Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight

Human epidermal growth factor receptor 2 (HER2) is amplified and/or overexpressed in approximately 15% to 20% of invasive breast carcinomas. Synergistic activity against HER2-overexpressing breast cancer cell lines has been observed with trastuzumab plus vinorelbine and trastuzumab plus docetaxel; additive activity was seen with trastuzumab plus paclitaxel. These and other preclinical studies prompted intense evaluation of trastuzumab with a variety of cytotoxic agents within clinical trials. On the basis of its efficacy in phase II and/or phase III trials, the 2010 National Comprehensive Cancer Network Clinical Practice Guidelines list paclitaxel (with or without carboplatin), docetaxel, vinorelbine, and capecitabine as preferred first-line agents for use in combination with trastuzumab in patients with HER2-positive, metastatic breast cancer. Notably, of these regimens, only the combination of trastuzumab and paclitaxel has gained US Food and Drug Administration approval on the basis of a progression-free and overall survival (OS) advantage in the initial pivotal trial. A survival advantage was also noted in a randomized phase II trial comparing trastuzumab/ docetaxel to docetaxel alone, supporting approval of this regimen by the European Medicines Agency. Although reasonably welltolerated,docetaxelandpaclitaxelareassociatedwithalopecia,peripheral neuropathy, hypersensitivity reactions, and requirements for corticosteroid premedication. Fatigue, hematological toxicity, and febrile neutropenia can be seen with either taxane, though more frequently with docetaxel. For these reasons, many oncologists choose to partner trastuzumab with vinorelbine, or, less frequently, capecitabine, in the first-line setting. However, until now, no adequately powered, randomized trial has directly compared the approved taxanebased regimens to nontaxane regimens in this setting. In this issue of Journal of Clinical Oncology, Andersson et al present results of the Herceptin Plus Navelbine or Taxotere (HERNATA) study—a randomized, phase III trial that enrolled patients with HER2-positive, metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy for the treatment of advanced disease. The primary study end point was time to progression (TTP). A total of 284 patients were randomly assigned to docetaxel 100 mg/m once every three weeks or to vinorelbine (30 mg/m or 35 mg/m, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle. Trastuzumab was administered to all patients on a standard once every 3 weeks schedule. Notably, all but four patients were taxane naive at study entry. The study was designed to have 90% power to reject the null hypothesis of similar TTP, assuming inferiority of vinorelbine with a hazard ratio (HR) of 1.77. As reported by Andersson et al, no differences were observed in TTP (median, 12.4 months for docetaxel, 15.3 months for vinorelbine; HR, 0.94; 95% CI, 0.71 to 1.25; P .67), objective response rate (59.3% in both arms), or OS (median, 35.7 v 38.8 months; HR, 1.01; 95% CI, 0.71 to 1.42; P .98). Time to treatment failure—defined as time from date of random assignment to the date of last study chemotherapy (ie, date of last vinorelbine or docetaxel, allowing for continuation of trastuzumab)—was significantly shorter in the docetaxel group (median, 5.6 v 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P .0001). The rate of grade 3 or 4 toxicity associated with docetaxel was significantly higher across a variety of domains, including hematologic toxicity, febrile neutropenia, infections, edema, nail changes, and sensory neuropathy. As a result, there were more frequent dose reductions of docetaxel in comparison with vinorelbine. Furthermore, the rate of treatment discontinuation resulting from toxicity was approximately three-fold higher with docetaxel (20.1% v 6.5%; P .001). What are the clinical and research implications of the HERNATA findings? Although the study was not powered to demonstrate equivalence, from a clinical perspective, given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine, we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer. Moreover, assuming HRs of 0.80 and 1.25 as cut points between clinically equivalent and clinically different, Bayesian analysis conditioned on results of the HERNATA trial indicate that the probability that trastuzumab plus vinorelbine is actually inferior to trastuzumab plus docetaxel is only 3%, whereas the probability that they are equivalent is 80% (D.A. Berry, personal communication, September 2010). Placed in the context of existing data, the results are consistent with an evolving view that, in the presence of HER2-directed therapy, the choice of chemotherapy partner is a secondary consideration. The HERNATA results are consistent with those of the Trastuzumab Plus Vinorelbine or Taxane (TRAVIOTA) study, which terminated early as a result of poor accrual; TRAVIOTA also failed to show a statistically significant difference in objective response rate (taxane 40% v vinorelbine 51%; P .37) or TTP (median, 6.0 v 8.5 months; P .09) between arms. Including those treated on the HERNATA and TRAVIOTA trials, more than 400 women have received trastuzumab plus vinorelbine as part of at least seven prospective phase II or III trials conducted in the first-line setting, all of which have confirmed the clinical activity of this regimen. From a research perspective, several issues should be emphasized. First, it is unlikely that there will ever be another randomized trial comparing regimens of trastuzumab plus taxane versus trastuzumab plus vinorelbine, and we would argue that it would be a poor use of patient and financial resources. Although trastuzumab plus chemotherapy combinations have improved the lives of patients with HER2positive metastatic breast cancer, almost all patients eventually Editorials