Background: Based on our preclinical data, we conducted a phase I study oftrastuzumab-emtansine (T-DM1) in combination with Lapatinib and Nab-paclitaxel in patients with HER2 over-expressed stage IV breast cancer. Methods: Phase Ib study was conducted using 3+3 dose de-escalation design, with TDM1 with Lapatinib and nab-paclitaxel administered for a total of 4 cycles. Primary purpose was to evaluate the maximum tolerated dose (MTD) of T-DM1 with Lapatinib and Nab-paclitaxel. Safety, tumor response and pharmacokinetics (PK) were also assessed. Dose limiting toxicities (DLTs) were defined as ≥ grade 3 non hematological toxicity attributed to the study drugs. Key inclusion criteria were stage IV HER2 positive breast cancer, LVEF ≥ 45%, and peripheral neuropathy < grade 2. Results: The MTD was T-DM1 3.0 mg/kg every 3 weeks along with Lapatinib 750mg oral daily and Nab-paclitaxel 80mg/m² weekly. Twenty four patients, median age 50 (47.9-55.9) years were enrolled. The dose limiting toxicities were diarrhea and elevated liver function tests. At MTD, 42.9% (6/14) experienced grade 3 or higher toxicity. Fourteen patients with median of 1 (range 0-5) prior metastatic treatments were evaluable for response. 12 patients (85.7%) had an objective response including 6 CR and 2 PR. T-DM1 pharmacokinetics was unaffected by Lapatinib. Conclusions: T-DM1 with Lapatinib and Nab-paclitaxel therapy was relatively well tolerated with significant anti-tumor activity observed. Clinical trial information: NCT02073916