Herceptin® (Trastuzumab)

Full Prescribing Information, including Boxed Warnings

What Is Herceptin? Herceptin® (Trastuzumab) is the first monoclonal antibody approved for use in women with breast cancer who have tumors that overexpress the human epidermal growth factor receptor-2 (HER2) protein. The U.S. Food and Drug Administration (FDA) first approved Herceptin in September 1998 for the weekly treatment of patients with HER2-positive metastatic breast cancer both as a first-line therapy in combination with paclitaxel and as a single agent for those who have received one or more chemotherapy regimens. Since this initial approval, nearly 420,000 women have been treated with Herceptin worldwide. Herceptin's efficacy and safety profile is well-established.

In November 2006, the FDA approved Herceptin as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel, for the adjuvant treatment of patients with HER2-positive, node-positive, breast cancer. Adjuvant therapy is given to women with early-stage (localized) breast cancer who have had initial treatment — surgery with or without radiation therapy — with the goal of reducing the risk of cancer recurrence and/or the occurrence of metastatic disease.

In January 2008, the FDA approved Herceptin as a single agent for the adjuvant treatment of HER2-positive, node-negative (ER/PR-negative or with one high-risk feature), or node-positive breast cancer, following multi-modality anthracycline-based therapy based on the one-year HERA data. The FDA approval expanded Herceptin's adjuvant label to include the use of Herceptin as a single agent and in patients with early-stage HER2-positive node-negative disease, including tumors that are hormone receptor-negative, grade 2 or 3 or >2 cm, or age <35. Herceptin also may be administered as a single agent in an every-three-week dosing schedule for one year, which may provide another treatment option for patients.

In May 2008, the FDA approved two new Herceptin-containing regimens for the adjuvant treatment of HER2-positive node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer based on the results of the BCIRG 006 study. The first regimen is in combination with docetaxel and carboplatin, (also known as TCH for Taxotere®, carboplatin, and Herceptin) which does not contain an anthracycline component. The second is part of a treatment regimen containing anthracycline (doxorubicin), cyclophosphamide, and docetaxel (AC-TH). The approval of the non-anthracycline TCH regimen added an important treatment option for patients as it reduced the rate of congestive heart failure (0.4% vs. 2%) as compared to the Herceptin anthracycline-containing regimen in the 006 study and significantly reduced the relative risk of recurrence by one-third, compared to chemotherapy alone. In comparison to AC-TH, TCH provided a similarly effective treatment option with less cardiotoxicity, which may potentially allow more patients to benefit from Herceptin therapy.

Research has shown that women with HER2-positive breast cancer have a more aggressive disease, greater likelihood of recurrence, poorer prognosis, and decreased survival compared to women with HER2-negative breast cancer.

Clinical Trial Results In Metastatic Breast Cancer
Herceptin was proven effective in HER2-positive metastatic breast cancer clinical trials, both as a single agent and in combination with paclitaxel. In the Phase III combination trial, Herceptin plus chemotherapy improved overall survival rates and slowed disease progression of women as a first-line therapy.

Herceptin was the first anti-HER2 agent to demonstrate an improvement in survival in a Phase III trial. In December 2001, Genentech received FDA approval to include, in the product label, data that showed an improved median overall survival for women with HER2-positive metastatic breast cancer treated initially with Herceptin and chemotherapy, compared to chemotherapy alone (median 25.1 months compared to 20.3 months).

A summary of metastatic trial data follows:

After one year, data showed that 79 percent of patients receiving Herceptin plus chemotherapy were alive compared to 68 percent of patients receiving administration of chemotherapy alone.

In addition to improving survival, Herceptin, when combined with chemotherapy, was shown to improve overall response rates, from 32 percent in women treated with chemotherapy alone to 49 percent with the addition of Herceptin. The median time to disease progression increased from 4.6 months in the chemotherapy alone group to 7.6 months in the Herceptin plus chemotherapy group.

In the trial evaluating Herceptin alone, 14 percent of 222 women who had failed one or two prior chemotherapy regimens had objective tumor responses with tumor shrinkage of 50 percent or greater. Herceptin also was shown to have a median duration of response of nine months. Median survival in this single-arm study was 13 months.

In the Adjuvant Setting
Herceptin, in addition to standard therapy, was proven effective in the adjuvant treatment of HER2-positive breast cancer. Results from a planned interim analysis of more than 3,700 patients, enrolled in two NCI-sponsored trials (NSABP B-31 and NCCTG N9831), showed that the addition of Herceptin to standard therapy reduced the relative risk of breast cancer recurrence by 52 percent (or a hazard ratio of 0.48) in women with HER2-positive breast cancer, compared to patients who received standard therapy alone.

In the HERA study, results from the one-year arm showed a significant reduction of the relative risk of breast cancer recurrence by 46 percent (or a hazard ratio of 0.54) in women taking Herceptin for 52 weeks, with HER2-positive lymph node-positive and high-risk, lymph node-negative breast cancer, compared to those patients who received standard adjuvant therapy alone.

The BCIRG 006 study demonstrated improved disease-free survival (DFS) with both Herceptin-containing arms, compared to the chemotherapy alone arm. Adding Herceptin to Taxotere following AC chemotherapy (AC-TH), or adding Herceptin to Taxotere and carboplatin chemotherapies (TCH), resulted in improved DFS compared to chemotherapy alone. The study showed a reduction in relative risk of disease recurrence by 40 percent in patients on AC-TH (based on a hazard ratio of 0.60) and a reduction in relative risk of disease recurrence by 33 percent in patients on TCH (based on a hazard ratio of 0.67), as compared to the AC-T arm. Compared to AC-TH, TCH provided a similarly effective treatment option with less cardiotoxicity, which may potentially allow more patients to benefit from Herceptin. Congestive heart failure (CHF) occurred in 0.4 percent of patients in the TCH arm compared to 2 percent of patients in the AC-TH arm. No cardiac deaths were reported. Grade 3 - 4 cardiac ischemia or infarction occurred in 0.3 percent of patients randomized to the AC-TH arm and in 0.2 percent of the TCH arm vs. none in the AC-T arm. Adverse events were similar to those seen in previous trials of Herceptin plus chemotherapy, with the exception of a low incidence of CHF in the TCH arm.

There are now four large randomized adjuvant trials (NCCTG N9831, NSABP B-31, HERA, and BCIRG 006) involving more than 10,000 patients, demonstrating that the addition of Herceptin to chemotherapy increased DFS for patients with early-stage HER2-positive breast cancer.

Boxed WARNINGS and Additional Important Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF). The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.

Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment. More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin containing regimens.

Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Exacerbation of chemotherapy-induced neutropenia has also occurred.

Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman.

The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Please see the Herceptin full prescribing information including Boxed WARNINGS and additional important safety information.

Mechanism of Action Herceptin is a humanized monoclonal antibody (also called a biologic therapy). Antibodies are part of the body's normal defense against bacteria, viruses and abnormal cells such as cancer cells. Therapeutic monoclonal antibodies are created and produced in a laboratory through a complex and resource-intensive process. Their name comes from the fact that they are produced from a single cell.¹

Based on preclinical studies, Herceptin works on both the extracellular and the intracellular domains of the HER2 receptor^2-5

• Continuously suppresses HER2 activity that may lead to tumor proliferation³
• Leads to cell stasis and death³
• In preclinical studies, synergy with Herceptin enhanced the effects of chemotherapy^4,6,7
• Herceptin provides constant inhibition of the HER2 receptor
  • Extended half-life enables Herceptin to maintain constant exposure

Mechanism of action of herceptin^3-5,8-10

Administration Herceptin can be administered in a physician's office.

The recommended dose for HER2-positive metastatic breast cancer is a loading dose of 4 mg/kg of Herceptin administered over a 90-minute period and subsequent weekly infusions of 2 mg/kg administered over a 30-minute period. Herceptin is given as a weekly infusion until disease progression.

The recommended dose for the adjuvant treatment of HER2-positive breast cancer is a loading dose of 4 mg/kg of Herceptin administered over a 90-minute period and subsequent weekly infusions of 2 mg/kg administered over a 30-minute period. Herceptin is given concurrently with paclitaxel or docetaxel for the first 12 weeks and without paclitaxel for an additional 40 weeks or with docetaxel/carboplatin for 18 weeks and without docetaxel/carboplatin for 34 weeks. After 40 weeks, Herceptin should not be administered concurrently with doxorubicin (anthracyclines) and cyclophosphamide. Herceptin also may be administered as a single agent in an every-three week dosing schedule for one year with an initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 90 minutes IV infusion every three weeks for 52 weeks.

Dosing should be modified for infusion reactions and cardiomyopathy.

For full prescribing information, including Boxed WARNINGS and important safety information for Herceptin, please call 800-821-8590 or visit www.herceptin.com.

 

May 2008

¹ Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci. 1992;89:4285-4289.

² Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26:60-70.

³ Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidyli-nositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Research. 2002;62:4132-4141.

⁴ Arnould L, Gelly M, Penault-Llorca F. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259-267.

⁵ Bianco AR. Targeting c-erb2 and other receptors of the c-erB family: rationale and clinical applications. J Chemother. 2004;16:52-54.

⁶ Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Nat Cancer Inst. 2004;96:739-749.

⁷ Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825-2831.

⁸ Lewis GD, Figari I, Fendly B. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37:255-263.

⁹ Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61:1-13.

¹⁰ Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 2000;19:6102-6114.