Preclinical and Preliminary Clinical Activity of NVP-BKM120, an Oral Pan-Class I PI3K Inhibitor, in the Brain

ABSTRACT Background 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. Methods 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). Results 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. Conclusions 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. Disclosure 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.