The evidence supporting the use of this protocol comes from a phase 3, open-label, randomised controlled trial (ToGA) in which the clinical efficacy and safety of trastuzumab was investigated in combination with chemotherapy for first-line treatment of HER-2 positive advanced gastric or gastro-oesophageal junction cancer.r
Patients were randomised to receive either trastuzumab plus chemotherapy (T+C) or chemotherapy alone (C). Chemotherapy consisted of either capecitabine 1000 mg/m2 BD D1-14 plus cisplatin 80 mg/m2 D1 every 3 weeks or infusional fluorouracil 800 mg/m2 D1-5 plus cisplatin 80 mg/m2 D1 every 3 weeks. Trastuzumab was given as 8 mg/kg for the first cycle followed by 6 mg/kg every 3 weeks. The chemotherapy regimen was chosen between 5-FU/cisplatin and capecitabine/cisplatin at the investigator's discretion and could be determined on an individual patient basis.
Between September 2005 and December 2008 584 patients were randomised and received at least one dose of study treatment – 294 in the C+T group, 290 in the C group alone. The primary endpoint was overall survival, secondary endpoints progression-free survival, time to progression, overall tumour response and safety.r
At a median follow up of 17.1 to 18.6 months, median overall survival was 13.8 months in the C+T group and 11.1 months in the C group, HR 0.74. Overall tumour response rate, time to progression, and duration of response were significantly improved in the T+C group vs C alone. A post-hoc subgroup analysis of patients with high (IHC 2+ and FISH + or IHC 3+) levels of HER2 expression showed a median survival of 16.0 months in the T+C group vs 11.8 months in the C group alone, with a HR of 0.65.r
(A) Median overall survival and (B) progression-free survival in the primary analysis populationr
© Lancet 2010
The toxicities in the two arms were comparable, except that a higher number of trastuzumab-treated patients had grade 3 or 4 diarrhoea (9% versus 4%) and an asymptomatic decrease in left ventricular ejection fraction (LVEF, 5% versus 1%). Only one patient developed grade 3 to 4 cardiac failure (versus two in the control group) and there were no differences in overall cardiac adverse events (6% in both groups). The other most common grade 3 or 4 adverse effects reported were nausea (7% in both groups), neutropenia (27% in C+T vs 30% in C), and anaemia (12% in C+T, 10% in C ). Treatment-related mortality was 3% (10 deaths) in C+T group and 1% (3 deaths) in C group.r
© Lancet 2010