PD09-05: SU2C Phase Ib Study of pan-PI3K Inhibitor BKM120 Plus Aromatase Inhibitor Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC).

摘要: Background: Experimental evidence and clinical data suggest that PIK3CA mutations (present in approximately 35% of ER+ cancers) are associated with de novo or acquired resistance to antiestrogen therapy. Considering most breast cancers resistant therapy retain ER estrogen sensitivity, treatment single-agent PI3K-targeted may be insufficient inhibit tumor growth. Materials Methods: To evaluate safety/tolerability, we initiated a phase Ib trial letrozole the pan-PI3K inhibitor BKM120 (Novartis) post-menopausal patients ER+/HER2−MBC. Letrozole (2.5 mg/d) (100 were given on 28-day cycle. When necessary, was reduced 80 60 mg/day. Treatment continued until unacceptable toxicity progression disease. Disease assessed every 2 months. FDG-PET imaging performed at weeks identify changes indicative pharmacodynamic modulation PI3K/AKT. Results: Twenty have been accrued; all but had previously progressed an aromatase (AI) metastatic setting. Median age 56 years; 85% bone disease, 70%, visceral metastases. Twelve still treatment, these currently Three discontinued within months initiation due grade 3 transaminitis, irritability, hyperglycemia, despite dose reductions and/or optimal treatment. Most common toxicities summarized table below. Transaminase elevation only DLT 100 mg/d BKM120. Of 12 evaluable completed least 8 1 partial response, 7 stable 4 disease (RECIST). So far for >4 Over 50% >25% reduction their peak SUV 2-week scan. Discussion: The + combination is active ER+/HER2− MBC refractory previous AI. At this time, patients’ primary diagnostic biopsies being analyzed presence PIK3CA, AKT1, PTEN loss (immunohistochemistry). appears useful biomarker PI3K pathway inhibition. Correlation mutational analysis benefit will presented meeting. Despite overall safe side effect profile, alternative administration schedule planned enhance tolerability combination. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-05.