NE Oncology Issue – February 2014

Wildiers H, et al. ECC 2013:LBA15


Trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, is approved in Canada for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane, separately or in combination. There is no clear standard of care for patients with progressive disease (PD) after ≥2 HER2-directed regimens for MBC. TH3RESA is an ongoing phase III study evaluating trastuzumab emtansine versus treatment of physician’s choice (TPC) in this patient population. At ECC 2013, Wildiers and colleagues presented the final analysis of progression-free survival (PFS) and the first interim analysis of overall survival (OS) for this study.1

Study design

  • Patients with centrally confirmed HER2-positive unresectable locally advanced breast cancer (LABC) or MBC with PD after ≥2 HER2-directed regimens, including trastuzumab and lapatinib, in the unresectable recurrent/metastatic setting and a taxane (any setting) were randomized 2:1 to trastuzumab emtansine (3.6 mg/kg intravenous [iv] every three weeks [q3w]) or TPC, respectively.
  • After EMILIA2 data were reported, which showed a significant improvement in median PFS and OS with trastuzumab emtansine than with capecitabine plus lapatinib, crossover from TPC to trastuzumab emtansine was allowed post-progression.
  • Co-primary end points were PFS by investigator assessment and OS.
  • Key secondary end points were objective response rate (ORR) by investigator assessment and safety.


Key findings

Baseline characteristics and disposition

  • By the Feb 11, 2013 clinical data cutoff, 602 patients were randomized: 404 patients to the trastuzumab emtansine arm and 198 patients to the TPC arm.
    • A total of 44 patients in the TPC arm have crossed over to trastuzumab emtansine after documented PD.
  • Patients’ baseline characteristics were well balanced between the two treatment arms (trastuzumab emtansine vs. TPC), including:
    • Age (<65 years): 85.4% vs. 82.8%;
    • Race (white): 80.4% vs. 81.3%;
    • ECOG Performance Status 0/1: 44.8%/49.8% vs. 41.4%/51.0%;
    • Disease extent (MBC/unresectable LABC): 96.8%/3.2% vs. 94.4%/5.6%.
  • Patients in each treatment arm had received a median of 4 prior regimens (excluding hormonal therapy) in the recurrent/metastatic setting, and the majority (75.1%) had visceral disease.
  • TPC comprised HER2-directed regimens (83.2%) and single-agent chemotherapy (16.8%). (Table 1)
    • Of the HER2-directed regimens, the majority contained trastuzumab, with chemotherapy plus trastuzumab (68.5%) being the most frequently used of all regimens.
    • The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.
  • A greater proportion of patients from the TPC arm discontinued the study than those from the trastuzumab emtansine arm (36.9% vs. 21.0%).
    • The reasons for study discontinuation (TPC vs. trastuzumab emtansine) were death (22.2% vs. 15.1%), withdrawal by patient (13.1% vs. 4.7%), physician’s decision (1.0% vs. 0.5%), and other (0.5% vs. 0.7%).


  • At a median follow-up of 7.2 months in the trastuzumab emtansine arm and 6.5 months in the TPC arm, median PFS by investigator assessment was significantly longer with trastuzumab emtansine than with TPC (6.2 vs. 3.3 months; stratified HR = 0.528 [95% CI: 0.422–0.661], p <0.0001). (Figure 1)
    • The increased benefit with trastuzumab emtansine remained similar when median PFS with trastuzumab emtansine was compared with that for patients who received trastuzumab-containing regimens (6.2 vs. 3.2 months; stratified HR = 0.558 [95% CI: 0.437–0.711], p <0.0001).
  • PFS benefit with trastuzumab emtansine was consistent across subgroups, including age, visceral involvement, and number of prior regimens.
  • At an observed 21% of targeted events, the first interim OS analysis showed a similar trend of benefit with trastuzumab emtansine compared with TPC (median: not reached vs. 14.9 months; stratified HR = 0.552 [95% CI: 0.369–0.826], p = 0.0034), but the efficacy stopping boundary (HR <0.363 or p <0.0000013) was not crossed. (Figure 2)
  • The ORR by investigator assessment in patients with measurable disease was significantly improved with trastuzumab emtansine compared with TPC (31.3% vs. 8.6%; difference: 22.7% [95% CI: 16.2–29.2%], p <0.0001). (Figure 3)
  • The percentage of patients experiencing adverse events (AEs) of any grade was slightly higher in the trastuzumab emtansine arm vs. the TPC arm (93.5% vs. 88.6%).
  • Of the AEs of any grade (trastuzumab emtansine vs. TPC): (Table 2)
    • More thrombocytopenia (15.1% vs. 3.3%) was reported with trastuzumab emtansine.
    • More diarrhea (9.9% vs. 21.7%), neutropenia (5.5% vs. 21.7%), and abdominal pain (6.5% vs. 12.5%) were reported with TPC.
  • Fewer grade ≥3 AEs overall were reported for trastuzumab emtansine vs. TPC (32.3% vs. 43.5%). (Table 2)
    • More grade ≥3 thrombocytopenia (4.7% vs. 1.6%) was reported with trastuzumab emtansine.
    • More grade ≥3 neutropenia (2.5% vs. 15.8%), febrile neutropenia (0.2% vs. 3.8%), and diarrhea (0.7% vs. 4.3%) were reported with TPC.
  • The TPC arm reported higher incidences of AEs leading to treatment discontinuation (10.9% vs. 6.7%) and AEs leading to dose reduction (19.6% vs. 9.4%).

Key conclusions

  • Trastuzumab emtansine demonstrated improved efficacy compared with TPC.
    • The ORR 31.3% vs 8.6%, p <0.0001
    • There was a significant improvement in PFS (HR = 0.528; p <0.0001) and a clear and consistent treatment effect across subgroups.
    • The interim OS analysis favoured trastuzumab emtansine (HR = 0.552; p = 0.0034) but efficacy stopping boundary was not crossed.
  • Safety favoured trastuzumab emtansine, with fewer grade ≥3 AEs and fewer discontinuations and dose reductions due to AEs compared with those for TPC.
  • These data reaffirm the results from the EMILIA study,2 demonstrating a consistent benefit with trastuzumab emtansine in patients with previously treated HER2-positive advanced breast cancer.

References: 1. Wildiers H, Kim SB, Gonzalez-Martin A, et al. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs. treatment of physician’s choice. ECC 2013:LBA15. 2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–91.

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Spotlight Article


Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.



Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Canadian Perspective


Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC

Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.

Investigator Commentary


Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.