BOSTON—The combination of weekly trastuzumab(Drug information on trastuzumab) (Herceptin) and vinorelbine (Navelbine) gave promising results in a phase II study of metastatic breast cancer. After a median of 21 weekly courses of therapy, the combination has produced a 71% overall response rate (all partial responses) in 34 evaluable patients. The regimen has been well tolerated, and no patient has experienced symptomatic congestive heart failure.
“On the basis of these initial findings, we believe this regimen merits further exploration in patients with breast cancer,” Eric Winer, MD, said at the San Antonio Symposium.
The rationale for combining the two drugs includes nonoverlapping toxicities and in vitro studies suggesting synergistic antican-cer activity, said Dr. Winer, an oncologist at the Dana-Farber Cancer Institute.
Both agents have shown activity as single agents in metastatic breast cancer, he added. Herceptin has been associated with response rates of 12% to 23% and vinorelbine with response rates of 16% to 35%. In combination with paclitaxel (Taxol) or doxorubicin(Drug information on doxorubicin)-cyclophosphamide, Herceptin treatment has led to response rates as high as 62%.
The investigators initially set out to evaluate the combination in previously treated patients with metastatic breast cancer. Patients could not have received prior Herceptin or vinorel-bine. However, based on encouraging preliminary results in the first 15 patients, the eligibility was extended to include untreated patients. A total of 40 patients have been enrolled, and 34 were evaluable for response.
More than 70% of the patients demonstrated 3+ overexpression of HER-2. The patients had what Dr. Winer characterized as moderately heavy disease burden, including involvement of two sites in 47% of patients, three or more sites in 44%,
liver involvement in 71%, and lung involvement in 62%. Only one patient did not have either liver or lung involvement.
About half the patients had previous adjuvant chemotherapy, and 62% had received one or more chemotherapy regimens for metastatic disease. Dr. Winer said that 62% of patients had prior anthracycline exposure, 62% had prior taxane exposure, and 43% had been treated with drugs from both classes.
The Regimen
The regimen consists of weekly doses of both drugs. Herceptin is given as a 4 mg/kg loading dose, followed by 2 mg/kg weekly. Vinorelbine is given at a dose of 25 mg/m² by IV push immediately after Herceptin. Treatment is repeated weekly for 6 weeks, followed by 2 weeks off treatment. To date, a total of 707 cycles of therapy have been administered, and the number of cycles received has ranged between 1 and 45 (median, 21). The vinorelbine dose was reduced in 10% of cycles and omitted in 4%.
In addition to the 24 partial responses, two patients have had stable disease during treatment. The median time to progression is 31 weeks. Of the 15 patients who had exposure to both doxorubicin and taxanes, the response rate was 73%.
The regimen has been well tolerated, as fewer than one third of patients have developed grade 3-4 neutropenia, and one patient has developed febrile neutropenia. “The only grade 3-4 nonhematologic toxicity seen was a single episode of grade 3 headache and grade 3 pancreatitis, both in the same patient who also had heavy alcohol(Drug information on alcohol) intake,” Dr. Winer said.
Monitor Cardiac Function
Although no patient developed symptomatic congestive heart failure, three patients did discontinue treatment because of an asymptomatic decline in left ventricular ejection fraction of more than 15%, to a value of less than 50%. One of those patients had a baseline ejection fraction of 50%, and the other two had preexisting cardiac disease or a borderline ejection fraction.
“Weekly concurrent treatment with Herceptin and vinorelbine appears feasible and is well tolerated,” Dr. Winer concluded. “The most common toxicity is neutropenia, which is easily managed with vinorelbine dose reductions or omissions, required in about 15% of courses.” Dr. Winer and his colleagues believe that cardiac function requires monitoring with this regimen, particularly in patients with a borderline left ventricular ejection fraction.
“The 71% response rate suggests the combination has considerable activity in patients with HER-2-positive metastatic breast cancer,” he said.
He noted that a confirmatory trial in the first-line setting is planned, and other investigators are interested in evaluating the regimen in patients with prior Herceptin exposure.
