Herceptin® Alone or in Combination with Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Pivotal Trials

Large pivotal phase II and III clinical trials investigated the therapeutic efficacy and safety of the humanized anti-HER2 monoclonal antibody, Herceptin®, alone and in combination with standard chemotherapy, respectively, in HER2-positive metastatic breast cancer. Eligible patients were HER2 2+ and 3+ overexpressors, as determined by immunohistochemistry (IHC). Herceptin was well tolerated in both trials. Single-agent second/third-line Herceptin produced durable tumor responses. First-line Herceptin in combination with chemotherapy, in particular paclitaxel, significantly improved time to disease progression, duration of response and time to treatment failure. Combination therapy also provided a significant 25% improvement in overall survival. These clinical benefits have led to the approval of Herceptin for clinical use in the USA and elsewhere. Greater efficacy was noted in IHC 3+ patients compared with the overall population in both trials. Retrospective fluorescent in situ hybridization (FISH) testing of patient-tumor HER2 status revealed similar clinical outcomes in IHC 3+ and FISH-positive patients, consistent with the reported high concordance between IHC and FISH. Responses in the single-agent Herceptin trial were seen exclusively in FISH-positive patients. Approximately a quarter of HER2 2+ patients test FISH positive and may therefore benefit from therapy. Numerous studies are underway or planned to evaluate other Herceptin combinations and regimens in the metastatic and adjuvant settings.