Herceptin is the first of a new generation of non-cytotoxic, non-hormonal compounds showing considerable promise in the management of metastatic breast cancer. Based on the seminal work of Slamon and co-workers, the humanized monoclonal anti-Her-2-neu antibody entered clinical trials in the early 1990s. While the initial phase II clinical trial publication by Baselga and co-workers did not receive the kind of attention it should have been given, discovery of activity in heavily pre-treatment patients with the use of a relatively non-toxic antibody led to further trials establishing the effectiveness of this unique compound.
Two pivotal trials were initiated, with one investigating the use of Herceptin in patients failing one or two prior chemotherapy regimens for metastatic breast cancer. In this trial the response rate was 20% as assessed by the investigator and 14% by an external Response Evaluation Committee. Patients with 3+ Her-2-neu over-expression appeared to benefit more (17% vs 7%) than Her-2-neu 2+ over-expressors. Toxicity was mild with fever and chills seen in about 30% of patients, but generally only with the 4 mg/kg loading dose and seldom with the 2 mg/kg maintenance doses.
In the other pivotal trial, patients were randomized to chemotherapy alone or with Herceptin as first-line therapy for metastatic breast cancer. Women who had not received prior anthracycline therapy were randomized to anthracycline ± Herceptin, while patients with prior adjuvant anthracycline were randomized to paclitaxel ± Herceptin. Herceptin plus chemotherapy was superior to chemotherapy alone in all parameters of effectiveness, including a 5-month survival advantage at two years of follow-up.