Vinorelbine 'Preferred' Chemo in HER2-Positive Advanced Breast Cancer

Toxicity, not efficacy, is key

Nick Mulcahy

January 26, 2011

January 26, 2011 — What's the best chemotherapy to use in combination with trastuzumab in women with HER2-positive metastatic and locally advanced breast cancer?

The answer is not found in the efficacy data; instead, it is found in toxicity results, according to the Scandinavian authors of a new study on the subject.

On that score, the investigators found, in a phase 3 trial of first-line therapies, that vinorelbine (Navelbine) had significantly fewer adverse effects than docetaxel (Taxotere) when each was combined with trastuzumab (Herceptin). Efficacy, measured by time to progression, was comparable between the 2 regimens.

Results from the Herceptin Plus Navelbine or Taxotere (HERNATA) trial, which comprised 284 women from Denmark, Sweden, and Norway, were first presented at the European Breast Cancer Conference in 2010 and have now been published in the January 20 issue of the Journal of Clinical Oncology.

The results reflect what medical oncologists have been finding out on their own in clinical practice, suggest the authors of an editorial that accompanies the study.

"Many clinicians choose to partner trastuzumab with vinorelbine or, less frequently, capecitabine" in this first-line setting because the taxane alternatives are generally more toxic, say 2 breast cancer oncologists, Nancy U. Lin, MD, and Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, who wrote the editorial.

This study firmly establishes . . . trastuzumab plus vinorelbine as an acceptable, and even preferred, option.

"Given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine," they write, "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."

The study authors, led by Michael Andersson, MD, from Rigshospitalet in Copenhagen, Denmark, are less definitive. They conclude their paper by saying that "vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balance."

But they also write that "the choice of a first-line chemotherapy drug . . . may not be important . . . regarding treatment efficacy, but it certainly is important in terms of toxicity." In other words, the authors indirectly champion vinorelbine over taxanes, including docetaxel.

According to Dr. Lin and Dr. Winer, only the taxane paclitaxel is currently approved by the US Food and Drug Administration for use in combination with trastuzumab in HER2-positive metastatic breast cancer. Docetaxel is approved for use in combination therapy by the European Medicines Agency. Vinorelbine is approved by neither agency in this setting at this point. However, the National Comprehensive Cancer Network lists vinorelbine — along with paclitaxel (with or without carboplatin), docetaxel, and capecitabine — as preferred first-line agents in this setting.

The editorialists believe that more research studies are not needed to further define which chemotherapy is optimal in this setting. "In our view, little will be gained by playing musical chairs with chemotherapeutic agents," they write.

Trastuzumab is the "great equalizer," they add, "rendering the specific choice of chemotherapy secondary."

What is needed in research is an expansion of investigations into "individualized and targeted" therapies; they need to "claim the limelight," say Dr. Lin and Dr. Winer.

Study Findings

The study, which was supported by Roche and Sanofi-Aventis, enrolled patients with HER2-positive metastatic or locally advanced breast cancer who had not received previous chemotherapy or HER2-targeted therapy for the treatment of their advanced disease.

A total of 284 patients were randomized to treatment with either docetaxel 100 mg/m2 once every 3 weeks (n =1 43) or vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle (n = 141). Trastuzumab was administered to all patients once every 3 weeks.

Treatment was continued until progression, intolerable toxicity, or patient withdrawal.

The primary study end point was time to progression, which was not statistically significantly different: the median for docetaxel was 12.4 months and for vinorelbine was 15.3 months (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.71 to 1.25; = .67).

This efficacy outcome favoring vinorelbine was surprising, explain the study authors.

"At the time of conception of the study, it was believed that the vinorelbine plus trastuzumab combination was inferior to docetaxel plus trastuzumab in terms of efficacy," they write.

There was no difference in most of the secondary end points, including overall survival. Median overall survival was 35.7 months for docetaxel and 38.8 months for vinorelbine (HR, 1.01; 95% CI, 0.71 to 1.42; = .98).

The one exception to this — time to treatment failure — cast docetaxel in a negative light. Median time to treatment was significantly shorter for docetaxel than for vinorelbine (5.6 vs 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; < .0001).

Toxicity is where the 2 agents were most different, say both the authors and the editorialists. More patients in the docetaxel group than in the vinorelbine group discontinued therapy because of toxicity (20.1% vs 6.5%; < .001).

With docetaxel, compared with vinorelbine, there were also significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% vs 10.1%), leucopenia (40.3% vs 21.0%), infection (25.1% vs 13.0%), fever (4.3% vs 0.0%), neuropathy (30.9% vs 3.6%), nail changes (7.9% vs 0.7%), and edema (6.5% vs 0.0%).

Dr. Andersson reports receiving honoraria from Roche and Sanofi-Aventis, the 2 companies that sponsored the study. Some of the study coauthors reported financial ties to these companies and others. Dr. Lin reports receiving research funding from Genentech, GlaxoSmithKline, Boehringer Ingelheim, and Infinity Pharmaceuticals. Dr. Winer reports receiving research funding from Genentech.

J Clin Oncol. 2010;29:251-253, 264-271. Abstract, Abstract

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