Tyverb in combination with trastuzumab in hormone receptor-negative (HR-) HER2+ metastatic breast cancer

The EGF104900 study

Reference:
Blackwell K, Burstein H, Storniolo A, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585–2592.

Blackwell K, Burstein H, Storniolo A, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with HER2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–1130.

European Medicines Agency June 2013. Assessment report: Tyverb. EMA/H/C/795/II/22. Available from www.ema.europea.eu (Accessed 4 September 2015).

Background:
Tyverb (lapatinib) is a reversible tyrosine kinase inhibitor that potently inhibits both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Clinical evidence has shown the efficacy of lapatinib in HER2-positive breast cancer.

The present studies evaluate the efficacy of Tyverb in combination with trastuzumab for the treatment of patients with metastatic breast cancer (MBC) whose tumours overexpress HER2 (ErbB2) and whose disease has progressed on prior trastuzumab therapy(ies).

Purpose:
To evaluate the safety and efficacy of Tyverb in combination with trastuzumab in women with MBC who experienced progression on prior trastuzumab-containing regimens.

Methods:

  • Phase III multicentre, randomised, open-label trial.
    A total of 296 women with HER2+ MBC were enrolled in the study. All women had progressed on prior trastuzumab-containing regimens and had received prior anthracycline- and taxane-based regimens in either the adjuvant or metastatic settings.
  • A total of 148 women received Tyverb 1500 mg daily and 148 women received Tyverb 1000 mg daily in combination with intravenous (IV) trastuzumab 2 mg/kg weekly (after the initial 4 mg/kg loading dose).
  • Progression-free survival (PFS) was the primary endpoint of the trial and overall survival (OS) was a secondary endpoint.

Results:
For patients with HR-/HER2+ MBC, median OS was 17.2 months for Tyverb in combination with trastuzumab and 8.9 months for Tyverb monotherapy*. The hazard ratio (HR) was 0.62, with a 95% confidence interval (CI) between 0.42 and 0.90.

  • For patients with HR-/HER2+ MBC, median PFS was 15.4 weeks for Tyverb in combination with trastuzumab and 8.2 weeks for Tyverb monotherapy* (HR: 0.73; 95% CI 0.52–1.03).
  • The combination of Tyverb plus trastuzumab was associated with no unexpected side effects, and the overall incidence of adverse events was similar in both treatment groups (94% receiving combination therapy vs 90% receiving Tyverb monotherapy*).
  • The most frequent adverse events were diarrhoea, rash, nausea, and fatigue; diarrhoea was higher in the Tyverb in combination with trastuzumab arm.
  • Serious adverse events were experienced by 26% of patients in the Tyverb in combination with trastuzumab arm and 16% of patients in the Tyverb monotherapy arm.
  • Eleven patients in the Tyverb in combination arm with trastuzumab arm and 3 patients in the Tyverb monotherapy arm experienced cardiac events; 10 events in the combination arm and 3 events in the monotherapy are were ≥ grade 3 left ventricular systolic dysfunction or decrease in left ventricular ejection fraction.
*Lapatinib is not approved for use as a single agent.

Tyverb in combination with trastuzumab: efficacy

References: 1. Blackwell K, Burstein H, Storniolo A, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: Final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585–2592. 2. Blackwell K, Burstein H, Storniolo A, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–1130. 3. European Medicines Agency June 2013. Assessment report: Tyverb. EMA/H/C/795/II/22. Available from www.ema.europea.eu (Accessed 4 September 2015).