Background: Although HER2-targeted therapy has improved outcomes in HER2+ breast cancer (BC) patients (pts), CNS mets continue to be a significant source of morbidity and mortality. Inability of drugs like trastuzumab to cross the blood-brain barrier (BBB) renders the CNS a sanctuary site for mets. L is a small molecule tyrosine kinase EGFR1/HER2 inhibitor that crosses the BBB and is active against CNS mets. C is a new taxane approved for prostate cancer that is also active in taxane-resistant metastatic breast cancer (MBC) and distinguishes itself by its ability to cross the BBB. The activity shown by C in taxane-resistant MBC as well as the CNS penetrance of both C and L make this an attractive combination for HER2+ MBC pts with CNS mets. Methods: This is an open-label, non-randomized, phase II study with a lead-in safety cohort (NCT01934894). Pts ≥ 18 yrs with HER2+ (by FISH or IHC 3+) MBC and CNS mets are eligible. Patients must have either at least 1 untreated measurable CNS lesion ≥ 5mm in longest dimension on MRI or at least 1 previously treated (by WBRT and or/SRS) CNS lesion with evidence of intra-cranial disease progression following WBRT or SRS. Pts must have had at least 1 prior HER2 therapy; first line MBC pts are eligible only if they progressed during or within 6 mos of adjuvant therapy. Prior treatment (tx) with C is not permitted. During the lead-in, cohorts of 3 pts will be treated with escalating doses of q 3 weeks (wks) C and daily L to determine the tolerability and optimal dose. Subsequent pts will be treated with the identified optimal dose combination. Each tx cycle is 3 wks and systemic and intra-cranial disease restaging will occur every 2 cycles for the first 8 cycles and then every 3 cycles until PD or unacceptable toxicity. The primary study objectives are to determine the safety and CNS ORR (ORR=CR+PR) of the combination of C and L in HER2+ MBC pts. Secondary objectives include evaluation of the clinical benefit rate ([CBR]CR+PR+SD ≥ 6 mos), 3- and 6-mo PFS rate for CNS mets, and response rate and CBR for extra-cranial mets. The trial is ongoing. Clinical trial information: NCT01934894.