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Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer

Nicholas Robert, Brian Leyland-Jones, Lina Asmar, Robert Belt, Des Ilegbodu, David Loesch, Robert Raju, Elizabeth Valentine, Robert Sayre, Melody Cobleigh, Kathy Albain, Cecelia McCullough, Lea Fuchs, Dennis Slamon

From US Oncology Research Inc, Houston, TX; Departments of Oncology and Medicine, McGill University, Montreal, Quebec, Canada; Rush-Presbyterian-St Luke's Medical Center, Chicago; Loyola University Medical Center, Maywood, IL; and the University of California, Los Angeles, School of Medicine,Los Angeles, CA

Address reprint requests to Nicholas Robert, MD, 8503 Arlington Blvd, Suite 400, Fairfax, VA 22031; e-mail: nicholas.robert{at}usoncology.com

PURPOSE: This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2–overexpressing metastatic breast cancer (MBC).

PATIENTS AND METHODS: HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2–overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m² every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m² and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone.

RESULTS: Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01).

CONCLUSION: The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2–overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.

Supported by grants from Bristol-Myers Squibb Co, Princeton, NJ, and Genentech Inc, South San Francisco, CA.

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

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