EMILIA

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Verma S, et al. "Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer". The New England Journal of Medicine. 2012. 367(19):1783-1791.
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Clinical Question

Among patients with advanced HER2-positive breast cancer previously treated with trastuzumab and a taxane, does trastuzumab-emtansine prolong PFS and OS when compared to lapatanib+capecitabine?

Bottom Line

Among patients with advanced HER2-positive breast cancer previously treated with trastuzumab and a taxane, trastuzumab-emtansine prolongs PFS and OS when compared to lapatanib+capecitabine.

Major Points

The 2012 Emtansine vs. Capecitabine plus Lapatinib in Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer (EMILIA) trial randomized 991 women with HER2-positive, unresectable, locally advanced, or metastatic breast cancer previously treated with trastuzumab and a taxane to either trastuzumab-emtansine (T-DM1) or standard-of-care lapatinib+capecitabine. At a mean follow-up of about 18 months, T-DM1 was associated with prolonged progression-free survival (9.6 vs. 6.4 months) and overall survival (30.9 vs. 25.1). The antibody-drug conjugate was associated with fewer grade ≥3 adverse events (40.8% vs. 57%) and serious events resulting in treatment discontinuation (5.9% vs. 10.7%), and did not appear to increase the incidence of cardiotoxicity (1 vs. 5 events).

Guidelines

In February 2013, the FDA approved T-DM1 for use in patients with metastatic, HER2-positive breast cancer and previous treatment with trastuzumab and a taxane,[1] but no major guidelines have been released to reflect the results of this trial.

Design

  • Multicenter, randomized, open-label trial
  • N=991 Women with HER2+, unresectable, locally advanced or metastatic breast cancer who were previously treated with a taxane and trastuzumab
    • Lapatinib and capecitabine (n=496)
    • T-DM1 (n=495)
  • Setting: 213 centers in 26 countries
  • Enrollment: 2009-2011
  • Median follow-up: 18.6 months
  • Analysis: Intention-to-treat
  • Primary outcomes: PFS, objective response rate

Population

Inclusion Criteria

  • Progression of unresectable, locally-advanced or metastatic HER2+ breast cancer
  • Previous treatment with a taxane and trastuzumab
  • LVEF ≥50%
  • ECOG 0-1

Exclusion Criteria

  • Prior treatment with T-DM1, lapatinib, or capecitabine
  • Peripheral neuropathy ≥grade 3
  • Symptomatic CNS metastases or treatment of CNS disease within prior 2 months
  • Serious cardiac arrhythmia
  • ACS in prior 6 months

Baseline Characteristics

From the T-DM1 group.

  • Age: 53 years
  • Race: White 72%, Asian 19%, Black 6%, other 1%
  • Geographic area: USA 27%, W. Europe 32%, Asia 17%, other 25%
  • ECOG status
    • 0: 60%
    • 1: 39%
    • Unavailable: <1%
  • Disease site: Visceral 67%, non-visceral 33%
  • Histologic hormone-receptor status:
    • ER+ and/or PR+: 57%
    • ER-, PR-: 41%
    • Unknown: 2%
  • Prior therapies: Anthracycline 61%, other chemotherapy 78%, biologic agent (not trastuzumab or pertuzumab) 3%, endocrine therapy 41%
  • Chemotherapy for locally-advanced or metastatic disease:
    • 0 or 1: 61%
    • >1: 39%
  • Prior trastuzumab:
    • Early or metastatic breast cancer: 84%
    • Early breast cancer: 16%

Interventions

Randomization to one of two groups:

  • Lapatinib 1250mg PO daily and capecitabine 1000mg PO q12h for 14 days of each 21 day cycle
  • T-DM1 3.6mg/kg IV every 21 days

Outcomes

Comparisons are lapatinib+capecitabine vs. T-DM1.

Primary Outcome

Progression-free survival (median)
6.4 months vs. 9.6 months (HR 0.65; 95% CI 0.55-0.77; P<0.001)
Overall survival (median)
30.9 months vs. 25.1 months (HR 0.68; 95% CI 0.55-0.85; P<0.001)
1-year survival: 85.2% vs. 78.2% (no statistics given)
2-year survival: 64.7% vs. 51.8% (no statistics given)

Secondary Outcomes

Objective response rate
30.8% vs. 43.6% (difference 12.7%; 95% CI 6.0-19.4%; P<0.001)
Complete or partial response
30.8% s. 43.6% (P<0.001)
Complete: 0.5% vs. 1.0% (no statistics given)
Partial: 30.3% vs. 42.6% (no statistics given)
Duration of either response: 6.5 months vs. 12.6 months (no statistics given)

Adverse Events

Any
97.7% vs. 95.9%
Serious
18.0% vs. 15.5%
Grade 3-4
57.0% vs. 40.8%
Thrombocytopenia, grade 3-4
0.2% vs. 12.9%

Funding

F. Hoffman-La Roche/Genentech, the manufacturers of T-DM1 under the trade name Kadcyla.

Further Reading

  1. FDA press release announcing approval of T-DM1