Public Release: 

T-DM1 improved overall survival for heavily pretreated patients with HER2-positive breast cancer

American Association for Cancer Research

SAN ANTONIO -- Among patients with HER2-positive, metastatic breast cancer that had progressed despite treatment with two or more forms of HER2-targeted therapy (trastuzumab [Herceptin] and lapatinib [Tykerb]), median overall survival was increased for those treated with trastuzumab emtansine (T-DM1 [Kadcyla]) compared with those who received treatment of physician's choice, according to results from the phase III TH3RESA clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

The HER2-targeted antibody-drug conjugate T-DM1 was approved by the U.S. Food and Drug Administration in February 2013 for treating patients with HER2-positive, metastatic breast cancer that had progressed after treatment with trastuzumab and a taxane.

"The National Comprehensive Cancer Network guidelines, which are widely used as the standard for cancer care, were recently changed to recommend using T-DM1 as a preferred treatment for patients with trastuzumab-exposed HER2-positive, metastatic breast cancer, meaning that it is generally used after a patient's metastatic disease has progressed following treatment with a combination of a taxane-based chemotherapy and trastuzumab, with or without pertuzumab (Perjeta)," said Hans Wildiers, MD, PhD, a professor of medical oncology at KU Leuven in Belgium. "However, there are a lot of patients who received second- or later-line treatment before this recommendation was put in place and TH3RESA was designed to establish whether T-DM1 could benefit patients in later lines as well.

"Previously published results from TH3RESA showed that T-DM1 almost doubled progression-free survival," continued Wildiers. "Here we show that T-DM1 actually increased overall survival for heavily pretreated patients with HER2-positive, metastatic breast cancer. This is very important because several breast cancer therapies that increase progression-free survival do not in fact increase overall survival, and these patients urgently need new treatment options."

All 602 patients with HER2-positive, metastatic breast cancer enrolled in TH3RESA had been previously treated with a chemotherapy regimen that included a taxane and, after a diagnosis of metastatic disease, two or more regimens that included HER2-targeted therapeutics, including trastuzumab and lapatinib. Patients were randomly assigned 3.6 milligrams of T-DM1 per kilogram of body weight every three weeks or treatment of physician's choice.

After a median follow-up of 30.5 months, the median overall survival was significantly longer among the 404 patients assigned T-DM1 compared with the 198 patients assigned treatment of physician's choice: 22.7 months compared with 15.8 months. The overall survival benefit was seen regardless of patient age, hormone-receptor status, visceral involvement, and number of prior treatment regimens.

The incidence of grade 3 or higher adverse events was higher among patients assigned treatment of physician's choice compared with those assigned T-DM1: 47.3 percent compared with 40.0 percent.

"Not only did the population of patients assigned T-DM1 have increased median overall survival, they also had reduced incidence of grade 3 and higher adverse events," said Wildiers. "The fact that these patients lived longer with less toxicity suggests that T-DM1 is a good treatment option even for patients who have received two or more HER2-targeted treatment regimens."


This study was supported by Roche. Wildiers' institution has received compensation from Roche for lectures he has presented at national meetings and for consulting work, as well as an unrestricted research grant for academic research.

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The mission of the 2015 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit

Abstract: S5-05

Title: Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study

Authors: Hans Wildiers1, Sung-Bae Kim2, Antonio Gonzalez-Martin3, Patricia M LoRusso4, Jean-Marc Ferrero5, Ron Yu6, Melanie Smitt6 and Ian Krop7. 1University Hospitals Leuven, Leuven, Belgium; 2Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 3Centro Oncológico MD Anderson International España, Madrid, Spain; 4Yale Cancer Center, Yale University Medical Center, New Haven, CT; 5Centre Antoine Lacassagne, Nice, France; 6Genentech, Inc, South San Francisco, CA and 7Dana-Farber Cancer Institute, Boston, MA.


Introduction: The phase 3, randomized, open-label, TH3RESA study (BO25734/TDM4997g; NCT01419197) compared trastuzumab emtansine (T-DM1) with treatment of physician's choice (TPC) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), previously treated with a taxane (any setting), and both trastuzumab and lapatinib (advanced setting). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints. Results of the primary PFS analysis and the first interim OS analysis showed significantly improved PFS with T-DM1 compared with TPC and a trend for improved OS, although the stopping boundary was not reached (Krop IE, et al. Lancet Oncol 2014). The incidence of grade ??3 adverse events (AEs) was lower with T-DM1 vs TPC (32% vs 43%). Here we report the results from the second interim analysis of OS from TH3RESA, which will serve as the final OS results.

Methods: Eligible patients were randomized 2:1 to receive T-DM1 (3.6 mg/kg IV every 3 weeks) or TPC. The pre-specified OS efficacy stopping boundary was an observed hazard ratio (HR) <0.75 or p<0.012. Crossover from TPC to T-DM1 following progressive disease was allowed from Sept 2012 onward.

Results: From Sept 14, 2011 to Nov 19, 2012, 602 patients were randomized to T-DM1 (n=404) or TPC (n=198). TPC comprised HER2-directed regimens (83%) and single-agent chemotherapy (17%). At the data cutoff for this analysis (Feb 13, 2015), 93 patients (47%) had crossed over from TPC to T-DM1. At a median follow-up time of 30.5 months, OS was significantly longer with T-DM1 vs TPC (median OS 22.7 vs 15.8 months; HR=0.68 [95% CI, 0.54-0.85; p=0.0007]) and these results crossed the OS efficacy stopping boundary. A sensitivity analysis, in which patients were censored when they switched from TPC to T-DM1, also showed an OS benefit with T-DM1 vs TPC (median 22.7 vs 15.6 months; HR=0.58 [95% CI: 0.43-0.77; p=0.0002]). The OS benefit was consistently observed across subgroups defined by age, visceral involvement, hormone receptor status, number of prior regimens, and TPC type. The T-DM1 group had nearly twice the mean exposure to the planned study treatment as the TPC group (7.93 vs 4.08 months). In treated patients, the incidence of grade ??3 AEs was 40.0% and 47.3% in the T-DM1 and TPC arms, respectively. Grade ??3 AEs occurring in ??3% of either treatment arm were neutropenia (T-DM1, 2.5%; TPC, 15.8%), febrile neutropenia (T-DM1, 0.2%; TPC, 3.8%), thrombocytopenia (T-DM1, 6.0%; TPC, 2.7%), anemia (T-DM1, 3.5%; TPC, 3.3%), dyspnea (T-DM1, 2.5%; TPC, 3.8%), diarrhea (T-DM1, 0.7%; TPC, 4.3%), and asthenia (T-DM1, 1.0%; TPC, 3.3%).

Conclusions: In this population of patients with advanced breast cancer who previously received a taxane, trastuzumab, and lapatinib, treatment with T-DM1 resulted in a statistically significant and clinically meaningful improvement in OS compared with TPC. A lower incidence of grade ??3 AEs was observed with T-DM1 and its safety profile was consistent with previous studies.

This research will be presented at a press conference at the 2015 San Antonio Breast Cancer Symposium, moderated by SABCS Co-director Kent Osborne, MD, director of the Dan L Duncan Cancer Center at Baylor College of Medicine, Friday, Dec. 11, 7:30 a.m. CT in Room 217D of the Henry B. Gonzalez Convention Center. Reporters who cannot attend the press conference in person can call in using the following information:

  • United States/Canada (toll-free): 866-297-6395
  • International (toll): 1-847-944-7317
  • Conference code number: 41320577

To interview Hans Wildiers, contact Julia Gunther at or 267-250-5441.

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