Herceptin (trastuzumab) - 2 indications

Scroll down for information on each indication:

• HER2-overexpressing metastatic breast cancer; approved October 1998
• HER2-overexpressing gastric cancer; approved October 2010

General Information

Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). 

Herceptin is specifically indicated for the following:

Adjuvant Breast Cancer

Herceptin 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 consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• as part of a treatment regimen with docetaxel and carboplatin
• as a single agent following multi-modality anthracycline based therapy.

Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin

Metastatic Breast Cancer

• in combination with paclitaxel for 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.

Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin

Metastatic Gastric Cancer

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. Select patients for therapy based on an FDA-approved companion diagnostic for Herceptin.

Herceptin is supplied as a solution for intravenous administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Herceptin (trastuzumab) is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). HER2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. HER2 is over-expressed in certain cancers.

Side Effects

Adverse effects associated with the use of Herceptin for adjuvant breast cancer may include, but are not limited to, the following:

• headache
• diarrhea
• nausea
• chills

Adverse effects associated with the use of Herceptin for metastatic breast cancer may include, but are not limited to, the following:

• fever
• chills
• headache
• infection
• congestive heart failure
• insomnia
• cough
• rash

Adverse events associated with the use of Herceptin for gastric cancer may include, but are not limited to, the following:

• neutropenia
• diarrhea
• fatigue
• anemia
• stomatitis
• weight loss
• upper respiratory tract infections
• fever
• thrombocytopenia
• mucosal inflammation
• nasopharyngitis
• dysgeusia

The Herceptin drug label comes with the following Black Box Warning: Cardiomyopathy: Herceptin can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy. Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Embryo-Fetal Toxicity: Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception

Indication 1 - HER2-overexpressing metastatic breast cancer

approved October 1998

Dosing/Administration

Adjuvant Treatment, Breast Cancer

Administer according to one of the following doses and schedules for a total of 52 weeks of Herceptin therapy:

During and following paclitaxel, docetaxel, or docetaxel/carboplatin:

• Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
• One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30 - 90 minutes every three weeks.

As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:

• Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
• Subsequent doses at 6 mg/kg as an intravenous infusion over 30 - 90 minutes every three weeks

Extending adjuvant treatment beyond one year is not recommended.

Metastatic Treatment, Breast Cancer

Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression.

Clinical Trial Results

The FDA approval of Herceptin for adjuvant breast cancer was based on integrated analysis of two randomized, open-label, clinical trials (Studies 1 and 2) with a total of 4,063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (Study 3) with a total of 3,386 women at definitive Disease-Free Survival analysis for one-year Herceptin treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3,222 patients (Study 4). In the joint analysis the Disease Free Survival rate at 3.5 years was 86.7%. 

The FDA approval of Herceptin for metastatic breast cancer was based on a randomized, controlled clinical trial in combination with chemotherapy (Study 5, n = 469 patients) and an open-label, single agent clinical trial (Study 6, n = 222 patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress the HER2 protein. Study 5 data: Trial results showed that patients treated with Herceptin and chemotherapy experienced tumor progression later than patients treated with chemotherapy alone. The median time to disease progression was increased by 65 percent (from 4.6 to 7.6 months). Approximately 28 percent of women treated with Herceptin plus chemotherapy did not show evidence of tumor progression at one year compared to 14 percent of the women treated with chemotherapy alone. Study 6 data: The overall response rate assessed by the Response Evaluation Committee (REC) was 16 percent (34 of 213) with eight patients experiencing a complete response (4 percent) and 26 experiencing a partial response (12 percent). The median duration of response was 9 months.

Indication 2 - HER2-overexpressing gastric cancer

approved October 2010

Dosing/Administration

Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression.

Clinical Trial Results

The FDA approval of Herceptin for gastric cancer was based on an open-label, multi-center trial in 594 patients with HER2 gene amplified or overexpressing cancer who were not previously treated for metastatic gastric or gastroesophageal junction adenocarcinoma. The subjects received Herceptin administered in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). The Herceptin arm received an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. In both study arms, cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion and capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively continuous intravenous infusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for 6 cycles. The primary endpoint was overall survival. The final overall survival analysis based on 351 deaths was statistically significant. In the FC arm, 62.2% of the subjects had passed versus 56% in the FC+H arm (p=0.0193). A follow-up analysis was conducted one year after the final analysis. At this timepoint, in the FC arm 76.7% of the subjects had passed versus 74.2% in the FC+H arm.