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

Abstract

1028 Background: T-DM1 is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20–100 times more potently than vincristine. 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-sensitive and T-insensitive HER2+ BC xenografts. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T- DM1 given IV q3 wks to pts with advanced HER2+ BC who have progressed on a T-containing regimen. Dose levels for successive cohorts were doubled until a related gr 2 AE was observed. Further escalation utilized a 3+3 modified Fibonacci design. Results: Twenty-four pts (median age 50.5 [range 35–70]; all PS 0–1; median number prior metastatic chemo regimens 3 [range 1–7]) have received 156 doses of T- DM1 at 6 dose levels (0.3 mg/kg, 3 pts; 0.6 mg/kg, 1 pt; 1.2 mg/kg, 1 pt; 2.4 mg/kg, 1 pt; 3.6 mg/kg, 15 pts; 4.8 mg/kg, 3 pts). Related grade (gr) 1–2 AEs include TA elevations (gr 1, 5 pts; gr 2, 2 pts), thrombocytopenia (TCP; gr 1, 6 pts; gr 2, 3 pts), fatigue (gr 1, 5 pts; gr 2, 2 pts), anemia (gr 1, 4 pts; gr 2, 3 pts), and neuropathy (gr 1; 2 pts). Related gr 3–4 AEs include rapidly reversible TCP (gr 3, 1 pt; gr 4 [DLT], 2 pts both at 4.8 mg/kg) and neutropenia (gr 3, 1 pt). No cardiac-specific toxicity has been observed. T-DM1 clearance decreased with increasing dose as predicted preclinically. Six of 16 pts at 2.4 or 3.6 mg/kg have had partial responses (5 confirmed); 5 more have stable disease ongoing after 130 to 260 days. Conclusions: The MTD and recommended phase II dose of T-DM1 given IV q3 wks is 3.6 mg/kg. At the MTD, gr ≥2 AEs related to T-DM1 have been infrequent and manageable. T-DM1 PK is compatible with q3-week dosing. Objective tumor responses have been observed at doses at or below the MTD. A phase II trial in advanced HER2+ BC pts who have progressed on a T-containing regimen is underway; weekly dosing is also being explored. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.