Trastuzumab-Based Combos Effective in Advanced Cancer

SAN ANTONIO—Novel regimens pairing gemcitabine (Gemzar) and vinorelbine (Navelbine) with trastuzumab (Herceptin) showed significant antitumor activity and good tolerability in heavily pretreated HER-2-positive patients with metastatic breast cancer, in studies reported at the 24th Annual San Antonio Breast Cancer Symposium.

"It is becoming increasingly clear that patients with HER-2-positive metastatic breast cancer will get trastuzumab as the backbone of their therapy," said Dr. Joyce O’Shaughnessy, a principal investigator of one of these studies. "We need to determine the contribution of additional agents to this important treatment."

Dr. O’Shaughnessy, co-director of Breast Cancer Research, Baylor-Sammons Cancer Center and US Oncology, Dallas, reported the first results from a multicenter phase II study of 64 heavily pretreated patients whose breast cancers overexpressed HER-2 at the 2+ or 3+ level by immunohistochemistry and who had not yet been treated with trastuzumab or gemcitabine. For 72% of the patients, this novel combination was at least third-line treatment.

Objective partial responses were observed in 22 (37%) of 59 evaluable patients. Among the 38 patients with 3+ overexpression of HER-2, 17 responded (45%); among the 21 patients with 2+ overexpression, 5 patients responded (24%). In addition, 22 of the 59 evaluable patients (37%) had stable disease for a median of 4 months, and the median duration of response was 5.8 months, Dr. O’Shaughnessy reported.

The combination therapy appeared to boost the response rate above that achieved with the individual agents in prior studies in heavily treated patients with gemcitabine and trastuzumab alone. Trastuzumab in late-line therapy produces about a 15% response rate, and the response to gemcitabine, in patients pretreated with anthracyclines and taxanes, is about 10% to 20%, she said.

"Our overall response rate was 37%, so conservatively we can say that this response may be additive," she commented. "And when we look at the patients with 3+ overexpression of HER-2, and see a 45% response rate in very heavily pretreated patients, this would even suggest possible synergy. A 45% response rate in a multicenter community-based trial is an impressive result in this patient population."

Trastuzumab Plus Vinorelbine

In another phase II multicenter study presented at San Antonio Mohammad Jahanzeb, MD, research director, Boca Raton Comprehensive Cancer Center, and his colleagues evaluated 40 patients with previously untreated metastatic breast cancer who received weekly doses of trastuzumab and vinorelbine (30 mg/mē) without a break. Four weeks constituted a treatment cycle.

At the time of the report, 37 patients had received at least two cycles and were evaluable for response. Four complete responses and 25 partial responses were observed, for an overall response rate of 78%. Four patients were stable and four had progressed, Dr. Jahanzeb reported.

Response seemed to correlate with the degree of HER-2 positivity, in that higher responses were seen in 3+ overexpressors by immunohistochemistry (82%), compared with 2+ overexpressors (58%), and in patients testing positive for HER-2 by fluorescence in situ hybridization (FISH) (83% vs 54% for FISH-negative patients).

The achievement of a good response rate in FISH-negative patients is "a hypothesis-generating observation," he said, possibly indicating an unusual synergistic interaction. "Even in FISH-negative patients, trastuzumab may have enhanced vinorelbine efficacy," he said.

Herceptin/Docetaxel/Platinum Effective in Advanced Breast Cancer

SAN FRANCISCO—Very high response rates were achieved in a pilot study with the combination of docetaxel (Taxotere), platinum salts, and trastuzumab (Herceptin) in advanced breast cancer. The study, under the leadership of Dennis J. Slamon, MD, of UCLA, involved 62 patients, most of whom had visceral metastases and prior adjuvant chemotherapy. More than half tested positive for HER-2/neu by fluorescence in situ hybridization (FISH).

The study evaluated the safety and efficacy of combining docetaxel, cisplatin (Platinol) or carboplatin (Paraplatin), and trastuzumab as a precursor to the phase III BCIRG 006 trial, which recently began accrual.

BCIRG 006 is randomizing women with HER-2-positive, node-positive or high-risk node-negative operable breast cancer to receive adjuvant doxorubicin (Adriamycin)/cyclophosphamide/doce-taxel with or without trastuzumab or trastuzumab, docetaxel, and either carboplatin or cisplatin.

Mark Pegram, MD, also of UCLA, presented the poster at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 193).

The results of this pilot study confirmed that the combination of docetaxel, a platinum, and trastuzumab is very active and not cardiotoxic. Preliminary response data showed overall response rates of 86% with the cisplatin combination in patients who were FISH-positive, and 81% in FISH-negative patients.

In patients receiving the combination of docetaxel, carboplatin, and trastuzumab, overall responses were seen in 65% of FISH-positive patients and 41% of FISH-negative patients.

This regimen, indeed, capitalized on the synergy of these combined agents while avoiding the toxicity of doxorubicin followed by trastuzumab, Dr. Pegram said. "Cardiotoxicity could be a major concern in adjuvant therapy. Remember that stage II patients have significant survival rates, and we don’t want cardio-toxicity issues long-term," he said.

Herceptin + Chemo Increases Survival in Metastatic Breast Cancer

ASCO—Updated results of a phase III trial show that the addition of the anti-HER2/neu monoclonal antibody (MoAb) Herceptin (trastuzumab) to chemotherapy improves survival in patients with metastatic breast cancer, compared with chemotherapy alone.

Herceptin plus either AC (Adriamycin and cyclophosphamide) or paclitaxel (Taxol) reduced the relative risk of death by about one-quarter and extended median survival time by the same amount, Larry Norton, md, said at ASCO.

The 469 patients with HER2-overex-pressing metastatic breast cancer enrolled in the trial were divided into two strata. Patients who had not received prior adjuvant chemotherapy (n = 281) were randomized to doxorubicin (or epirubicin) and cyclophosphamide with or without Herceptin, whereas those who had been previously exposed to adjuvant chemotherapy (n = 188) were randomized to paclitaxel with or without the MoAb.

Preliminary results of the trial had shown significant improvements in time to progression, response rate and duration, and 1-year survival in patients treated with combination therapy, albeit at the cost of increased cardiotoxicity. The updated results, obtained after a median follow-up of 29 months, showed that Herceptin combined with either chemotherapy regimen decreased the relative risk of death by 24% and increased median survival time from 20.3 to 25.4 months.

‘This Changes Everything’

“With these results, Herceptin joins a very short list of agents that have proven, in a randomized trial, to improve overall survival for metastatic breast cancer,” George Sledge, Jr., MD, of Indiana University, said in his discussion of the trial. He noted that “this changes everything.” Testing for HER2 and use of Herceptin in HER2-positive patients should be considered part of standard care for patients with metastatic breast cancer, he said.

Nevertheless, further study is warranted to address many unresolved issues surrounding the use of Herceptin in breast cancer. One of the most important of these, according to both Dr. Sledge and Dr. Norton, is integration of the MoAb into the adjuvant setting.

Further study also is needed, Dr. Norton said, to compare Herceptin plus weekly paclitaxel with Herceptin plus the more traditional, every-3-week schedule of the taxane.

A Phase II Trial

Weekly paclitaxel plus Herceptin showed favorable results in another trial presented at ASCO. In this phase II cooperative study conducted at Memorial Sloan-Kettering and M.D. Anderson, Herceptin plus weekly paclitaxel showed activity in patients with metastatic breast cancer with toxicity similar to that seen in previous studies of paclitaxel alone.

Herceptin plus weekly paclitaxel produced responses in 62% of patients with HER2-positive disease and 44% of those with HER2-negative cancers, for an overall response rate of 52%.