A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients (pts) with advanced HER2+ breast cancer (BC)

Abstract

1029 Background: T-DM1 is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive BC, and 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. T-DM1 binds to HER2 without inducing downregulation with affinity similar to T. T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts; principal preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. In a phase I study of T-DM1 given every 3 weeks, the MTD was 3.6 mg/kg, with DLT of gr 4 thrombocytopenia (TCP); tumor responses were seen at doses at or below MTD. The effect of more frequent dosing of T-DM1 on its exposure and safety profile is unknown. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV once weekly to pts with advanced HER2+BC who have progressed on a T- containing regimen. Dose levels for successive cohorts are escalated if DLT is observed in <1/3 of pts within 21 days of first study treatment according to a 3+3 evaluation scheme. Results: Seven pts (median age 53 (range 44–63); all PS 0–1); median number prior metastatic chemo regimens 2 (range 1–4) have received 72 doses of T-DM1 at 3 dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 1 pt) on a weekly schedule. Related mild-moderate AEs include fatigue (grade [gr] 1, 3 pts; gr 2, 1 pt), TA elevations gr 2, 1 pt), and headache (gr 2; 1 pt). Related gr >2 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt). No cardiac-specific toxicity has been observed. No DLTs have been observed. Concentration-time profiles appear consistent with predictions based on allometric scaling. Four pts have had partial responses (none confirmed as of the data cutoff date). Conclusions: Related gr ≥2 AEs have been infrequent and manageable, and objective tumor responses observed, on a weekly schedule of T-DM1. Dose escalation will continue until an MTD is identified. A phase II trial of T-DM1 on a q3-week schedule in advanced HER2+ BC is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech, Inc. Genentech™ BioOncology Genentech, Inc. Genentech, Inc.