Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 1042
© 2007 American Society of Clinical Oncology

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Abstract

A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC)

The Institute for Drug Development, San Antonio, TX; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Genentech, Inc., South San Francisco, CA; Sarah Cannon Cancer Center, Nashville, TN

1042

Background: ADCs utilize tumor-specific and/or over-expressed surface antigens that undergo internalization to deliver highly potent anti-tumor agents via linkage to antigen-specific monoclonal antibodies (MoAbs). T-DM1 contains the humanized anti-HER2 MoAb trastuzumab (T) previously demonstrated to prolong survival in HER2+ BC to which a highly potent antimicrotubule drug (DM1) derived from maytansine has been chemically linked. Maytansine has been studied as a free drug with responses noted in breast and lung cancer pts; principal adverse events (AEs) were nausea, vomiting, diarrhea, and neuropathy. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials. T-DM1 has activity in T-resistant HER2+ BC xenografts; its principal preclinical toxicities were reversible transaminase elevations, reversible decreases in platelets, and neuropathy. Methods: This ongoing first-in-human phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV q3 weeks to pts with HER2+ metastatic BC who have progressed on a T-containing regimen. Results: Seven pts (median age 58 (range 47–70); all PS 0–1; median number prior chemo regimens 6 (range 5–11)) have received 24 doses of T-DM1 at 5 dose levels (0.3–4.8 mg/kg). Related grade (gr) 1–2 AEs include elevations in hepatic transaminases (2 pts), fatigue (2 pts), anemia (1 pt), and thrombocytopenia (TCP, 1 pt). Related gr 3–4 AEs have been limited to rapidly reversible gr 4 TCP at 4.8 mg/kg (1 pt). There has been no cardiac toxicity. Consistent with preclinical modeling, dose dependent decrease in clearance was observed for T-DM1 across dose levels. One pt at 2.4 mg/kg has maintained an ongoing partial response for 6 cycles. Conclusions: At these initial doses, gr =2 AEs related to T-DM1 have been infrequent and manageable; gr 4 (dose-limiting) rapidly reversible TCP was seen at 4.8 mg/kg. T-DM1 PK is consistent with q3-week dosing. Objective tumor response has been observed. Enrollment is ongoing to determine the maximum tolerated dose of q3-week T-DM1.

No significant financial relationships to disclose.

Abstract presentation from the 2007 ASCO Annual Meeting