Tyverb in combination with an aromatase inhibitor in HR+/HER2+ metastatic breast cancer
The EGF30008 registration study
Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.
Johnston S, Pippen J, Jr., Pivot X, et al. J Clin Oncol. 2009;27:5538–5546.
This was the pivotal phase III study evaluating the safety and efficacy of Tyverb (lapatinib) in combination with the aromatase inhibitor (AI) letrozole in women with hormone receptor (HR) and HER2-positive metastatic disease.
To compare the efficacy and safety of using Tyverb in combination with letrozole with the AI alone in the treatment of postmenopausal women with HR+ metastatic breast cancer who were previously untreated in the metastatic setting. Inclusion was not dependent on HER2 status so that it could be determined whether Tyverb in combination with letrozole could also have an effect in HR+/HER2- patients.
- Phase III, multicentre, randomised clinical trial recruiting women with previously untreated metastatic breast cancer (stage IIIb, IIIc, IV) who were positive for the oestrogen (ER) receptor (ER+) and/or progesterone receptor positive (PgR+). Patients could be HER2+, HER2- or HER2 status unknown.
- A total of 1286 patients were enrolled, of whom 219 had HR+/HER2+ metastatic breast cancer. Only data for the HR+/HER2+ population are presented here in line with the European Medicines Agency marketing authorisation for Tyverb.
- In the HR+/HER2+ patients, treatment was administered continuously, with six 250 mg (1500 mg) tablets of Tyverb given each day in combination with 2.5 mg of letrozole (n=111) or letrozole given alone (n=108).
- The primary endpoint was progression-free survival (PFS).
- Tyverb plus letrozole increased the median PFS by 5.2 months in the HR+/HER2+ population (8.2 months vs. 3.0 months, respectively), and led to a significant (29%) reduction in the risk of progression compared with letrozole alone (hazard ratio: 0.71; P=0.019). Overall survival (OS) data are not yet mature. At the time of the interim analysis, OS was 33.3 months with Tyverb plus letrozole and 32.3 months for letrozole monotherapy. The overall response rate was 28% versus 15% comparing the combination therapy and the AI alone (P=0.021).
- The corresponding clinical benefit rates were 48% and 29%, respectively.
- Adverse events in the total safety population (n=1278) were primarily grade 1 or 2 and no individual grade 4 event was reported in more than two patients (<1%) in either group. The most common adverse events associated with Tyverb were diarrhoea and rash.
- In the HR+/HER2+ population, grade 1 and 2 diarrhoea and rash were the most frequently reported events. Grade 3 diarrhoea was observed in 9% of patients treated with Tyverb in combination with letrozole. Diarrhoea resolved with no action in the majority of cases.
- Any serious adverse event related to study drug occurred in 8% of patients receiving the combination compared with 4% of patients receiving letrozole-placebo.
- There were a total of 16 fatalities related to serious adverse events (8 deaths in each arm), of which only 3 were deemed related to study drug (1 in letrozole-lapatinib arm [hepatobiliary] and 2 in letrozole-placebo arm).
- Treatment-related LVEF decline occurred in 7 patients; 2 patients in the letrozole monotherapy arm (0.3%) and 5 patients (0.8%) in the Tyverb plus letrozole arm.
- One patient experienced elevated liver enzymes in the letrozole monotherapy group (0.2%) compared with 8 patients in the combination arm (1.3%); of these 2 women in the combination arm and the patient in the letrozole monotherapy arm required drug discontinuation.
- These data demonstrate that Tyverb in combination with letrozole can significantly improve PFS compared with letrozole monotherapy in patients with HR+/HER2+ metastatic breast cancer.
Tyverb in combination with an AI: efficacy