FP: Fluoropyrimidine/cisplatin

a Odds ratio

Patients were recruited to the trial who were previously untreated for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction not amenable to curative therapy. The primary endpoint was overall survival which was defined as the time from the date of randomization to the date of death from any cause. At the time of the analysis a total of 349 randomized patients had died: 182 patients (62.8 %) in the control arm and 167 patients (56.8 %) in the treatment arm. The majority of the deaths were due to events related to the underlying cancer.

Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours with higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). The median overall survival for the high HER2 expressing group was 11.8 months versus 16 months, HR 0.65 (95 % CI 0.51-0.83) and the median progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95 % CI 0.51-0.79) for FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95 % CI 0.51-1.11) in the IHC 2+/FISH+ group and the HR was 0.58 (95 % CI 0.41-0.81) in the IHC 3+/FISH+ group.

In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent benefit on overall survival with the addition of Herceptin in patients with ECOG PS 2 at baseline [HR 0.96 (95 % CI 0.51-1.79)], non measurable [HR 1.78 (95 % CI 0.87-3.66)] and locally advanced disease [HR 1.20 (95 % CI 0.29-4.97)].

Immunogenicity

903 breast cancer patients treated with Herceptin, alone or in combination with chemotherapy, have been eva luated for antibody production. Human anti-trastuzumab antibodies were detected in one patient, who had no allergic manifestations.

There are no immunogenicity data available for Herceptin in gastric cancer.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Herceptin in all subsets of the paediatric population in Breast and Gastric cancer. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

 The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer, early breast cancer and advanced gastric cancer patients. Formal drug-drug interaction studies have not been performed with Herceptin.

Breast Cancer

Short duration intravenous infusions of 10, 50, 100, 250, and 500 mg trastuzumab once weekly in patients demonstrated non-linear pharmacokinetics where clearance decreased with increasing dose.

Half-life

The elimination half-life is of 28-38 days and subsequently the washout period is up to 27 weeks (190 days or 5 elimination half-lives).

Steady State pharmacokinetics

Steady state should be reached by approximately 25 weeks. In a population pharmacokinetic (two compartment, model-dependent) assessment of Phase I, II and III clinical trials in metastatic breast cancer, the median predicte