Download 2016 department of medicine research day

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.