Efficacy in metastatic disease The sponsor is seeking approval for the new SC regimen in the treatment of metastatic disease. The population included in the pivotal study consisted of subjects with localised or locally advanced disease. Patients with metastatic disease were excluded. The study also compared the proposed SC regimen with the 6-mg/kg q3 weeks IV regimen. In Australia the only regimen approved for use in metastatic disease is the 2-mg/kg q1 week regimen (see Table 20). This was the dosage regimen used in the pivotal efficacy studies in this setting. An application for approval of the 6-mg/kg q3 weeks IV regimen in metastatic disease was not approved by the TGA. Table 20: Approved indications and approved and proposed dosage regimens. Shaded areas indicate changes that are the subject of the current application. Approved Indication RoA Loading dose Subsequent doses Duration Localised Breast Cancer Treatment of HER2-positive localised breast cancer following surgery, and in association with chemotherapy and, if applicable, radiotherapy. IV 8 mg/kg 6 mg/kg every 3 weeks 1 year IV 4 mg/kg 2 mg/kg every 1 week 1 year SC - 600 mg every 3 weeks 1 year Locally Advanced Breast Cancer Treatment of HER2-positive locally advanced breast cancer in combination with neoadjuvant chemotherapy followed by adjuvant HERCEPTIN. IV 8 mg/kg 6 mg/kg every 3 weeks 1 year SC - 600 mg every 3 weeks 1 year Metastatic Breast Cancer Treatment of patients with metastatic breast cancer who have tumours that overexpress HER2: As monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease; In combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or IV 4 mg/kg 2 mg/kg every 1 week Until disease progression SC - 600 mg every 3 weeks Until disease progression
‘investigators might have adopted a more conservative attitude towards patients receiving subcutaneous trastuzumab in this open-label trial, resulting in differences in clinical management (that is,, a higher rate of hospital admission)’. Exploratory analyses of the rates of SAEs (and Grade ≥ 3 AEs) by quartiles of body weight at baseline as well as by quartiles of AUC values were performed. Table 31 shows SAE rates according to body weight and AUC quartiles. Table 31: Study BO22227 – SAEs according to bodyweight and AUC There was no pattern suggestive of increasing SAE rates with increasing AUC or decreasing body weight. The results for Grade ≥ 3 AEs were similar. Further analyses of patients with low bodyweights showed that the SAE rate in these subjects was actually lower than the SAE rate in the population as a whole (Table 32). These data suggest that the higher SAE rate in the SC arm is unlikely to be due to the fixed dose SC regimen producing higher AUC values in low body weight subjects. 32: Study BO22227 – SAEs/Grade ≥ 3 AEs in subjects with low bodyweight Multiple logistic regression analyses were conducted comparing the occurrence of SAEs (and ≥ 3 AEs) between treatment arms. AUC (median AUC value of Cycle 7 and 12) and body weight were included as covariates. None of the covariates showed a statistically significant effect on the frequency of SAEs or Grade ≥ 3 AEs. Discontinuation due to adverse events The proportion of patients who developed at least one AE leading to study withdrawal was higher in the SC arm – 2.7% (IV) versus 5.7% (SC). These AEs are listed in Table 33. Further information on these subjects is given in Tables 34 and 35. Table 33: Study BO22227 – AEs leading to withdrawal