Gerburg M. Wulf and Ursula A. Matulonis contributed equally to this work CONTRIBUTORS PAK contributed to study concept, design, oversight, data collection and interpretation and writing of the manuscript. WTB contributed to the study design, data analysis and interpretation, writing and creation of figures. MB, LCC, JFL, MKB contributed to patient recruitment and study design and conception. CA and RLC and SNW contributed to the study design, data interpretation, critically reviewed manuscript drafts. ROC contributed to patient data collection, data interpretation and critically reviewed manuscript drafts. CA and RLC contributed to patient data collection. SHK contributed to data interpretation and writing. JE contributed preclinical data and data interpretation. GC contributed data analysis, data interpretation, manuscript writing. JC contributed to data collection. PK contributed to study oversight, data collection and interpretation. BK contributed to preclinical and correlative work. SP contributed to preclinical work supporting this study. EW contributed to patient recruitment, study design and conception. SF contributed to collection and assembling of data. CW contributed to data collection and assembly. KC contributed to data interpretation, critically reviewed manuscript drafts, and contributed to patient data collection. ELM contributed to patient recruitment, study design and conception. WL contributed to study design, data analysis, data interpretation, reviewed manuscript drafts. GBM contributed to the development of the concepts and the initiation of the trial. EMS contributed to the study design, data collection, data analysis, data interpretation and critically reviewed manuscript drafts. ADD performed preclinical studies supporting this paper. GMW contributed to study design, data collection, analysis and interpretation, writing. UAM contributed to the initial study design, holds the FDA IND for this study, enrolled patients to this trial, contributed to data collection, data interpretations and analysis, reviewed manuscript drafts. All authors participated in writing the paper and approved the final version of the paper.

BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.