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Journal of Clinical Oncology, Vol 28, No 16 (June 1), 2010: pp. 2698-2704

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

Ian E. Krop, Muralidhar Beeram, Shanu Modi, Suzanne F. Jones, Scott N. Holden, Wei Yu, Sandhya Girish, Jay Tibbitts, Joo-Hee Yi, Mark X. Sliwkowski, Fred Jacobson, Stuart G. Lutzker, Howard A. Burris
From the Dana-Farber Cancer Institute, Boston, MA; Institute for Drug Development, San Antonio, TX; Memorial Sloan-Kettering Cancer Center, New York, NY; Sarah Cannon Research Institute, Nashville, TN; and Genentech, South San Francisco, CA.

Corresponding author: Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute, 44 Binney St, Mayer 2, Boston, MA 02115; e-mail: Ian_krop@dfci.harvard.edu.

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.

Supported by Genentech, South San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00932373 [ClinicalTrials.gov] .