Tyverb in combination with capecitabine for HER2+ metastatic breast cancer EGF100151 pivotal study

Efficacy and safety from the EGF100151 registration study

Reference:
Cameron D, Casey M, Press M, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.
Breast Cancer Res Treat. 2008;112:533–543.

Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomised trial.
The Oncologist. 2010;15:924–934.

Background:
Tyverb (lapatinib) is an oral small molecule dual tyrosine kinase inhibitor that targets the ErbB1 (epidermal growth factor receptor) and HER2 receptors (human epidermal growth factor receptor type 2).
Purpose:
To compare Tyverb plus capecitabine with capecitabine alone in women with progressive, HER2-positive, advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane and trastuzumab.

Methods:

  • Phase III, international, multicentre, randomised, open-label study involving 399 patients with HER2+ locally advanced or metastatic breast cancer who have progressed despite treatment with anthracyclines, taxanes and trastuzumab for metastatic disease.
  • Women were randomised to treatment with Tyverb in combination with capecitabine (n=198) or capecitabine monotherapy (n=201).
  • Tyverb was administered continuously at a dose of 1250 mg/day in combination with capecitabine 2000 mg/m2/day on Days 1–14 of a 21-day cycle. When used as monotherapy, the dose of capecitabine was 2500 mg/m2/day.

Results:

  • The primary endpoint of independently assessed time to progression was 6.2 months with Tyverb–capecitabine combination therapy and 4.3 months with capecitabine alone (P=0.00013).
  • The addition of Tyverb to capecitabine was associated with a 43% reduction in the risk of disease progression (hazard ratio: 0.57, 95% confidence interval 0.43–0.77; P=0.00013) compared with capecitabine monotherapy.
  • Patients receiving Tyverb in combination with capecitabine had an increased overall response rate compared with those given capecitabine monotherapy (23.7% vs. 13.9%; P=0.017). The respective clinical benefit rates were 29.3% and 17.4% (P=0.008).
  • The majority of adverse events were grade 1 or 2. Diarrhoea and rash were more common with Tyverb plus capecitabine treatment than with capecitabine alone.
  • Reports of grade 3 and 4 adverse events were low and similar in both treatment arms. Serious hepatobiliary events were reported in 4 patients (1.9%) treated with Tyverb plus capecitabine and 3 patients (1.6%) treated with capecitabine alone.
  • LVEF decreases were reported in 2.5% of patients treated with Tyverb plus capecitabine and 1.0% of patients treated with capecitabine alone. There were no withdrawals due to decreased LVEF in the combination arm.
  • Serious adverse events resulted in 12 deaths, these included a cardiorespiratory arrest in the combination arm and a cardiac arrest and a respiratory arrest in the capecitabine arm.

Conclusions:
When compared with capecitabine alone, the combination of Tyverb and capecitabine is superior in the treatment of women with advanced breast cancer whose tumours over-express HER2+ and who had progressed after treatment with regimens that included an anthracycline, a taxane and trastuzumab.

The Lapatinib Expanded Access Programme

Reference: 1. Cameron D, Casey M, Press M, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008;112:533–543.  2. Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924-934.