Issue 1 - San Antonio Breast Cancer Symposium

Abstract 710
A phase 2 study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer (MBC)
patients previously treated with conventional chemotherapy, lapatinib and trastuzumab
Ian Krop, Dana Farber Cancer Institute, Boston, MA; Patricia LoRusso, Karmanos Cancer Institute, Detroit, MI; Kathy D. Miller,
Indiana University Melvin-Bren Simon Cancer Center, Indianapolis, IN; Shanu Modi, Memorial Sloan-Kettering Cancer Center, New
York, NY; Denise Yardley, Sarah Cannon Research Institute, Nashville, TN; George Rodriguez, South Texas Oncology/Hematology,
San Antonio, TX; Sam Agresta, BioOncology, Genentech, South San Francisco, CA; Maoxia Zheng, BioOncology, Genentech, South
San Francisco, CA; Lukas Amler, BioOncology, Genentech, South San Francisco, CA; Hope Rugo, UCSF Comprehensive Cancer
Center, San Francisco, CA
Background: T-DM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of the anti-microtubule
agent DM1. In a prior phase 2 study, single agent T-DM1 was well tolerated and had significant activity (objective response rate
[ORR] of 26% by independent review [IRF]) in 112 patients (pts) with pre-treated HER2+ MBC (Vogel CL et al, J Clin Oncol, 27:15s,
2009 [suppl; abstr 1017]). To confirm and extend these findings, we conducted a phase 2 study that enrolled a more homogenous
population of HER2+ MBC pts who had all received prior anthracycline, taxane, capecitabine, trastuzumab, and lapatinib therapy
and progressed on the last regimen received (at least 2 HER2-directed regimens had to be given for metastatic disease).
Methods: This is an open-label, single-arm study of T-DM1 given at 3.6 mg/kg IV q3w. Primary objectives are to assess ORR by
IRF and evaluate the safety of T-DM1. Key secondary objectives assess the clinical benefit rate (CBR = ORR + stable disease [SD]
at 6 months), duration of response (DoR) and progression-free survival (PFS). Pts remain on study until disease progression
or unmanageable toxicity. Key exploratory objectives were the assessment of ORR and clinical benefit rate (CBR) by IRF in
retrospectively tested, centrally confirmed HER2+ patients.
Results: The study completed enrollment of 110 patients. This analysis has a median follow-up of 8.3 months (range 0.7-13.1).
Median age was 52.5 y (range 34–77). Pts received a median of 7 agents for metastatic disease (range 1–15). Median
durations of prior trastuzumab and lapatinib treatment in metastatic setting were 19.4 and 6.9 months respectively. The
ORR was 32.7% and the CBR was 44.5% by IRF. Median DoR and PFS have not reached maturity. In retrospectively tested,
centrally confirmed HER2+ patients, the ORR was 39.5% and the CBR was 52.6% by IRF. T-DM1 was well tolerated, with no
dose-limiting cardiotoxicity. One pt with pre-existing non-alcoholic fatty liver disease died with hepatic dysfunction. The
most common adverse events were fatigue (59.1% of pts), nausea (37.3%), and thrombocytopenia (29.1%); 41.8% of pts
experienced at least one grade 3 or above adverse event.
Conclusions: In this study, single agent T-DM1 demonstrates a 32.7% ORR with an acceptable safety profile in a well defined,
homogeneous, and extensively pretreated population that has not been previously studied. Centrally confirmed HER2 positivity
strongly correlated with objective response. These results confirm the activity of T-DM1 in treatment resistant HER2+ MBC. An
ongoing global randomized phase 23 study is evaluating T-DM1 compared with lapatinib plus capecitabine in pts with advanced
HER2+ who have been previously treated with a taxane and trastuzumab.
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