Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1+docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1+docetaxel±pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).
Phase Ib (part 1) explored dose escalation, with T-DM1+docetaxel administered for ≥6 cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered ≤6 cycles of T-DM1+docetaxel or T-DM1+docetaxel+pertuzumab. Phase IIa explored the MTDs identified in phase Ib.
Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg)+pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (MBC, 72%; LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced adverse events requiring dose modification. In MBC (median prior systemic agents=5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel.
T-DM1 combined with docetaxel±pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced adverse events requiring dose reductions with these T-DM1-combinations.ClinicalTrials.gov identifier. NCT00934856.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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