Neoadjuvant Regimens Compared in HER2-Positive Breast Cancer

Key Points

  • In women with HER2-positive breast cancer, docetaxel, carboplatin, and trastuzumab plus pertuzumab resulted in a higher pathologic complete response rate than did ado-trastuzumab emtansine plus pertuzumab.
  • This regimen was also associated with higher rates of grade 3 or 4 and serious adverse events.

The phase III KRISTINE trial has shown that neoadjuvant therapy with docetaxel, carboplatin, and trastuzumab (Herceptin) plus pertuzumab (Perjeta) resulted in a higher pathologic complete response rate vs ado-trastuzumab emtansine (Kadcyla) plus pertuzumab, as well as a higher incidence of severe adverse events. These study results were reported by Hurvitz et al in The Lancet Oncology.

Study Details

In the open-label trial, 444 women with HER2-positive stage II or III operable breast cancer and left ventricular ejection fraction ≥ 55% from 68 Translational Research in Oncology sites in Asia, Europe, the United States, and Canada were randomized between June 2014 and June 2015 to receive neoadjuvant ado-trastuzumab emtansine plus pertuzumab (n = 223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n = 221). Patients received six 21-day cycles of trastuzumab emtansine at 3.6 mg/kg plus pertuzumab at an 840-mg loading dose and 420-mg maintenance doses or docetaxel at 75 mg/m², carboplatin AUC = 6, trastuzumab at an 8-mg/kg loading dose and 6-mg/kg maintenance doses plus pertuzumab. Randomization was stratified by hormone receptor status, stage, and geographic location. The primary endpoint was the rate of pathologic complete response (ypT0/is, ypN0) in the intention-to-treat population based on local assessment of tumor samples taken at surgery performed between 14 days and 6 weeks after completion of neoadjuvant therapy.

Pathologic Complete Response

Pathologic complete response was observed in 99 patients (44.4%) in the ado-trastuzumab emtansine plus pertuzumab group vs 123 (55.7%) in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference = –11.3 percentage points, P = .016). An exploratory multivariate analysis indicated that treatment with ado-trastuzumab emtansine plus pertuzumab (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.42–0.93) and positive hormone receptor status (OR = 0.43, 95% CI = 0.28–0.65) were associated with a lower likelihood of pathologic complete response.

Adverse Events

During neoadjuvant treatment, grade 3 or 4 adverse events occurred in 64% of the docetaxel, carboplatin, and trastuzumab plus pertuzumab group vs 13% of the ado-trastuzumab emtansine plus pertuzumab group, and serious adverse events occurred in 29% vs 5%, respectively. The most common grade 3 or 4 adverse events were decreased platelet count (1% vs 5%), fatigue (1% vs 3%), increased alanine transaminase (1% vs 2%), and hypokalemia (1% vs 2%) in the ado-trastuzumab emtansine plus pertuzumab group and neutropenia (25% vs < 1%), diarrhea (15% vs < 1%), and febrile neutropenia (15% vs 0) in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group. No deaths occurred during neoadjuvant treatment.

The investigators concluded: “Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade ([ado-]trastuzumab emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.”

The study was funded by F. Hoffmann–La Roche and Genentech.

Sara A. Hurvitz, MD, of David Geffen School of Medicine, University of California, Los Angeles, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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