Herceptin® (Trastuzumab)

Full Prescribing Information, including Boxed WARNINGS

Herceptin in Early-Stage and Advanced Breast Cancer Herceptin® (trastuzumab) was the first targeted medicine approved by the U.S. Food and Drug Administration (FDA) designed to treat human epidermal growth factor receptor 2 (HER2)-positive breast cancer, a more aggressive form of the disease.

In September 1998, Herceptin was approved in combination with chemotherapy (paclitaxel) for treatment of women who had not received previous medicines for their advanced (metastatic) HER2-positive breast cancer (first-line treatment). It was also approved as a medicine to be used alone for women who had received prior chemotherapy (second- and third-line treatment).¹

In November 2006, Herceptin was approved for treating early-stage (adjuvant) HER2-positive breast cancer when given with chemotherapy (doxorubicin, cyclophosphamide and paclitaxel), a combination called AC-TH. In January 2008, it was also approved as a stand-alone medicine following anthracycline-based chemotherapy.¹ In May 2008, Herceptin and chemotherapy (docetaxel and carboplatin), known as TCH, was approved. This treatment regimen has been associated with a lower risk of heart damage when compared to other combinations of Herceptin and chemotherapy.¹ Another AC-TH combination, comprised of Herceptin, doxorubicin, cyclophosphamide and docetaxel, was also approved in May 2008.¹

Breast cancer is the second leading cause of cancer deaths in women in the United States.² Approximately 15-30 percent of breast cancers are HER2-positive.³

WARNINGS

• Herceptin treatment can result in heart problems, including those without symptoms (reduced heart function) and those with symptoms (congestive heart failure). The risk and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline).
• Some patients have had serious infusion reactions and lung problems; fatal infusion reactions have been reported. In most cases, these reactions occurred during or within 24 hours of receiving Herceptin. Patients receiving their first dose of Herceptin may have chills and fever as well as nausea, vomiting, pain, headache, dizziness, shortness of breath, low blood pressure, rash, and weakness.

Herceptin "Firsts" in Early-Stage and Advanced Breast Cancer

• Herceptin is the first and only FDA-approved, HER2-targeted biologic medicine that may help women with advanced HER2-positive breast cancer live longer, when given with chemotherapy, compared to chemotherapy alone (median overall survival: 25.1 months vs. 20.3 months; hazard ratio 0.80; p=0.046)
• Herceptin is the first and only FDA-approved, HER2-targeted biologic medicine to lower women's risk of their early-stage breast cancer returning following one year of Herceptin treatment when used with standard adjuvant therapy (treatment, including chemotherapy, radiation, hormone therapy, and biological therapy, given after initial surgery or radiation when no visible signs of the disease remain to help prevent disease recurrence)

Herceptin Indications Adjuvant indications Herceptin® (Trastuzumab) is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:

• As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• With docetaxel and carboplatin
• As a single agent following multi-modality anthracycline based therapy

* High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Metastatic indications Herceptin is indicated:

• In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Herceptin is indicated:

• In combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.

Important Safety Information, including Boxed WARNINGS Herceptin treatment can result in heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). One patient died in an adjuvant (early) breast cancer trial from significantly weakened heart muscle. The risk and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline).

Before taking the first dose of Herceptin and during treatment, a patient’s doctor should check to see if there are any health conditions that may increase the patient’s chance of having serious heart problems. This includes a review of the patient’s health history and tests to see how well the heart muscle is working. These tests may include an echocardiogram or a MUGA scan. Some early breast cancer patients may also need to have a test done after they have finished taking Herceptin to see how well their heart muscle is working.

Some patients have had serious infusion reactions and lung problems; fatal infusion reactions have been reported. These reactions usually occur during or within 24 hours of receiving Herceptin.

The patient’s doctor may need to completely stop Herceptin treatment if the patient has a severe allergic reaction, swelling, lung problems, inflammation of the lung, or severe shortness of breath.

Herceptin can cause harm to the fetus (unborn baby), in some cases death to the fetus, when taken by a pregnant woman. Women who could become pregnant need to use effective birth control methods during Herceptin treatment and for at least 6 months after treatment with Herceptin. Nursing mothers treated with Herceptin should discontinue nursing or discontinue Herceptin.

Worsening of low white blood cell counts associated with chemotherapy has also occurred.

Patients must have a HER2 test to determine if their breast or stomach cancer is HER2 positive before using Herceptin, as benefit has only been shown in patients that are HER2 positive.

The most common side effects associated with Herceptin in patients with breast cancer are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, shortness of breath, rash, low white and red blood cells, and muscle pain.

The most common side effects associated with Herceptin in patients with stomach cancer are low white blood cell counts, diarrhea, fatigue, low red blood cell counts, inflammation of the lining of the mouth, weight loss, upper respiratory tract infections, fever, low platelet counts, swelling of mucus membranes, swelling of the nose and throat, and a change in taste.

Because everyone is different, it is not possible to predict what side effects any one person will have. Patients with questions or concerns about side effects should talk to their doctor.

Patients should read the Herceptin Full Prescribing Information including Boxed WARNINGS, at www.herceptin.com.

How Herceptin Works (Proposed Mechanism of Action)

• Herceptin is a biologic medicine (not chemotherapy) that specifically inhibits the HER2 protein⁴
• Based on preclinical studies, Herceptin works by attaching to HER2 receptors and blocking signals that make the cancer more aggressive, and also by signaling the body's immune system to destroy the cancerous cells⁴

Herceptin Clinical Studies in Advanced (Metastatic) Breast Cancer First-Line Treatment In Advanced Breast Cancer

• In the Phase III study (H0648g), 469 women received Herceptin plus chemotherapy (either an anthracycline and cyclophosphamide or paclitaxel) or chemotherapy alone^1,5
  • Seventy-eight percent of women who received Herceptin plus chemotherapy lived at least one year, compared to sixty-seven percent who received chemotherapy alone⁵
  • Women who received Herceptin plus chemotherapy lived nearly five months longer compared to women who received chemotherapy alone (median overall survival: 25.1 months vs. 20.3 months)⁵
  • Women who received Herceptin plus chemotherapy lived nearly three months longer without their disease worsening compared to women who received chemotherapy alone (median time to disease progression: 7.4 months vs. 4.6 months)⁵

Second- And Third-Line Treatment In Advanced Breast Cancer

• In a different Phase III study (H0649g), 222 women whose disease had progressed after receiving one or more breast cancer treatments received Herceptin only^1,6
  • Half the women lived 13 months or longer (median overall survival)⁶
  • Fourteen percent saw their tumors shrink by at least half (overall response rate)¹

Herceptin Clinical Studies in Early-Stage Breast Cancer (Adjuvant Treatment)

• In two Phase III studies (NCCTG N9831 and NSABP B-31), 3,752 women received either one year of Herceptin plus standard chemotherapy (doxorubicin, cyclophosphamide and paclitaxel) or chemotherapy alone⁷
  • Women who received Herceptin plus chemotherapy had a 52 percent lower risk of their cancer returning compared to women who received chemotherapy alone⁷
• In another Phase III study (HERA) of 5,081 women, the third of women who received one year of Herceptin had a 46 percent lower risk of their cancer returning compared to the third of women who received no treatment. The remaining third of women received Herceptin for two years. This part of the HERA study is ongoing.⁸
• In a fourth Phase III study (BCIRG 006), 3,222 women received either chemotherapy alone or one of two Herceptin and chemotherapy combinations: Herceptin plus docetaxel and carboplatin (TCH) or Herceptin plus doxorubicin, cyclophosphamide and docetaxel (AC-TH)¹
  • Women who received either the TCH or AC-TH combination had similar reductions in the risk of their disease returning (33 percent and 40 percent, respectively)¹
  • Women who received the TCH combination, rather than the AC-TH combination, had a lower rate of congestive heart failure (0.4 percent vs. 2 percent, respectively),¹ the inability of the heart to maintain output sufficient to meet the body's needs⁹
• Patients receiving their first dose of Herceptin may have chills and fever as well as nausea, vomiting, pain, headache, dizziness, shortness of breath, low blood pressure, rash, and weakness. In most cases, these reactions occurred during or within 24 hours of receiving Herceptin.
• Herceptin can cause heart problems including an inability to pump blood effectively, irregular heartbeats, high blood pressure, disabling heart failure, weakening of the heart muscle, and sudden loss of heart function leading to death. Herceptin may cause reduced heart function even if there are no symptoms. In 2 of the clinical trials, among 32 patients with significant heart problems, one died of significantly weakened heart muscle. All others were on heart medication at their last checkup. Approximately half of the surviving patients had heart function that returned to normal while on ongoing heart medications.

Herceptin Development Program

• In early-stage breast cancer, the HERA trial is underway to determine the clinical benefit of two years of Herceptin
• Herceptin is currently being studied in combination with other targeted medicines

 

References ¹ Herceptin [package insert]. South San Francisco, Calif.: Genentech, Inc. 2009.

² American Cancer Society. Cancer Facts and Figures 2009. http://www.cancer.org. Accessed May 5, 2009.

³ American Cancer Society. Breast Cancer Facts and Figures 2007-2008. http://www.cancer.org. Accessed May 5, 2009.

⁴ Valabrega D, et al. Trastuzumab: Mechanism Of Action, Resistance And Future Perspectives In HER2-Overexpressing Breast Cancer. Annals of Oncology. 2007;18: 977-984.

⁵ Slamon DJ, et al. Use Of Chemotherapy Plus A Monoclonal Antibody Against Her2 For Metastatic Breast Cancer That Overexpresses Her2. N Engl J Med. 2001;344:783-792.

⁶ Cobleigh MA, et al. Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. J Clin Oncol. 1999;17:2639-2648.

⁷ Romond EH, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. N Engl J Med. 2005;353:1673-84.

⁸ Piccart-Gebhart MJ. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. N Engl J Med. 2005;353:1659-72.

⁹ Dorland's Medical Dictionary for Health Consumers. Saunders: 2007.