A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer.
BACKGROUND
We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here.


METHODS
Patients were administered escalating doses of T-DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics.


RESULTS
Twenty-eight patients received weekly T-DM1, and the MTD was determined to be 2.4 mg/kg. In general, T-DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade ≥ 3 AEs were reported in 19 patients (67.9%); treatment-related AEs occurred in 25 (89.3%) patients. Exposure to weekly T-DM1 was dose-proportional at ≥ 1.2 mg/kg, and accumulation of T-DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6-month clinical benefit rate was 57.1%.


CONCLUSIONS
The results suggest that a weekly dose of T-DM1 2.4 mg/kg has antitumor activity and is well tolerated in patients with HER2-positive metastatic breast cancer.
Institute for Drug Development, San Antonio, Texas. murali.beeram@stoh.com.
Muralidhar
M
Beeram
Ian E
IE
Krop
Howard A
HA
Burris
Sandhya R
SR
Girish
Wei
W
Yu
Michael W
MW
Lu
Scott N
SN
Holden
Shanu
S
Modi
D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab
D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human