Abstract P1-12-07: Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of patients with HER2-positive metastatic breast cancer with progression in the CNS after trastuzumab (TRIO-US B-09)
Authors: Hurvitz SA , Martinez DA , Singh R , Taguchi J , Chan D , Dichmann R , Castrellon A , Barstis J , Hu E , Berkowitz J , Mani A , DiCarlo B , Smalberg I , Hobbs E , Slamon DJ 
Published: March 2017

Abstract
Background: Improving outcomes for patients with HER2+ CNS metastases remains an unmet clinical need. Lapatinib (L) plus capecitabine (C) yields a 20% objective response rate (ORR) in the CNS in patients with previously treated HER2+ breast cancer brain metastases (Lin N, Clin Cancer Res 2009). Everolimus (E), an oral inhibitor of the mammalian target of rapamycin (mTOR), penetrates into the CNS in murine xenograft models (Meikle L, J Neurosci 2008). TRIO-US B09 is an investigator-initiated trial evaluating the safety and clinical activity of the novel combination of L+C+E for the treatment of patients with HER2+ breast cancer brain metastases.
Methods: Patients with trastuzumab-pretreated, HER2+ metastatic breast cancer (MBC) with progression of disease (PD) in the brain and a measurable brain lesion participated. Patients were excluded if they had a prior mTOR inhibitor or an ECOG PS&gt;2. Prior L and/or C, and prior surgery and/or radiation to the brain were allowed. The primary endpoint was CNS ORR at 12 weeks (cycle 3) by RECIST 1.1. Secondary endpoints included safety, progression-free survival, overall survival and extra-CNS ORR. To test the safety of the combination of L+C+E, a 3+3 dose escalation phase was conducted (starting doses: L 1000 mg QD, E 5 mg QD, C: 750 mg/m2 BID d1-14). Treatment was given Q21 days. Patients were evaluated for dose limiting toxicities during C1. Tumor imaging was conducted every 3 cycles. MRI of the brain was performed every 2 cycles through cycle 6 and then every 3 cycles. Neurological symptom assessment was conducted on day 1 of every cycle. Study participants continued to receive treatment until PD, unacceptable toxicity or withdrawal of consent for 12 mos.
Results: Nineteen patients were enrolled at 11 sites in the US and treated with at least one dose of study drug. Of 18 patients with data available, median age was 58.5 (45-68), median number of systemic therapies for MBC was 2 (0-6), and 94.4% had prior radiation and/or surgical resection of brain metastases. 10 patients participated in the dose escalation phase of the study. The maximum tolerated doses were determined to be L 1000 mg QD, E 10 mg QD + C 1000 mg/m2BID days 1-14; however, given tolerability concerns, dose expansion proceeded with Cohort 2 dose for C (750 mg/m2 BID d1-14). Of 17 eligible patients with imaging results available to date, 2 (12%) had a partial response in the CNS at week 12, one of whom continues on study (currently in cycle 13). Stable disease was observed in 7 patients. The most common grade 3/4 adverse events (AE) (CTCAE v4.0) related to E and/or L in 18 treated patients were anorexia (5.5%), dehydration (5.5%), diarrhea (17%), fatigue (5.5%), fever (5.5%) hyperglycemia (5.5%), hypokalemia (11%), and oral mucositis (17%).
Conclusions: This is the first report of this regimen for patients with HER2+ MBC to the brain. This regimen is generally well-tolerated and shows promising activity in the CNS of heavily pretreated patients. Final efficacy and toxicity analyses for all 19 patients will be presented.
Citation Format: Hurvitz SA, Martinez DA, Singh R, Taguchi J, Chan D, Dichmann R, Castrellon A, Barstis J, Hu E, Berkowitz J, Mani A, DiCarlo B, Smalberg I, Hobbs E, Slamon DJ. Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of patients with HER2-positive metastatic breast cancer with progression in the CNS after trastuzumab (TRIO-US B-09) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-07.