Preclinical and phase I/II studies of Herceptin demonstrated a dose-related, non-linear pharmacokinetic profile. The results of a dose-finding study supported a regimen comprising an initial intravenous (i.v.) dose of 4 mg/kg with subsequent weekly doses of 2 mg/kg. However, pharmacokinetic and safety data suggested that increased dose and reduced frequency of Herceptin administration are feasible. In addition, evidence shows that Herceptin plus paclitaxel has additive antitumor efficacy in vitro, and this regimen produces significant clinical benefits. These observations form the rationale for conducting a phase I/II trial of Herceptin (8 mg/kg initial dose, 6 mg/kg maintenance dose) plus paclitaxel, both given 3-weekly. Preliminary results are promising, with serum trough Herceptin concentrations being similar and AUC being greater than those observed with weekly Herceptin plus 3-weekly paclitaxel. Two further trials are proposed: 3-weekly Herceptin as first-line monotherapy of metastatic breast cancer; and 3-weekly Herceptin with the oral 5-fluorouracil derivative, Xeloda (capecitabine). Subcutaneous (s.c.) administration of Herceptin would further simplify administration and studies are also underway to clinically evaluate s.c. administration of Herceptin in combination with paclitaxel. With the recent development of oral taxanes, it is predicted that combinations including an oral taxane, Xeloda and either 3-weekly or possibly s.c. Herceptin may become future therapies for breast cancer patients.
Copyright 2001 S. Karger AG, Basel