As a new feature of OncoFacts, we will be highlighting some of the most interesting and potentially practice-changing clinical trials for different malignancies. Because of my particular interest in breast cancer, I have chosen to highlight these clinical trials first. I will begin by highlighting some trials for early breast cancer, and then will review a trial for advanced breast cancer.

Adjuvant Therapy for HER2-positive Early Breast Cancer

BETH: A multicenter phase III randomized trial of adjuvant therapy for patients with HER2-positive node-positive or high-risk node-negative breast cancer comparing chemotherapy plus trastuzumab with chemotherapy plus trastuzumab plus bevacizumab

Why is this trial being done? The use of trastuzumab given concurrently with chemotherapy has become a standard of care for women with HER2-amplified, high-risk, early breast cancer. Breast Cancer International Research Group (BCIRG) 006 trial compared doxorubicin + cyclophosphamide (AC) followed by docetaxel (AC → T) to the same regimen with trastuzumab given concurrently with the docetaxel (AC → TH), and to docetaxel + carboplatin with concurrent trastuzumab (TCH). This trial has shown that the 2 trastuzumab-containing regimens to be superior to the regimen without the trastuzumab. In addition, the trial showed that the known cardiac toxicity of trastuzumab was significantly reduced in the TCH, non-anthracycline regimen. As a result, TCH has become one of several standard regimens for women with HER2-amplified breast cancer in the adjuvant setting. However, despite this very effective regimen, there is room for improvement in an attempt to further improve the development of distant metastases. It has been described that tumors that express amplification of the HER2 neu gene frequently upregulate vascular endothelial growth factor (VEGF) expression. Pegram et al have described in an abstract that the combination of trastuzumab and bevacizumab for women with HER2-amplified metastatic breast cancer has a greater than 50% response rate. As a result, this current trial is being performed to assess the benefit of adding bevacizumab to the TCH regimen in the adjuvant setting.

Who is eligible? Women with pT1-3, node-positive and HER2-amplified breast cancer, or women with pN0 breast cancer as long as they meet one of the following criteria: pathologic tumor size >2.0 cm, ER-negative and PR-negative, histologic and/or nuclear grade 2 or 3, or age <35 years. Women must have undergone definitive surgery for their breast cancer as well.

Study Schema:

1. TCH (docetaxel 75 mg/m² plus carboplatin [AUC6]) given by IV every 3 weeks x 6. Trastuzumab 8 mg/kg IV during cycle 1, and then 6 mg/kg IV concurrent with the chemotherapy on cycles 2-6, followed by trastuzumab 6 mg/kg every 3 weeks for a total of 1 year.
2. TCH as described above plus bevacizumab 15 mg/kg on days 1 during cycles 1-6, followed by the same dose given every 3 weeks concurrently with the trastuzumab for a total of 1 year.

Statistical Outcomes: 3500 women meeting eligibility criteria will be randomized. The trial was initiated in April 2008, and the estimated final collection date for the primary outcome of invasive disease-free survival (IDFS) is estimated to be in August 2012.

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT00625898?term=beth%3A+a+multicenter+
phase+iii+randomized+trial+of+adjuvant&rank=1. Accessed September 4, 2009.

ALTTO: Adjuvant lapatinib and/or trastuzumab treatment optimization Study

Why is this trial being done? Trastuzumab has become a standard of care when given concurrently with taxane-based chemotherapy for women with high-risk, HER2-positive early breast cancer. Lapatinib, an oral small molecule inhibitor of the HER2 tyrosine kinase receptor, has been approved in the metastatic setting for women with HER2-amplified breast cancer who have failed prior trastuzumab. The ALTTO study is being performed to evaluate whether there is an efficacy or safety superiority when using chemotherapy concurrent with trastuzumab or lapatinib, or with both anti-HER2 agents given either concurrently or sequentially.

Who is eligible? Women with fully resected HER2-amplified early breast cancer with lymph node involvement, or node-negative pT >1.0 cm. Women must have received a minimum of 4 cycles of an anthracycline-based adjuvant chemotherapy regimen and be randomized to 1 of 4 arms within 12 weeks of the end of that regimen.

Study Schema: After completion of a minimum of 4 cycles of an anthracycline-based chemotherapy, patients are randomized to 1 of 4 arms:

1. Trastuzumab IV every 3 weeks for 52 weeks
2. Lapatinib orally daily for 52 weeks
3. Trastuzumab weekly for 12 weeks followed by a 6 week washout, followed by lapatinib orally daily for 34 weeks
4. Lapatinib daily for 52 weeks with concurrent trastuzumab IV every 3 weeks for 52 weeks.

These 4 arms may be given concurrently with a taxane.

Statistical Outcomes: 8000 women will be randomized with the primary statistical endpoint being DFS. The study was initiated in May 2007, and the estimated final data collection date for the primary outcome is June 2010. Secondary outcomes include OS, time to recurrence, time to distant recurrence, and incidence of brain metastases.

ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT00490139?term=ALTTO&rank=2. Accessed September 4, 2009.

OncoFacts™ Editor:

Christy Russell, MD

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