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 trastuzumab 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)].

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with trastuzumab in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of trastuzumab were eva luated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects, including patients with HER2-positive MBC, EBC, AGC or other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving trastuzumab via an intravenous infusion. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to non-linear elimination, total clearance increased with decreasing concentration. Therefore, no constant value for half-life of trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval (see Table 16). MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central compartment volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC). Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The non-linear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 µg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with AGC. In the final population PK model, in addition to primary tumour type, body-weight, serum aspartate aminotransferase and albumin were identified as statistically significant covariates affecting the exposure of trastuzumab. However, the magnitude of effect of these covariates on trastuzumab exposure suggests that these covariates are unlikely to have a clinically meaningful effect on trastuzumab concentrations.

The population predicted PK exposure values (median with 5th-95th Percentiles) and PK parameter values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated with the approved q1w and q3w dosing regimens are shown in Table 14 (Cycle 1), Table 15 (steady-state), and Table 16 (PK parameters).