The HERA trial

Study Design^1,2

The HERA (HERceptin Adjuvant) trial, an international multicenter, randomized, open-label, controlled clinical trial conducted by the Breast International Group (BIG), evaluated the effect of 1 and 2 years of Herceptin in the adjuvant treatment of HER2+ breast cancer.

The primary endpoint was disease-free survival (DFS)

Following completion of surgery and multi-modality anthracycline-based chemotherapy with or without radiotherapy, patients were assigned to an observation group or were given Herceptin every 3 weeks for 1 year or 2 years.

Patients with ER+ and/or PR+ disease could receive systemic adjuvant hormonal therapy

HERA showed 12 months of Herceptin significantly improved DFS

Herceptin reduced the risk of recurrence by 46%^1,2

Data from the 1-year Herceptin arm are presented below and on the following pages

Absolute risk was reduced by 7.6% in the 1-year Herceptin arm at year 2 (95% confidence interval: 3.5%-11.8%)².
The risk of distant disease recurrence was reduced by half (hazard ratio=0.50, 95% confidence interval: 0.39-0.64; P<0.0001)².
Benefit of 12 months of Herceptin was consistent with that seen in the Joint Analysis¹.

Consistent benefit seen across diverse patient subgroups

HERA further demonstrated DFS benefit regardless of nodal involvement²

*Patients who received neoadjuvant chemotherapy (approximately 11% of all patients), or in whom this parameter was not assessed, are not included in this list.

There were insufficient numbers of patients with low tumor grade, within specific ethnic/racial subgroups (Black or Hispanic), and >65 years of age to determine if the treatment effect for these subgroups was different from that of the overall population¹.
Patients with node-negative tumors were eligible for the trial if the primary tumor size was >1cm¹.
32% of patients enrolled had node-negative disease².
- 96% of patients with node-negative disease had high-risk features¹
- Please see high-risk criteria in “Patient indication criteria” on the Treatment Guidelines page.

Cardiac findings from HERA

Median follow-up was 12.4 months in the observation arm and 12.6 months in the 1-year Herceptin arm¹.
2.6% of patients (44/1678) discontinued Herceptin due to cardiac toxicity¹.

Adjuvant indications

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

Adjuvant indications
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 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 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

Boxed WARNINGS and Additional Important Safety Information

Cardiotoxicity
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 for breast cancer and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.
Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.
- In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens.
- Herceptin can also cause asymptomatic decline in LVEF.
Cardiac Monitoring
Candidates for treatment with Herceptin should undergo a thorough baseline cardiac assessment, including history, physical examination, and an assessment of LVEF by echocardiogram or MUGA scan.
- Patients should undergo frequent monitoring for decreased left ventricular function during and after Herceptin treatment.
- More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction.
Infusion reactions and Pulmonary Toxicity
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
Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia.
- In postmarketing reports, serious and fatal infusion reactions have been reported. Discontinue Herceptin in all patients with severe or life-threatening infusion reactions.
Herceptin use can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis.
- Such events can occur as sequelae of infusion reactions.
- Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
Neutropenia
Exacerbation of chemotherapy-induced neutropenia has also occurred
- In controlled clinical trials, severe neutropenia and febrile neutropenia occurred more frequently in metastatic breast cancer patients receiving Herceptin with myelosuppressive chemotherapy compared to chemotherapy alone.
- The incidence of septic death was not significantly increased.
Pregnancy Category D
Herceptin can cause fetal harm when administered to a pregnant woman.
Post-marketing reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimester.
Most Common Adverse Events
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.

References:
1. Herceptin Prescribing Information. Genentech, Inc. March 2009.
2. Data on file. Genentech, Inc.

The HERA trial

Study Design1,2