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.
SAN ANTONIONovel 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 (abstract 523).
The study evaluated the efficacy and toxicity of gemcitabine 1,200 mg/m² given weekly for 2 weeks with the third week off on a 21-day cycle, plus weekly trastuzumab, until disease progression.
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."
Toxicity was not enhanced by the addition of gemcitabine to trastuzumab, and there were no unexpected cardiac toxicities, she said.
Trastuzumab Plus Vinorelbine
In another phase II multicenter study presented at San Antonio (abstract 429), 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/m²) 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.
As in the US Oncology gemcitabine study, the novel combination was well tolerated, with grade 4 hematologic toxicity limited to neutropenia and occurring in 14% of cycles; grade 3 neutropenia occurred in 20% of cycles. Six patients required hospitalization for fever (three with neutropenia). One patient had grade 4 fatigue, and one patient each had grade 3 fatigue, neuropathy, and constipation. No severe nausea, vomiting, cardiotoxicity, or alopecia was reported.
Both Dr. O’Shaughnessy and Dr. Jahanzeb stressed the value of having a trastuzumab-based regimen that does not produce alopecia. "Even my 90-year-old patients worry about losing their hair," Dr. Jahanzeb noted.