Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer

2014 ◽  
Vol 57 (16) ◽  
pp. 6949-6964 ◽  
Author(s):  
John M. Lambert ◽  
Ravi V. J. Chari
Keyword(s):  
Breast Cancer ◽  
Trastuzumab Emtansine ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Drug Conjugate ◽  
Her2 Positive Breast Cancer ◽  
Antibody Drug ◽  
Positive Breast Cancer

Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer

2010 ◽  
Vol 28 (16) ◽  
pp. 2698-2704 ◽  
Author(s):  
Ian E. Krop ◽  
Muralidhar Beeram ◽  
Shanu Modi ◽  
Suzanne F. Jones ◽  
Scott N. Holden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Objective Response ◽  
Chemotherapeutic Agents ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Drug Conjugate ◽  
Her2 Positive Breast Cancer ◽  
Antibody Drug ◽  
Positive Breast Cancer

Purpose Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Patients and Methods Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Results Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. Conclusion At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.

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