - Cambridge/US
  • 8Oncology, Novartis, Paris/FR
  • 9Vall d'Hebron University Hospital, Barcelona/ES



New therapies that penetrate the blood–brain barrier (BBB) are needed to combat brain metastases (BM). Activity of BKM120, an oral pan-class I PI3K inhibitor, in the brain was assessed in vivo, with additional evidence collected from Ph I/II clinical trials.


The ability of BKM120 to penetrate the BBB and inhibit PI3K signaling was determined by: (1) comparison of IHC staining of insulin-induced S473P-AKT levels in the brains of untreated/BKM120-treated (5 mg/kg, po, once) rats; and (2) regular monitoring of drug concentrations and S473P-AKT levels over 24 hrs upon BKM120 (50 mg/kg, po, once) or pan-PI3K inhibitor GDC0941 (150 mg/kg, po, once) treatment in plasma, tumor and brain tissue of Rat1-myr-p110 tumor-bearing (subcutaneous) mice. Activity of BKM120 against BM was also assessed in 1 preclinical model of HER2+ breast cancer (BC) BM and in 2 clinical trials of pts with advanced solid tumors (CBKM120X2101) and metastatic NSCLC (CBKM120D2201).


BKM120 strongly reduced insulin-induced S473P-AKT in the brain vs. untreated controls, with the most notable effects observed in the cerebellum. Uptake of BKM120 in Rat1-myr-p110 tumor-bearing mice over 24 hrs was similar across plasma, tumor and brain tissues, with the highest concentration of BKM120 at 1 hr post-administration. At this time point, BKM120 completely reduced S473P-AKT in both tumor and brain samples. In contrast, uptake of GDC0941 was undetectable in the brain and had no effect on S473P-AKT levels in this tissue. Uptake of GDC0941 and inhibition of S473P-AKT was similar to BKM120 in plasma and tumor. In addition, BKM120 strongly inhibited growth of BM by human HER2+ BC cells MDA-MB-453 in immunodeficient Rag2−/-/Il2rg−/- mice. In 2 clinical trials, 4 pts with BM have been treated with single-agent BKM120 to date: 1 pt with metastatic BC had a 29% reduction in a brain lesion, while disappearance of a non-target brain lesion was seen in 1 pt with squamous NSCLC.


Preclinical data suggest that BKM120 penetrates the BBB and inhibits PI3K signaling in the brain. This unique property of BKM120 is not a class effect. Preliminary clinical evidence supports these findings. Clinical trials of BKM120 in pts with BM are planned.


M. Maira: Stock ownership and employee of Novartis.

C. Schnell: Stockholder and employee of Novartis.

C. Chouaid: Member of the advisory boards for Lilly, Amgen, Roche and has undertaken research sponsored by Lilly, Amgen, Roche, Novartis and AstraZeneca.

D. Lam: Employee of Novartis.

E. Di Tomaso: Employee of Novartis.

C. Massacesi: Employee of Novartis.

All other authors have declared no conflicts of interest.