Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane

Reporter: J Taylor Whaley
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2012

Presenter: Kimberly L. Blackwell, MD
Presenter's Affiliation: Duke University Medical Center, Durham, NC


  • Breast cancer is the most common malignancy affecting women in the United States and Europe. The treatment of breast cancer has evolved enormously in the past few decades.
  • The current standard of care for systemic treatment of breast cancers includes chemotherapy, endocrine therapy, and molecular targeted therapies when indicated. As we continue to learn more about the biology of breast cancer, the number and efficacy of targeted therapies will continue to increase.
  • Overexpression and amplification of HER2 is prognostically significant and associated with aggressive breast cancers, and the use of trastuzumab, a humanized monoclonal antibody to target HER2, has been highly effective.
  • The introduction of Herceptin, which was the first targeted therapy for HER2-positive breast cancer, was a landmark discovery; however, additional effective therapies are needed.
  • Despite the benefits of Herceptin, most patients with HER2-positive metastatic breast cancer will eventually have disease progression. Additionally, the continued treatment of cancer with chemotherapy is frequently limited by side effects and declining benefits over time. Trastuzumab emtansine (T--DM1) is a new, unique antibody-drug conjugate that combines the humanized antibody trastuzumab and the cytotoxic antimicrotubule agent T-DM1 using a stable linker known as MCC; it incorporates the antitumor activities of DM1 and the HER2-targeted delivery of trastuzumab.
  • A phase I trial of T-DM1 for patients with heavily pretreated HER2-positive breast cancer determined a recommended dose delivered every 3 weeks. Additionally, in phase II trials with approximately 100 heavily-treated patients in whom disease had progressed during HER2-directed therapy, T-DM1 was associated with objective response rates of 26% and 34%.
  • The results of single arm studies suggested T-DM1 was active in patients who had cancer refractory to trastuzumab-based combinations. The agent was well tolerated in both trials.
  • The goal of this trial was to determine the benefit of T-DM1 compared to the currently approved regimen of capecitabine plus lapatinib for metastatic breast cancer.

Materials and Methods

  • This is a prospective, phase 3, multi-center, international randomized study of T-DM1 vs. capecitabine and lapatinib, for trastuzumab refractory HER2+ metastatic breast cancer.
  • Entry criteria were as follows:
    • Pathologically confirmed HER2+ metastatic breast cancer, and prior therapy with trastuzumab and a taxane.
    • Patients must have demonstrated disease progression on trastuzumab based regimen.
    • No patients could have previously received capecitabine and lapatinib
  • Patients were randomized to one of the following until progressive disease or unmanageable toxicity:
    • Capecitabine (1000 mg/m2PO bid, days 1—14 q3w) + Lapatinib (1,250 mg PO daily)
    • T-DM1 (3.6 mg/kg IV q3w)
  • Primary end points were progression free survival by independent review, overall survival and safety. Progression free survival analysis had 508 events targeted with 90% power. If progression free survival reached significance, then an interim overall survival analysis (efficacy boundary: HR= 0.617) was planned.Final overall survival analysis had 632 events targeted with 80% power. Final analysis is estimated to occur in 2014.
  • Secondary endpoints were progression free survival by investigator, objective response, duration of response, and time to symptom progression.
  • Patients were stratified by world region, number of prior chemo regimens, and presence of visceral disease.


  • 991 pts were enrolled; 978 received treatment from February 2009-October 2011. 495 patients were enrolled on the experimental arm with T-DM1.
  • Median durations of follow-up were 12.9 (T-DM1) and 12.4 months (Capecitabine + Lapatinib).
  • Baseline demographics, prior therapy and disease characteristics were balanced. Additionally, age, race, ECOG performance status, and number of metastatic lesions were well balanced as well. Approximately 70% of patients were white, 18% were Asian, and only 5% were African American/ Black.
  • 68% of patients had visceral metastases, 35% of patients had >3 sites of metastatic disease, and 55% of patients had hormonally-positive disease. More than 50% of patients had received trastuzumab for >1 year.
  • Dose reductions were required in 53% of patients for Capecitabine and 27% of patients for Lapatinib. Only 16% of patients required dose reductions for T-DM1.
  • There was a significant improvement in progression free survival favoring T-DM1 (median 9.6 vs 6.4 months). These results met the primary endpoint of improved progression free survival with an absolute difference of 3.2 months in median survival. Patients over the age of 65 years old achieved less benefit from T-DM1. No other subgroup analysis favored Capecitabine + Lapatinib.
  • The median survival for T-DM1 has not been reached vs. 23.3 months for the control arm of Capecitabine and Lapatinib. Interim analysis for overall survival significantly favored T-DM1 with an absolute difference in overall survival of 7.7% at one year and 18% at 2 years. However, the interim efficacy boundary was not crossed.
  • T-DM1 demonstrated a benefit across all baseline characteristics, including world regions, number of prior chemotherapy regimens, presence of visceral metastases, and ER/PR status.
  • Additionally, the objective response and duration of response improved from 30% to 44% with T-DM1. Patient reported outcomes, which included physical well-being, functional well-being and breast cancer specific-symptom progression, were also improved with T-DM1.
  • T-DM1 was well tolerated with no unexpected safety signals. The most common grade ?3 adverse events per treatment were for T-DM1:
    • Thrombocytopenia (12.8% vs 0.2%)
    • Increased AST (4.3% vs 0.8%) and increased ALT (2.9% vs 1.4%)
    • For Capecitabine and Lapatinib, adverse events included diarrhea (20.7% vs 1.6%), hand-foot syndrome (16.4% vs 0) and vomiting (4.5% vs 0.8%).
  • Increased rates of Grade 3 toxicity were seen in the Capecitabine and Lapatinib arm, 57 vs 41%. Not surprisingly, there was a higher treatment discontinuation arm in the control arm as well (11 vs 6%). Five deaths were recorded on the control arm vs 1 on T-DM1 arm.


Capecitabine + Lapatinib

Overall Survival, % (95% CI)

  • 1-year



  • 2-year



Objective response (OR)

% (95% CI)



Duration of response, (median months)



Dose reduction, %


53.4 (Capecitabine) 27.3 (Lapatinib)

Adverse Effects ? grade 3, %



Author's Conclusions

  • In this multi-institutional international study, T-DM1 conferred a significant and clinically meaningful improvement in progression-free survival compared with Capecitabine + Lapatinib.
  • These results support the use of T-DM1 as an active and well-tolerated novel therapy for HER2+ advanced breast cancer. T-DM1 demonstrated superior efficacy and increased progression free survival and overall survival.
  • TDM-1 was well tolerated with decreased Grade 3 toxicity and offers important therapeutic option in HER-2 positive metastatic breast cancer.

Clinical Implications

  • The authors presented the well-designed, adequately powered, appropriately randomized and stratified phase III EMILIA study that evaluated trastuzumab emtansine (T-DM1) in people with HER2-positive metastatic breast cancer who had previously received Herceptin and a taxane-based chemotherapy.
  • Initial clinical results with Herceptin were first reported 14 years ago at ASCO 1998. Just as this has become a significant advance in the treatment of breast cancer, the development of T-DM1 presents a similar development.
  • The goal in all of oncology is to improve therapy while reducing toxicity. Prior to development of T-DM1, treatment options were limited in patients with HER2+ metastatic breast cancer after progression following trastuzumab.
  • This study provides convincing evidence that TDM-1 is efficacious in refractory metastatic breast cancer and provides clinicians with a novel and effective new treatment in this setting. Additionally, as seen in the results, T-DM1 was more easily tolerated than the current standard of care.
  • Future studies will focus on the use of T-DM1 in combination with additional therapies as well as the use of T-DM1 in the adjuvant and neoadjuvant setting.


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