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2016 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: 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) Presenter: Rashi Singh Division: Hematology & Oncology ☐ Faculty ☐ Fellow ☐ Resident ☐ Post-doc Research Fellow ☐ Graduate Student ☒ Medical Student ☐Other Principal Investigator/Mentor: Hurvitz S Co-Investigators: Martinez D, Taguchi J, Chan DS, Dichmann R, Castrellon, Barstis J, Hu E, Berkowitz J, Mani, DiCarlo B, Smalberg I, Hobbs E, Slamon D. Thematic Poster Category: Clinical Observations and Clinical Trials 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 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 patient 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 >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 using 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 was conducted (starting doses: L 1000mg QD, E 5mg QD, C 750 mg/m2 BID days 1-14). 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 6 weeks through cycle 6 and then every 9 weeks. 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 months. 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% has prior radiation and/or surgical resection of brain metastases. 10 patients participated in the dose escalation phase of the study. The maximum tolerated dosease were determined to be L 1000mg QD + C 1000 mg/m2 BID days 1-14 + E 10mg QD; however, given tolerability concerns, dose expansion proceeded with Cohort 2 dose for C (750 mg/m2 BID days 1-14). Of 17 eligible patients with imaging results available to date, 2 (12%) had a partial response in the CNS at week 12. One patient continues on study (currently cycle 13), the other patient came off treatment (PD) during cycle 12. 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 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.