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Randomized Phase III Trial of Weekly Compared With Every-3-Weeks Paclitaxel for Metastatic Breast Cancer, With Trastuzumab for all HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840

Andrew D. Seidman, Donald Berry, Constance Cirrincione, Lyndsay Harris, Hyman Muss, P. Kelly Marcom, Grandella Gipson, Harold Burstein, Diana Lake, Charles L. Shapiro, Peter Ungaro, Larry Norton, Eric Winer, Clifford Hudis

From the Memorial Sloan-Kettering Cancer Center, New York, NY; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; University of North Carolina at Chapel Hill, Chapel Hill, NC; Dana-Farber Cancer Institute, Boston, MA; Vermont Cancer Center, Burlington, VT; and The Ohio State University Medical Center, Columbus, OH

Corresponding author: Andrew D. Seidman, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; e-mail: seidmana{at}mskcc.org

Purpose Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)–positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population.

Patients and Methods Patients were randomly assigned to paclitaxel 175 mg/m² every 3 weeks or 80 mg/m² weekly. After the first 171 patients, all HER-2–positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors.

Results In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003).

Conclusion Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.

Supported in part by National Cancer Institute Grants No. CA77651, CA33601, CA32291, CA77406, CA47577, CA77658, and CA47559.

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Optimal Schedule of Paclitaxel: Weekly Is Better
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