Introduction

The results of a multinational phase II study reported at the 25th Annual San Antonio Breast Cancer Symposium confirm the high activity of the vinorelbine (Navelbine) and trastuzumab (Herceptin) doublet as a first-line chemotherapeutic treatment regimen for metastatic breast cancer tumors overexpressing the HER2/neu protein.¹ The findings of the current study, reported by Arlene Chan, MD of Mount Hospital, Perth, Australia, build upon preclinical synergy demonstrated for the combination of vinorelbine and trastuzumab, as well as clinical benefit initially demonstrated as a second-line treatment option² and more recently, as a first-line chemotherapeutic treatment option for metastatic breast cancer.³ The reported objective clinical response rate of 70%, coupled with a favorable toxicity profile, suggests the vinorelbine/trastuzumab doublet constitutes a safe and effective new chemotherapeutic treatment option for metastatic breast cancer.

Vinorelbine/Trastuzumab: First-line Chemotherapy for Metastatic Breast Cancer

Currently, the study has enrolled 41 patients (60 patients planned) with HER2-positive metastatic breast cancer (40 patients were 3+ by IHC and one patient was FISH+) who have received no prior trastuzumab or chemotherapy for metastatic disease. The median patient age was 51 years (range, 30-71 years). Sixty-six percent of patients had received prior adjuvant/neoadjuvant chemotherapy (32% anthracycline; 12% taxane; 7% both), 51% of patients had received prior hormonal therapy, and 60% of patients exhibited visceral metastasis.

Patients were treated with weekly doses of intravenous vinorelbine (30 mg/m²) and trastuzumab (4 mg/kg loading dose, then 2 mg/kg) within 4-week cycles until disease progression. The number of cycles administered to date was 184 (median 4, range of 1-10). The weekly median dose administered for vinorelbine was 20 mg/m² and 2 mg/kg for trastuzumab.

In 37 patients evaluable for response (at least two cycles of treatment), objective clinical responses were observed in 70% (26/37) of patients. This included 7 complete responses (19%) and 19 partial responses (51%), while 7 patients (19%) had stable disease and 4 patients (11%) had progressed.

The vinorelbine/trastuzumab doublet was well tolerated. No severe neuropathy, nausea, vomiting, or alopecia was reported. One patient withdrew from the trial due to grade 3 cardiac toxicity and symptomatic cardiac dysfunction. The patient's cardiac dysfunction resolved with therapy. Grade 3 and 4 toxicities are displayed in Table 1.

Dr. Chan commented on the observed favorable cardiac safety profile. "Patients who received prior anthracyclines may well have had some preexisting cardiac effects from the anthracycline, but this was not exaggerated by the use of trastuzumab."

Comparing the tolerability of the vinorelbine/trastuzumab doublet to taxane-based chemotherapeutic regimens, Dr. Chan stated. "I have treated a lot of patients with trastuzumab in combination with docetaxel or paclitaxel. Very few patients, even though responding, are able to tolerate those combination doublets past 4 or 5 months of treatment. What they find intolerable are the asthenia, arthralgias and myalgias. Given an [alternative treatment] option, most patients on those doublets would rather continue on single-agent trastuzumab once they have experienced an initial response. Patients who have had experience with chemotherapy in the adjuvant setting can clearly tell the difference with the vinorelbine/trastuzumab combination."

Dr. Chan also recommended implanting a Portacath to facilitate venous access. "The majority of these patients are on treatment for many, many months. Our longest-treated patient is at 102 weeks, still responding and in complete remission. We generally begin patients with a peripheral line, but once we see they are responding, we often recommend a Portacath. With a Portacath, the patient can start treatment as soon as they come in the clinic. And the way, in which we maintain them, there is very little risk of clotting."

The response rate observed with vinorelbine/trastuzumab was considered impressive by Dr. Chan. "The response rate was not affected by adjuvant chemotherapy, either with anthracyclines, taxanes, or cyclophosphamide/methotrexate/fluorouracil, and it did not surprise me that patients can still respond to vinorelbine/trastuzumab," she said. "Considering the response rate and the favorable cardiac profile of vinorelbine/trastuzumab, this constitutes the best combination for this subgroup of [pretreated] patients."

The response rate observed in this study is consistent with previously published trials of vinorelbine/trastuzumab, in which response rates of 68-78% have been reported.^2-6 Moreover, the response rate in the study by Burstein et al,² was greater than 60% even in the second- and third-line setting.

Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts was in attendance at the meeting and commented on the current study in light of previous ones. "The remarkable thing about all these trials is how incredibly consistent they have been. There are now four or five large phase II trials with the combination of vinorelbine and trastuzumab, all showing robust response rates, and all with similar and well-tolerated side effect profiles. There is a nice critical mass of data for this regimen and we think it is a very useful one for our patients."

Synergy May Explain Benefit of Combination

Vinorelbine is a third-generation vinca alkaloid which has demonstrated significant single-agent activity and synergy with trastuzumab in treating breast cancer. The precise mechanism of action between HER2/neu-targeted therapies and cytotoxic agents is unclear, but it has been recently shown that vinca alkaloids may affect several members of the mitogen-activated protein (MAP) kinase pathway. This likely plays an important role in the induction of apoptosis by these agents. Further, it appears that downstream signal transduction pathways involving MAP kinase proteins may be mediated by the HER family of receptors.⁷ Further elaboration of these findings should provide a mechanistic explanation for the synergy seen with the vinorelbine/trastuzumab combination, according to Peter A. Kaufman, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

"Evolving evidence suggests that there is a balance between these pathways leading to either cell survival or apoptosis. With vinorelbine and trastuzumab, there may be particularly unique synergy in how they function through these pathways to induce cell death," Dr. Kaufman commented.

The clinical relevance of the vinorelbine/trastuzumab effect on several members of the MAP kinase pathway is being evaluated by Dr. Kaufman in a phase I study involving advanced breast cancer patients with HER2-positive tumors. The final results of his study will be reported at a later date, but the preliminary results were available for this meeting.⁸

While previously reported studies have typically used vinorelbine weekly in treating metastatic breast cancer, Dr. Kaufman's study used an escalated dosing schedule of vinorelbine administered on Days 1 and 8 of a 21-day cycle. "The premise being there is modest evidence suggesting vinorelbine can be delivered in a more consistent fashion on Days 1 and 8 without having to reduce the dose. Patients tend to develop nadir absolute neutrophil counts (ANCs) by Days 10 to 14 with weekly vinorelbine. We think we can deliver better dose intensity if we eliminate the dose at the time of the nadir and just give a Day 1 and 8 schedule," he explained.

The study included 13 patients with locally advanced breast cancer refractory to first-line chemotherapy and overexpression of HER2/neu (1-3+ by ICH analysis). Patients received escalating doses of vinorelbine at 20, 25, and 30 mg/m² on Days 1 and 8 every 21 days, in addition to conventionally dosed trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly).

With the trastuzumab dose remaining constant, responses to vinorelbine 20 mg/m² were seen in 0/2 evaluable patients, and in 1/3 and 3/5 evaluable patients receiving vinorelbine 25 mg/m² and 30 mg/m², respectively.

Dose-limiting toxicity was based on events occurring during the first cycle of treatment. No dose-limiting toxicities occurred in the first cycle of treatment at the vinorelbine dose of 20 mg/m² and 25 mg/m². At vinorelbine 30 mg/m², there were two dose-limiting toxicities (one case of febrile neutropenia and one of acute cholecystitis, which was judged not likely to be treatment-related). Asymptomatic grade 3 and 4 neutropenia was the primary toxicity noted with ongoing cycles of chemotherapy; occurring 5 times at the vinorelbine dose of 25 mg/m², and 9 times at the vinorelbine 30 mg/m² dose. Additional hematologic toxicities as well as non-hematologic toxicities were uncommon.

The maximally tolerated dose of vinorelbine without the use of growth factor support was found to be 30 mg/m². "This dose was clearly safe and tolerable in this dosing schedule, giving it on Days 1 and 8 of a 21-day schedule," Dr. Kaufman stated. "Given the potential efficacy and 33% reduction in clinic and therapy visits for patients receiving this dosing schedule compared to weekly vinorelbine, we believe this schedule warrants further investigation for the treatment of metastatic breast cancer."

Phase III Trastuzumab/Paclitaxel with/without Carboplatin Study

In another study reported at the 25th Annual San Antonio Breast Cancer Symposium, adding carboplatin to the combination of paclitaxel and trastuzumab enhanced the effectiveness of treatment for HER2-positive advanced breast cancer patients, in terms of response and time to progression.⁹ The study included 196 patients with advanced breast cancer (median age 55 years) who received the standard trastuzumab dosing schedule (loading dose 4 mg/kg, followed by 2 mg/kg weekly) plus paclitaxel 175 mg/m² over 3 hours every 3 weeks. Half the patients also received carboplatin dosed at an area-under-the-curve (AUC) of 6 every 3 weeks.

The addition of carboplatin improved the response rate from 36% to 52% (P<.01), and time to progression from 6.9 months to 11.2 months (P = .002), reported principal investigator Nicholas Robert, MD, of Fairfax-Northern Virginia Hematology-Oncology, Fairfax, Virginia.

Side effects with the trastuzumab/paclitaxel/carboplatin triplet included neutropenia in 86% of patients, leukopenia in 11%, thrombocytopenia in 9%, anemia in 5%, fatigue in 11%, neuropathy in 8%, and nausea in 6%.

Conclusion

The results of a multinational phase II study reported at the 25th Annual San Antonio Breast Cancer Symposium confirm the high activity of the vinorelbine (Navelbine) and trastuzumab (Herceptin) doublet as a first-line chemotherapeutic treatment regimen for metastatic breast cancer tumors overexpressing the HER2/neu protein. The reported objective clinical response rate of 70%, coupled with a favorable toxicity profile, suggests the vinorelbine/trastuzumab doublet constitutes a safe and effective new chemotherapeutic treatment option for metastatic breast cancer.

References
1. Chan A, Untch M, Petruzelka L, et al. Multinational phase II study of Navelbine (N) and Herceptin (H) as first-line therapy for HER2-overexpressing metastatic breast cancer (HER2+ MBC). 25th Annual San Antonio Breast Cancer Symposium, December 11-14, 2002, San Antonio, Texas. Abstract 434.
2. Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2001; 19:2722-2730.
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8. Kaufman PA, Schwartz G, Dragnev K, et al. Phase I trial of Herceptin (H) and Navelbine (Nvb) for patients with HER-2/neu(+) advanced breast cancer. 25th Annual San Antonio Breast Cancer Symposium, December 11-14, 2002, San Antonio, Texas. Abstract 431.
9. Robert N, Leyland-Jones B, Asmar L, et al. Phase III comparative study of trastuzumab and paclitaxel with and without carboplatin in patients with HER-2/neu positive advanced breast cancer. 25th Annual San Antonio Breast Cancer Symposium, December 11-14, 2002, San Antonio, Texas. Abstract 35.