Abstract
BackgroundAfter two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks.MethodsPatients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization), PS ≤2, normal left-ventricular ejection fraction (LVEF) and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m2) was given on days 1&8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg) every 21 days). A single-stage phase 2 design, with p0 = 0.45, p1 = 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients.ResultsFrom Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31–81). Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8–66.2); 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3–12.3), median overall survival 22.7 months (95% CI 19.5-NA). Fifteen patients (30%) developed brain metastases at a median time of 12 months (range 1–25). There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46%) had grade 3–4 neutropenia, 2 (4%) grade 3 anemia, 4 (8%) febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF.ConclusionAlthough lower than in initial studies, activity of 3-weekly trastuzumab plus vinorelbine fell within the range of results reported with weekly schedules. Toxicity was prevalently manageable. This combination is safe and active for metastatic breast cancer patients who received adjuvant taxanes with anthracyclines.
Highlights
After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks
Other eligibility criteria included: performance status ≤2 according to the Eastern Cooperative Oncology group (ECOG) scale, adequate bone marrow, renal and hepatic (SGOT and SGPT ≤2.5 × upper normal limit and bilirubin ≤1.5 × upper normal limit, unless due to liver metastases) function
The predominant metastatic sites were visceral, and 8 patients had bone metastases combined with visceral sites
Summary
After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks. Metastatic breast cancer is an incurable disease, frequently treated with chemotherapy, when hormonal treatment has failed or is not indicated because of lack of estrogen receptor expression in the tumor. One of the major advances for the treatment of metastatic breast cancer has been the introduction of trastuzumab, a monoclonal antibody directed against the HER2 extracellular domain. The combination of trastuzumab with chemotherapy has been shown to be effective in the treatment of metastatic breast cancer patients in a pivotal study, where the monoclonal antibody was combined with either adriamycin/cyclophosphamide or paclitaxel [3]; significant advantages were reported for all the efficacy end-points, including quality of life that has been reported more recently [4]. Many studies have been conducted combining trastuzumab with other chemotherapeutic agents frequently used in breast cancer treatment. Preclinical studies have demonstrated that synergistic effects can be obtained with the combination of trastuzumab with vinorelbine or taxanes [5,6]
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