Monoclonal Antibody Approved for Metastatic Breast Cancer

The FDA recently licensed a biological approach for the treatment of metastatic breast cancer. The intravenous monoclonal antibody, trastuzumab (Herceptin), is approved for use alone in certain patients who have tried chemotherapy with little success, or as a first-line treatment for metastatic disease when used in combination with paclitaxel (Taxol).

Trastuzumab is the second monoclonal antibody approved for the treatment of cancer. (The first, rituximab [Rituxan], was approved in November 1997 for patients with one type of non-Hodgkin’s lymphoma.) Trastuzu-mab is a monoclonal antibody bioengineered from part of a mouse antibody that is altered to closely resemble a human antibody. It binds to a protein called HER-2, which is found on the surface of some normal cells and plays a role in regulating cell growth. In laboratory experiments, trastuzumab inhibited tumor cell growth by this binding action.

In the case of metastatic breast cancer cells, approximately 30% of tumors produce excess amounts of HER-2. When breast cancer tumors produce excess HER-2, it appears that the cancer may be more aggressive. Only patients who have tumors with this characteristic have been studied and been shown to benefit from trastuzumab.

“We now have a new weapon in our fight against breast cancer,” said HHS secretary, Donna E. Shalala. “For certain women with advanced disease, this new product can mean new hope.”

“As an oncologist myself, I know nothing is more important than giving patients and their doctors new ways to fight serious and life-threatening illnesses,” said FDA acting commissioner, Michael A. Friedman, MD. “The increasing use of biological products such as Herceptin to treat the underlying causes of diseases is an exciting development in medicine. The FDA will continue to make the review of products for serious and life-threatening diseases one of our highest agency priorities.”

Benefits Demonstrated in Two Clinical Trials

The benefits of trastuzumab were shown in two clinical trials. The first was a randomized, controlled clinical trial, in which 469 patients with metastatic disease who overexpressed HER-2 were assigned to receive chemotherapy alone or in combination with trastuzumab. As a group, the women who received chemotherapy plus trastuzumab had less rapid tumor growth, higher 1-year survival rates, and a greater number of tumors that were reduced 50% or more in size.

Specifically, the median time to disease progression was 7.2 months for those receiving trastuzumab and chemotherapy and 4.5 months for patients receiving chemotherapy alone. The overall tumor response was 44% in the trastuzumab group and 29% in the chemotherapy-alone group. The 1-year survival rate for the trastuzumab combination treatment was 79%, as compared with 68% for chemotherapy alone.

In the second trial, trastuzumab was used alone in a group of 222 breast cancer patients who had relapsed following previous chemotherapy for metastatic disease. The overall tumor response rate was 14%, with 3% of patients having their tumors completely disappear. The duration of tumor responses ranged from 6 weeks to 18 months, with a median of 9 months.

In both clinical trials, the patients who responded best to trastuzumab had the highest levels of HER-2 protein.

Testing of tumors from women with metastatic breast cancer is critical in order to identify the 25% to 30% of patients who overexpress HER-2 and who can potentially benefit from trastuzumab treatment. A new test to measure HER-2 protein in tumors was approved by the FDA’s Center for Devices and Radiological Health (CDRH). The new test, the DAKO HercepTest, is manufactured by Dako, a company based in Denmark.

Side Effects

The selection of patients who are most likely to benefit from trastuzumab therapy is important because along with the benefit for certain patients comes possible serious risks. The use of trastuzumab, either alone or in combination with chemotherapy, can result in a weakening of the heart muscle, which can lead to congestive heart failure. This potentially life-threatening side effect was most common in patients who received trastuzumab in combination with an anthracycline, Adriamycin, and cyclophosphamide (AC). Because the benefit is not great enough to overcome this serious risk, trastuzumab is not approved for use together with AC.

All patients treated with trastuzumab should have their heart function assessed before starting treatment and be closely monitored during treatment. If patients have heart problems, physicians must be extremely cautious in deciding whether the potential benefit is worth this risk.

Other side effects that were more frequent with trastuzumab plus chemotherapy as compared to chemotherapy alone included leukopenia, anemia, diarrhea, abdominal pain, and infections. Side effects that occurred in about half of the patients during the first infusion included chills, fever, pain, weakness, nausea, vomiting and headache. These were treatable and were much less likely to occur with subsequent infusions.

Trastuzumab is administered as an intravenous infusion given weekly. It can be administered in an outpatient setting.