Pivotal Studies and Efficacy

Proven data in the adjuvant treatment of HER2+ breast cancer

Herceptin reduced risk of recurrence

  • The benefit of 52 weeks of Herceptin (trastuzumab) has been demonstrated in four trials including a total of more than 10,000 patients 1
Benefits of Joint Analysis and HERA studies

* HERceptin Adjuvant trial.

† Results presenterd here are based on the 1-year Herceptin and obersvation arms.

Joint Analysis: Two cooperative group trials with similar protocols evaluated the efficacy of adding 52 weeks of Herceptin to standard therapy in the adjuvant treatment of HER2+ breast cancer. All patients received doxorubicin/cyclophosphamide (AC) followed bypaclitaxel, and received hormonal therapy and/or radiotherapy as appropriate. For patients in the Herceptin arm, Herceptin was given weekly following completion of AC, in combination with paclitaxel for 12 weeks and then as a monotherapy.

Joint Analysis treatment regimen

*Note that study protocols were amended mid-trial to reflect updated knowledge about hormonal therapies in this population. Regimen depicted reflects final protocols.

  • In this regimen, Herceptin is administered on a weekly basis 1
  • Hormonal therapy and/or radiation therapy may be given concurrently with Herceptin, after completion of chemotherapy 1

HERA study design: This international, multicenter, randomized, open-label, controlled clinical trial evaluated the effect of one and two years of Herceptin in the adjuvant treatment of HER2+ breast cancer. Following completion of surgery and chemotherapy with or without radiotherapy, patients were assigned to an observation group or were given Herceptin every three weeks. Patients with ER+ and/or PR+ disease could receive systemic adjuvant hormonal therapy.

HERA treatment schema
  • In this regimen, Herceptin is administered as a single agent once every three weeks for one year, beginning after the completion of chemotherapy 1
  • Hormonal therapy may be given concurrently with Herceptin 1
Type of chemotherapy used in HERA - table

*Note that all chemotherapy was completed prior to initiation of Herceptin.

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

Positive benefit/risk ratio demonstrated in multiple clinical trials 1,2

Possible benefit versus risk in clinical trials

*At 3.5 years.

†At two years.

‡As determined by an external review committee.

§As reported by investigators.

Boxed WARNINGS and Additional Important Safety Information

Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. 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.

52 weeks of Herceptin significantly improved disease-free survival

Reduced relative risk of recurrence by 52% in the Joint Analysis 1,3

  • Two cooperative group trials (NSABP B-31 and NCCTG N9831) with similar protocols evaluated the efficacy of adding Herceptin to standard therapy 3
  • Results were combined in a Joint Analysis
  • The primary end point of the Joint Analysis was disease-free survival (DFS)
DFS Joint Analysis graph
  • Absolute risk was reduced by 15.3% in the Herceptin-containing arm at year 3.5 (95% confidence interval: 11.9%-18.6%) 2

Reduced relative risk of recurrence by 46% in HERA 1,4

  • A cooperative group trial (HERA),conducted by the Breast International Group (BIG), evaluated the efficacy of one and two years of Herceptin therapy following completion of surgery, chemotherapy, and/or radiotherapy 4
  • The primary endpoint was disease-free survival (DFS)
  • Data from the 1-year Herceptin arm are presented below and on the following pages
DFS HERA graph
  • Absolute risk was reduced by 7.6% in the one-year Herceptin arm at year two (95% confidence interval: 3.5%-11.8%) 2
  • The risk of distant disease was reduced by half (hazard ratio=0.50,95% confidence interval:0.39-0.64;P<0.0001) 2
  • Benefit of 52 weeks of Herceptin was consistent with that seen in the Joint Analysis 1

Boxed WARNINGS and Additional Important Safety Information1

Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction (LVEF). Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Herceptin can also cause asymptomatic decline in LVEF.

Consistent benefit seen across diverse patient groups

Joint Analysis showed consistent improvements in DFS regardless of hormone-receptor status, or tumor size 1,2

DFS by subgroup - Joint Analysis
  • These data are based on exploratory analyses for the risk of recurrence, second primary malignancy, or death
  • There were insufficient numbers of patients with node-negative disease, low tumor grade, or patients within specific ethnic/racial subgroups (Black, Hispanic, and Asian/Pacific Islander) to determine if the treatment effect for these subgroups was different from that of the overall population
  • 5% of patients enrolled had node-negative disease

HERA further demonstrated DFS benefit regardless of nodal involvement 2

DFS by subgroup - HERA

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

  • These data are based on exploratory analyses for the risk of recurrence, second primary malignancy, or death
  • There were insufficient numbers of patients with node-negative disease, low tumor grade, or patients within specific ethnic/racial subgroups (Black, Hispanic, and Asian/Pacific Islander) to determine if the treatment effect for these subgroups was different from that of the overall population
  • Patients with node-negative tumors were eligible for the trial if the primary tumor size was > 1 cm 1
  • 96% of patients with node-negative disease had high-risk features 1†
  • Please see criteria for patient eligibility for adjuvant Herceptin
  • 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 population 1

† High-risk features were defined as: tumor that was ER-negative and PR-negative, tumor size > 2cm, histologic and/or nuclear grade 2/3, and age < 35 years.

Boxed WARNINGS and Additional Important Safety Information1

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.

DFS advantage seen with Herceptin in multiple patient subgroups

In the Joint Analysis

DFS advantage in the Joint Analysis

In HERA

DFS advantage in HERA

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

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 syndrome.
  • 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® (trastuzumab) Full Prescribing Information, Genentech, Inc. May 2008.
  • 2. Data on file. Genentech, Inc.
  • 3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2+ breast cancer. N Engl J Med. 2005; 353:1673-1684 and supplementary appendix.
  • 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2+ breast cancer. N Engl J Med. 2005; 353: 1659-1672.


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