Evaluation of the PI3K inhibitor BAY 80-6946 in hematologic malignancies.

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e13576 Background: BAY 80-6946 is a new investigational compound that potently inhibits all PI3K Class I isoforms. BAY 80-6946 is under phase 1 clinical evaluation and PRs have been observed in solid tumors (ST) and follicular lymphoma (FL). The present analysis was performed to gain mechanistic insights into the activity of this compound in FL and potentially other hematological malignancies. Methods: Preclinical: The growth-inhibitory activity of BAY 80-6946 on hematological cancer cell lines (n= 32) was determined by the CellTiterGlo assay. GS-1101 (formerly called CAL-101) and cisplatin (CP) were also tested. Clinical: Specimens from subjects enrolled in a BAY 80-6946 Phase 1 trial MTD expansion were used. Levels of various cytokines and chemokines were determined by ELISA or multiplex immunoassay in plasma samples (n= 27) obtained prior to and during BAY 80-6946 treatment of 6 subjects (3 FL + 3 ST). Proteins examined included CXCL13 (involved in B-cell homing) and BAFF (involved in B-cell survival). Tumor tissue was used to determine PTEN expression via IHC and the mutational status of PTEN via sequencing. PIK3CA mutational status was evaluated in tumor tissue and plasma via BEAMing. Results: Preclinical: BAY 80-6946 was more potent on B-cell lymphomas and other hematological cancer cell lines than GS-1101 or CP (median IC50 in μM: BAY 80-6946= 0.49; GS-1101= 37; CP= 2.9). Clinical: Plasma levels of CXCL13 decreased and BAFF increased following BAY 80-6946 administration in all subjects examined (CXCL13 mean change: -58%; p= 0.004; BAFF mean change: +67%; p= 0.042). PTEN expression was lower in FL compared to ST. No mutations in PTEN or PIK3CA were identified in FL. Mutations in PIK3CA were identified in some ST. Conclusions: These preclinical results indicate that the observed early clinical activity of BAY 80-6946 in FL may be due to a direct anti-proliferative effect on malignant B-cells. The plasma chemokine/cytokine results support the possibility that the modulation of factors involved in B-cell homing and survival may play a mechanistic role in mediating this activity. Overall these results support the continued clinical evaluation of BAY 80-6946 in FL and other hematological malignancies.