Adjuvant Treatment of Breast Cancer

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

During and following paclitaxel, docetaxel, or docetaxel and 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 and carboplatin).
• One week following the last weekly dose of HERZUMA, administer HERZUMA at 6 mg/kg as an intravenous infusion over 30 to 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 to 90 minutes every three weeks.
• Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].

Metastatic Breast Cancer

• Administer HERZUMA, 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.

Metastatic Gastric Cancer

• Administer HERZUMA 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 to 90 minutes every three weeks until disease progression.

Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:

• Baseline LVEF measurement immediately prior to initiation of HERZUMA
• LVEF measurements every 3 months during and upon completion of HERZUMA
• Repeat LVEF measurement at 4 week intervals if HERZUMA is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.5)]
• LVEF measurements every 6 months for at least 2 years following completion of HERZUMA as a component of adjuvant therapy.

In NSABP B31, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In HERA (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity.

Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.

In HERA (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.

In BCIRG006, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the trastuzumab containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as compared to none in AC-T.

Adjuvant Breast Cancer

The information below reflects exposure to one-year trastuzumab therapy across three randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.

HERA

Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1)]. 

Clinically relevant adverse reactions in < 1% of patients who received trastuzumab in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%).

Adjuvant Treatment of Breast Cancer with Trastuzumab Beyond One Year

Extending adjuvant treatment beyond one year is not recommended [see Dosage and Administration (2.3)]. In HERA, a comparison of  trastuzumab administered once every 3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year trastuzumab compared to the 1-year trastuzumab treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab treatment arm (16.3%).

NSABP B31 and NCCTG N9831

The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received trastuzumab; the median treatment duration was 51 weeks [see Clinical Studies (14.1)]. 

In NSABP B31, only Grade 3 to 5 adverse events, treatment-related Grade 2 events, and Grade 2 to 5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity.

In NCCTG N9831, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity.

BCIRG006

Safety data from BCIRG006 reflect exposure to trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms.

The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once every three week dosing in the monotherapy period [see Clinical Studies (14.1)]. In BCIRG006, the toxicity profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA with the exception of a lower incidence of CHF in the TCH arm.

Metastatic Breast Cancer Studies

The safety of trastuzumab was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with metastatic breast cancer and in one single-arm study (H0649g) in patients with metastatic breast cancer (n = 222) [see Clinical Studies (14.1)]. Patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly. In H0648g, 58% of patients received trastuzumab for ≥ 6 months and 9% received trastuzumab for ≥ 12 months, respectively. In H0649g, 31% of patients received trastuzumab for ≥ 6 months and 16% received trastuzumab for ≥ 12 months, respectively.

Table 4 shows the adverse reactions (≥ 5%) in patients from H0648g and H0649g.

Metastatic Gastric Cancer

The safety of trastuzumab was evaluated in patients with previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma in an open label, multi-center trial (ToGA) [see Clinical Studies (14.3)]. Patients were randomized (1:1) to receive trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290). Patients in the trastuzumab plus chemotherapy arm received trastuzumab 8 mg/kg administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1 to 14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21 day cycles. Median duration of trastuzumab treatment was 21 weeks and the median number of trastuzumab infusions administered was eight.

The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience.

Cardiomyopathy

Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In HERA, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year trastuzumab arm); and in NSABP B31 and NCCTG N9831, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. Following initiation of trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year trastuzumab monotherapy compared to observation in HERA (see Table 6, Figures 1 and 2). The incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery.

Figure 1: NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or trastuzumab + paclitaxel therapy.

Figure 2: HERA: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

Figure 3: BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

The incidence of congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I to IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received trastuzumab concurrently with anthracyclines.

In ToGA, 5% of patients in the trastuzumab plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values.

Infusion Reactions

During the first infusion with trastuzumab, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of trastuzumab infusion); permanent discontinuation of trastuzumab for infusion reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent trastuzumab infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported.

Anemia

In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [H0648g]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [NSABP B31]), and of anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of trastuzumab as a single agent (H0649g), the incidence of NCI-CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer), on the trastuzumab containing arm as compared to the chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI-CTC Grade 3/4 anemia was 12.2% compared to 10.3%.

Neutropenia

In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4 to 5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected Grade 2 to 5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer) on the trastuzumab containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%.

Infection

The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]) and of selected Grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4% [NCCTG N9831]) were higher in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract.

In BCIRG006, the overall incidence of infection was higher with the addition of trastuzumab to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3 to 4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms.

In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.

Pulmonary Toxicity

Thrombosis/Embolism

In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [NSABP B31], 2.5% and 3.7% vs. 2.2% [BCIRG006] and 2.1% vs. 0% [H0648g]).

Diarrhea

Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% [NSABP B31]) and of NCI-CTC Grade 3 to 5 diarrhea (2.2% vs. 0% [NCCTG N9831]), and of Grade 1 to 4 diarrhea (7% vs. 1% [HERA; one-year trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients receiving trastuzumab as compared to controls. In BCIRG006, the incidence of Grade 3 to 4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1 to 4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patients receiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer.

Renal Toxicity

In ToGA (metastatic gastric cancer) on the trastuzumab-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-containing arm and 0.3% on the chemotherapy only arm.

In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of trastuzumab therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure.

Risk Summary

Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-marketing reports and published literature, use of trastuzumab products during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product [see Clinical Considerations].

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There is no information regarding the presence of trastuzumab products in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with neonatal toxicity [see Data]. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for HERZUMA treatment and any potential adverse effects on the breastfed child from HERZUMA or from the underlying maternal condition. This consideration should also take into account the trastuzumab product wash out period of 7 months [see Clinical Pharmacology (12.3)].

Data

In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of trastuzumab products). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA.

Contraception

Trastuzumab product exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized.

Cardiac Electrophysiology

The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.

Specific Populations

Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (< 65 (n=1294); ≥ 65 (n=288)), race (Asian (n=264); non-Asian (n=1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n=636) or moderate (CLcr 30 to 60 mL/min) (n=133)). The pharmacokinetics of trastuzumab products in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown.

Drug Interaction Studies

There have been no formal drug interaction studies performed with trastuzumab products in humans. Clinically significant interactions between trastuzumab and concomitant medications used in clinical trials have not been observed.

NSABP B31 and NCCTG N9831

In NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (NCCTG N9831) or was required to be performed at a reference laboratory (NSABP B31). Patients with a history of active cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible.

Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel (AC→paclitaxel) alone or paclitaxel plus trastuzumab (AC→paclitaxel + trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a total of 12 weeks in NSABP B31; paclitaxel was administered only by the weekly schedule in NCCTG N9831. Trastuzumab was administered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and Administration (2.5)]. Radiation therapy, if administered, was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. The major efficacy outcome measure of the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death. An additional efficacy outcome measure was overall survival (OS).

A total of 3752 patients were included in the joint efficacy analysis of DFS following a median follow-up of 2.0 years in the AC→paclitaxel + trastuzumab arm. The pre-planned final OS analysis from the joint analysis included 4063 patients and was performed when 707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel + trastuzumab arm. The data from both arms in NSABP B31 and two of the three study arms in NCCTG N9831 were pooled for efficacy analyses.

The patients included in the DFS analysis had a median age of 49 years (range, 22 to 80 years; 6% > 65 years), 84% were White, 7% Black, 4% Hispanic, and 4% Asian/Pacific Islander. Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+ tumors. 

HERA

In HERA, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or gene amplification (by FISH) as determined at a central laboratory. Patients with node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of congestive heart failure or LVEF < 55%, uncontrolled arrhythmias, angina requiring medication, clinically significant valvular heart disease, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg) were not eligible.

Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four cycles of chemotherapy to receive no additional treatment, or one year of trastuzumab treatment or two years of trastuzumab treatment. Patients undergoing a lumpectomy had also completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The major efficacy outcome measure was Disease-Free Survival (DFS), defined as in NSABP B31 and NCCTG N9831.

HERA was designed to compare one and two years of once every three week trastuzumab treatment versus observation in patients with HER2 positive EBC following surgery, established chemotherapy and radiotherapy (if applicable). A protocol specified interim efficacy analysis comparing one-year trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the trastuzumab arm.

Among the 3386 patients randomized to the observation (n = 1693) and trastuzumab one year (n = 1693) treatment arms, the median age was 49 years (range 21 to 80), 83% were White, and 13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of patients with node-negative disease had high-risk features: among the 1098 patients with node-negative disease, 49% (543) were ER- and PgR-, and 47% (512) were ER and/or PgR + and had at least one of the following high-risk features: pathological tumor size greater than 2 cm, Grade 2 to 3, or age < 35 years. Prior to randomization, 94% of patients had received anthracycline-based chemotherapy regimens.

After the DFS results comparing observation to one-year trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year [Hazard Ratios of two-years trastuzumab versus one-year trastuzumab treatment in the intent to treat (ITT) population for Disease-Free Survival (DFS) = 0.99 (95% CI: 0.87, 1.13), p-value = 0.90 and Overall Survival (OS) = 0.98 (0.83, 1.15); p-value = 0.78].

BCIRG006

In BCIRG006, breast tumor specimens were required to show HER2 gene amplification (FISH+ only) as determined at a central laboratory. Patients were required to have either node-positive disease, or node-negative disease with at least one of the following high-risk features: ER/PR-negative, tumor size > 2 cm, age < 35 years, or histologic and/or nuclear Grade 2 or 3. Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly controlled hypertension (diastolic > 100 mm Hg), any T4 or N2, or known N3 or M1 breast cancer were not eligible.

Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab (AC-TH), or docetaxel and carboplatin plus trastuzumab (TCH). In both the AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were administered every 3 weeks for four cycles; docetaxel 100 mg/m2 was administered every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target AUC of 6 mg/mL/min as a 30- to 60-minute infusion) were administered every 3 weeks for six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg) as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy. Disease-Free Survival (DFS) was the major efficacy outcome measure.

Among 3222 patients, the median age was 49 (range 22 to 74 years; 6% ≥ 65 years). Disease characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization, all patients underwent primary surgery for breast cancer.

The results for DFS for the integrated analysis of NSABP B31 and NCCTG N9831, HERA, and BCIRG006 and OS results for the integrated analysis of NSABP B31 and NCCTG N9831, and HERA are presented in Table 9. For NSABP B31 and NCCTG N9831, the duration of DFS following a median follow-up of 2.0 years in the AC→TH arm is presented in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 5. The duration of DFS for BCIRG006 is presented in Figure 6. For NSABP B31 and NCCTG N9831, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3 years of median follow up [AC→TH], the survival rate was estimated to be 86.9% in the AC→TH arm and 79.4% in the AC→T arm. The final OS analysis results from NSABP B31 and NCCTG N9831 indicate that OS benefit by age, hormone receptor status, number of positive lymph nodes, tumor size and grade, and surgery/radiation therapy was consistent with the treatment effect in the overall population. In patients ≤ 50 years of age (n = 2197), the OS hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n = 1866), the OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-positive disease (ER-positive and/or PR-positive) (n = 2223), the hazard ratio for OS was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative disease (ER-negative and PR-negative) (n = 1830), the hazard ratio for OS was 0.64 (95% CI: 0.52, 0.80). In the subgroup of patients with tumor size ≤ 2 cm (n = 1604), the hazard ratio for OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size > 2 cm (n = 2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80).

Figure 4: Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831)

Figure 5: Overall Survival in Patients with Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831)

Figure 6: Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (BCIRG006)

Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification were conducted for patients in NCCTG N9831 and HERA, where central laboratory testing data were available. The results are shown in Table 10. The number of events in NCCTG N9831 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn regarding efficacy within other subgroups due to the small number of events. The number of events in HERA was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH+/IHC unknown subgroups.

Previously Untreated Metastatic Breast Cancer (H0648g)

H0648g was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastatic breast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to receive chemotherapy alone or in combination with trastuzumab given intravenously as a 4 mg/kg loading dose followed by weekly doses of trastuzumab at 2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients, chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles). Sixty-five percent of patients randomized to receive chemotherapy alone in this study received trastuzumab at the time of disease progression as part of a separate extension study.

Based upon the determination by an independent Response Evaluation Committee, the patients randomized to trastuzumab and chemotherapy experienced a significantly longer median time to disease progression (TTP), a higher overall response rate (ORR), and a longer median duration of response (DoR), as compared with patients randomized to chemotherapy alone. Patients randomized to trastuzumab and chemotherapy also had a longer median overall survival (OS) (see Table 11). These treatment effects were observed both in patients who received trastuzumab plus paclitaxel and in those who received trastuzumab plus AC; however, the magnitude of the effects was greater in the paclitaxel subgroup.

Data from H0648g suggest that the beneficial treatment effects were largely limited to patients with the highest level of HER2 protein overexpression (3+) (see Table 12).

Previously Treated Metastatic Breast Cancer (H0649g)

Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (H0649g) in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or two prior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and 25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose of 4 mg/kg IV followed by weekly doses of trastuzumab at 2 mg/kg IV.

The ORR (complete response + partial response), as determined by an independent Response Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial response rate. Complete responses were observed only in patients with disease limited to skin and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, it was 6%.

420 mg Multiple-dose vial NDC 63459-305-47

HERZUMA (trastuzumab-pkrb) for Injection 420 mg/vial is supplied in a multiple-dose vial as a white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial (420 mg/vial) of HERZUMA and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative.

150 mg Single-dose vial NDC 63459-303-43

HERZUMA (trastuzumab-pkrb) for Injection 150 mg/vial is supplied in a single-dose vial as a white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one single-dose vial (150 mg/vial) of HERZUMA.

Store HERZUMA vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.