PLANTATION, FloridaThe humanized anti-HER2 antibody trastuzumab(Drug information on trastuzumab) (Herceptin) produced an overall response rate of 26% when used as first-line therapy in women with metastatic breast cancer whose tumors overexpress HER2.
Charles Vogel, MD, clinical professor at the Sylvester Cancer Center of the University of Miami, reported data from a trial comparing standard-dose and high-dose trastuzumab regimens at the ASCO annual meeting.
Trastuzumab alone is an effective and safe treatment for patients with recently diagnosed metastatic breast cancer, Dr. Vogel summarized. Survivals in this study were similar to those reported with first-line trastuzumab plus chemotherapy. Response rates are similar at the 2-mg/kg and 4-mg/kg maintenance dose, and trastuzumab is well tolerated and has a favorable safety profile.
The incidence of cardiac dysfunction in this trial was much lower than that in other trials with patients who had more prior anthracycline exposure, Dr. Vogel noted. He said that the only cardiac events were in two patients with extensive preexisting cardiac disease.
Single-agent trastuzumab is an important new option for first-line treatment of women with metastatic breast cancer whose tumors demonstrate evidence of HER2 gene amplification or 3+ HER2 gene overexpression by immunohistochemistry, he stated.
Trastuzumab as a Single Agent
Previous studies had shown a benefit from trastuzumab used with chemotherapy as first-line treatment for metastatic breast cancer, or used as a single agent for metastatic breast cancer progressing after initial chemotherapy. This study examined the usefulness of trastuzumab alone in lieu of chemotherapy in women with metastatic breast cancer.
Patients enrolled were women who did not wish to receive chemotherapy for metastatic breast cancer. They had progressive, metastatic disease with HER2 overexpression at 2+ or 3+ according to the clinical trials assay. They had to have no prior chemotherapy for stage IV disease. They had to have measurable disease; bone-only disease was excluded, Dr. Vogel said.
The trial included 114 women, with a mean age of 54 years: 50% were postmenopausal, 76% had tumors expressing HER2 at the 3+ level, 44% had lung metastases, and 39% had liver metastases. The median disease-free interval had been 17 months. Fifty-one percent of patients had received adjuvant anthracyclines, and 13% had undergone adjuvant high-dose therapy with transplantation.
Patients were randomized to a standard lower-dose regimen of trastuzumab (4 mg/kg IV loading and 2 mg/kg IV weekly maintenance until progression) or to a higher-dose regimen (8 mg/kg IV loading and 4 mg/kg IV weekly until progression).
The primary endpoints were overall response rate and safety. Secondary endpoints were duration of response, time to progression, and survival.
The mean duration of follow-up was 19 months. Only three patients were inevaluable.
One Unexpected Result
The response rate for the entire group was 26%. Response rates in the two dosage groups were similar: 25% for standard dose and 27% for high dose.
There were 7 complete responses and 23 partial responses, for an overall response rate of 26% in the intent-to-treat analysis, Dr. Vogel reported. Thirteen patients had stable disease for more than 6 months, for an overall clinical benefit rate of 38%.
All responders had tumors that overexpressed HER2 at the 3+ level. This was unexpected, Dr. Vogel said.
The median times to disease progression were similar: 3.5 months for standard-dose treatment and 3.8 months for high-dose treatment. However, most striking was a clinical benefit rate of 47% in 3+ overexpressors.
Median time to progression was 19 months in the subgroup of patients who were responders and 15 months in the patients who derived clinical benefit. The median time to progression was only 2 months for those not deriving clinical benefit.
It is worth remembering that the average response duration to first-line chemotherapy in patients with metastatic breast cancer is 8 to 10 months, Dr. Vogel said.
Similar Overall Survival
Overall survival times were also similar: 22.9 months for the standard-dose group and 25.8 months for the high-dose group. The estimated median duration of survival was 24 months. Please recall that there is a 20-month median survival for chemotherapy alone in prior Herceptin pivotal-trials, Dr. Vogel said.
Forty-three percent of the patients who had prior transplant derived clinical benefit from single-agent trastuzumab, he added.
Most adverse effects were mild to moderate in severity. The most common were pain, asthenia, fever, and chills. Dr. Vogel said that these typically occurred with the first dose of therapy and tended not to recur with subsequent infusions. The incidence of adverse events typically associated with chemotherapy, such as neutropenia and alopecia, was low.
Reports of serious cardiac events in other trials prompted a retrospective analysis of cardiac events by an independent review committee, Dr. Vogel noted.
Cardiac dysfunction was defined as congestive failure or at least a 10% decrease in left ventricular ejection fraction. The incidence of cardiac dysfunction was 2.8%.
This event rate appears lower than was seen in other studies where patients had greater previous exposure to anthracyclines. There were no drug-related deaths in this study. Both treatment discontinuations were due to cardiac events, he said. Both patients who developed cardiac dysfunction had significant underlying ischemic cardiac disease.