Single-Agent Herceptin Active in Metastatic Breast Cancer

MIAMI, Florida—Results of a recent study suggest that Herceptin (trastuzumab) may be effective as single-agent therapy in chemotherapy-naïve women with metastatic breast cancer, said lead investigator Charles Vogel, MD, clinical professor of medicine, University of Miami School of Medicine.

Speaking at the 36th Annual Meeting of the American Society of Clinical Oncology, Dr. Vogel explained that HER2 gene amplification or 3+ protein overexpression, which occurs in about 25% of human breast cancers, stimulates cell growth and is associated with poor prognosis.

In the pivotal trials providing the basis for Herceptin approval, objective responses were seen in 15% of previously treated women with metastatic breast cancer. Median survival was 13 months.

In other trials, adding Herceptin to chemotherapy improved time to progression, response rates, median duration of response, and time to treatment failure. Median duration of survival was 25 months compared with 20 months for chemotherapy alone.

In the current trial, 114 women (mean age, 54 years; 50% postmenopausal) who did not wish to receive chemotherapy for their progressive metastatic breast cancer were enrolled. All had no prior chemotherapy and all were 2+ (24%) or 3+ (76%) for HER2, according to immunohistochemical (IHC) assay, and were, in general, poor-prognosis patients, he said.

Forty-four percent and 39% of patients had lung or liver involvement, respectively, and 51% of patients had received adjuvant anthracyclines. Thirteen percent of patients had undergone adjuvant transplantation.

Patients were randomized to a standard lower-dose regimen of Herceptin (4 mg/kg IV loading and 2 mg/kg IV weekly until progression) or a higher-dose regimen (8 mg/kg IV loading and 4 mg/kg IV weekly until progression). Median follow-up was 19 months.

The primary endpoint of overall response in the two dosage groups was similar (25% and 27% in low- and high-dose groups, respectively) with 7 complete and 23 partial responses.

Thirteen patients demonstrated long-term stability of disease (greater than 6 months). The clinical benefit rates (complete response, partial response, and long-term stability of disease) were also similar: 36% for low dose and 40% for high dose. Interestingly, Dr. Vogel said, all responders had tumors that overexpressed HER2 at the 3+ level.

Median times to disease progression were similar at 3.5 months and 3.8 months for low and high dose, respectively. Overall survival was similar at 22.9 months and 25.8 months.

Time to progression among responders was 19 months. “Please recall that average time to progression for first-line chemotherapy is about 8 to 10 months,” Dr. Vogel stated. He emphasized also that the estimated median survival time of 24 months compares favorably to that for chemotherapy at 20 months.

Most adverse events were mild, with pain, asthenia, and fever most common. Dr. Vogel noted that they occurred mostly with the first dose and tended not to recur with subsequent infusions. Rash and fever occurred more often at the higher dose.

The incidence of adverse events associated typically with chemotherapy (eg, alopecia, stomatitis, leukopenia) was low. A 2.6% incidence of cardiac events was lower than in other studies where prior anthracycline exposure was greater.

Referring to recent reports in the literature and press regarding a total of 15 patient deaths among 25,000 patients treated with Herceptin, Dr. Vogel underscored that “there were no drug-related deaths in this study.” While allowing that some pulmonary toxicity in a small subset of women cannot be ruled out, Dr. Vogel commented later in an interview, “I have reviewed the deaths in that report, and it is evident that many of them were already oxygen-dependent and in-extremis at the outset of the trials.”

Dr. Vogel concluded: “Herceptin is an important new option for first-line treatment of women with metastatic breast cancer who have tumors with evidence of HER2 gene amplification or 3+ overexpression by IHC.”

He added, “It would not surprise me if Herceptin added to chemotherapy would provide further benefit, also—even if that were only an additive effect.”

ASCO discussant Douglas Yee, MD, University of Minnesota Cancer Center, pointed out, “Herceptin has very good activity and a favorable side-effect profile as treatment for advanced breast cancer. Interestingly, the time to progression for the responding patients was on the order of that seen with tamoxifen [Nolvadex] at about 19 months.”

Dr. Yee said that among appropriate patients, single-agent Herceptin could be given first. Lacking response, chemotherapy and Herceptin could be administered together. With a response, after chemotherapy has been stopped, Herceptin could be continued.