Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity

[see

2.5 Dosage Modifications for Adverse Reactions

Infusion Reactions

[SeeBoxed WarningandWarnings and Precautions (5.2)]

•Decrease the rate of infusion for mild or moderate infusion reactions
•Interrupt the infusion in patients with dyspnea or clinically significant hypotension
•Discontinue TRAZIMERA for severe or life-threatening infusion reactions.

Cardiomyopathy

[SeeBoxed Warning,Warnings and Precautions (5.1)]

Assess left ventricular ejection fraction (LVEF) prior to initiation of TRAZIMERA and at regular intervals during treatment. Withhold TRAZIMERA dosing for at least 4 weeks for either of the following:

•≥ 16% absolute decrease in LVEF from pre-treatment values
•LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.

TRAZIMERA may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.

Permanently discontinue TRAZIMERA for a persistent (> 8 weeks) LVEF decline or for suspension of TRAZIMERA dosing on more than 3 occasions for cardiomyopathy.

]

In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia.

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

14.1 Adjuvant Breast Cancer

The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressing breast cancer were evaluated in an integrated analysis of two randomized, open-label, clinical trials (NSABP B31 and NCCTG N9831) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized, open-label, clinical trial (HERA) with a total of 3386 women at definitive Disease-Free Survival analysis for one-year trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with a total of 3222 patients (BCIRG006).

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/m²and 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 weeks 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/m²and cyclophosphamide 600 mg/m²were administered every 3 weeks for four cycles; docetaxel 100 mg/m²was administered every 3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m²and 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).

Table 9: Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006)
CI = confidence interval.
	DFS events	DFS Hazard ratio (95% CI) p-value	Deaths (OS events)	OS Hazard ratio p-value
NSABP B31 and NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).
AC→TH (n = 1872)Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH arm. (n = 2031)Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC→TH arm).	133	0.48 Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. (0.39, 0.59) p< 0.0001stratified log-rank test.	289	0.64 (0.55, 0.74) p< 0.0001
AC→T (n = 1880) (n = 2032)	261		418
HERA At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm.
Chemo→ Trastuzumab (n = 1693)	127	0.54 (0.44, 0.67) p< 0.0001log-rank test.	31	0.75 p = NSNS = non-significant.
Chemo→ Observation (n = 1693)	219		40
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1075)	134	0.67 (0.54 – 0.84) p=0.0006 A two-sided alpha level of 0.025 for each comparison.	56
AC→TH (n = 1074)	121	0.60 (0.48 – 0.76) p< 0.0001	49
AC→T (n = 1073)	180		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.

Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification
	NCCTG N9831		HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
HER2 Assay Result IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory.	Number of Patients	Hazard Ratio DFS (95% CI)	Number of Patients	Hazard Ratio DFS (95% CI)
IHC 3+
FISH (+)	1170	0.42 (0.27, 0.64)	91	0.56 (0.13, 2.50)
FISH (−)	51	0.71 (0.04, 11.79)	8	—
FISH Unknown	51	0.69 (0.09, 5.14)	2258	0.53 (0.41, 0.69)
IHC < 3+ / FISH (+)	174	1.01 (0.18, 5.65)	299All cases in this category in HERA were IHC 2+.	0.53 (0.20, 1.42)
IHC unknown / FISH (+)	—	—	724	0.59 (0.38, 0.93)

Figure 4

Figure 5

Figure 6

Table 3: Adverse Reactions (≥ 1%) in HERA (All Grades)The incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed term.
Adverse Reactions	Trastuzumab (n = 1678) %	Observation (n = 1708) %
Nervous System
Headache	10	3
Paresthesia	2	0.6
Musculoskeletal
Arthralgia	8	6
Back pain	5	3
Myalgia	4	1
Bone pain	3	2
Muscle spasm	3	0.2
Infections
Nasopharyngitis	8	3
Urinary tract infection	3	0.8
Gastrointestinal
Diarrhea	7	1
Nausea	6	1
Vomiting	3.5	0.6
Constipation	2	1
Dyspepsia	2	0.5
Upper abdominal pain	2	1
General
Pyrexia	6	0.4
Peripheral edema	5	2
Chills	5	0
Asthenia	4.5	2
Influenza-like illness	2	0.2
Respiratory Thoracic Mediastinal
Cough	5	2
Influenza	4	0.5
Dyspnea	3	2
URI	3	1
Rhinitis	2	0.4
Pharyngolaryngeal pain	2	0.5
Sinusitis	2	0.3
Epistaxis	2	0.06
Cardiac
Hypertension	4	2
Dizziness	4	2
Ejection fraction decreased	3.5	0.6
Palpitations	3	0.7
Cardiac arrhythmiasHigher level grouping term.	3	1
Cardiac failure (congestive)	2	0.3
Skin & Subcutaneous Tissue
Rash	4	0.6
Nail disorders	2	0
Pruritus	2	0.6

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

2.3 Recommended Dosage

•
TRAZIMERA is for intravenous infusion only. Do not administer as an intravenous push or bolus.
•
TRAZIMERA has different dosage and administration instructions than subcutaneous trastuzumab products.
•
Do not mix TRAZIMERA with other drugs.
•
Do not substitute TRAZIMERA (trastuzumab-qyyp) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan.

Adjuvant Treatment of Breast Cancer

Administer according to one of the following doses and schedules for a total of 52 weeks of TRAZIMERA 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 TRAZIMERA, administer TRAZIMERA 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
[seeAdverse Reactions (6.1)]
.

Metastatic Breast Cancer

•Administer TRAZIMERA, 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 TRAZIMERA 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.

]

. 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

14.1 Adjuvant Breast Cancer

NSABP B31 and NCCTG N9831

[see

Dosage and Administration (2.5)

]

HERA

BCIRG006

Table 9: Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006)
CI = confidence interval.
	DFS events	DFS Hazard ratio (95% CI) p-value	Deaths (OS events)	OS Hazard ratio p-value
NSABP B31 and NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).
AC→TH (n = 1872)Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH arm. (n = 2031)Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC→TH arm).	133	0.48 Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. (0.39, 0.59) p< 0.0001stratified log-rank test.	289	0.64 (0.55, 0.74) p< 0.0001
AC→T (n = 1880) (n = 2032)	261		418
HERA At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm.
Chemo→ Trastuzumab (n = 1693)	127	0.54 (0.44, 0.67) p< 0.0001log-rank test.	31	0.75 p = NSNS = non-significant.
Chemo→ Observation (n = 1693)	219		40
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1075)	134	0.67 (0.54 – 0.84) p=0.0006 A two-sided alpha level of 0.025 for each comparison.	56
AC→TH (n = 1074)	121	0.60 (0.48 – 0.76) p< 0.0001	49
AC→T (n = 1073)	180		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)

Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification
	NCCTG N9831		HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
HER2 Assay Result IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory.	Number of Patients	Hazard Ratio DFS (95% CI)	Number of Patients	Hazard Ratio DFS (95% CI)
IHC 3+
FISH (+)	1170	0.42 (0.27, 0.64)	91	0.56 (0.13, 2.50)
FISH (−)	51	0.71 (0.04, 11.79)	8	—
FISH Unknown	51	0.69 (0.09, 5.14)	2258	0.53 (0.41, 0.69)
IHC < 3+ / FISH (+)	174	1.01 (0.18, 5.65)	299All cases in this category in HERA were IHC 2+.	0.53 (0.20, 1.42)
IHC unknown / FISH (+)	—	—	724	0.59 (0.38, 0.93)

Figure 4

Figure 5

Figure 6

]

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 weeks dosing in the monotherapy period

[see

14.1 Adjuvant Breast Cancer

NSABP B31 and NCCTG N9831

[see

Dosage and Administration (2.5)

]

HERA

BCIRG006

Table 9: Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006)
CI = confidence interval.
	DFS events	DFS Hazard ratio (95% CI) p-value	Deaths (OS events)	OS Hazard ratio p-value
NSABP B31 and NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).
AC→TH (n = 1872)Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH arm. (n = 2031)Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC→TH arm).	133	0.48 Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. (0.39, 0.59) p< 0.0001stratified log-rank test.	289	0.64 (0.55, 0.74) p< 0.0001
AC→T (n = 1880) (n = 2032)	261		418
HERA At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm.
Chemo→ Trastuzumab (n = 1693)	127	0.54 (0.44, 0.67) p< 0.0001log-rank test.	31	0.75 p = NSNS = non-significant.
Chemo→ Observation (n = 1693)	219		40
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1075)	134	0.67 (0.54 – 0.84) p=0.0006 A two-sided alpha level of 0.025 for each comparison.	56
AC→TH (n = 1074)	121	0.60 (0.48 – 0.76) p< 0.0001	49
AC→T (n = 1073)	180		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)

Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification
	NCCTG N9831		HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
HER2 Assay Result IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory.	Number of Patients	Hazard Ratio DFS (95% CI)	Number of Patients	Hazard Ratio DFS (95% CI)
IHC 3+
FISH (+)	1170	0.42 (0.27, 0.64)	91	0.56 (0.13, 2.50)
FISH (−)	51	0.71 (0.04, 11.79)	8	—
FISH Unknown	51	0.69 (0.09, 5.14)	2258	0.53 (0.41, 0.69)
IHC < 3+ / FISH (+)	174	1.01 (0.18, 5.65)	299All cases in this category in HERA were IHC 2+.	0.53 (0.20, 1.42)
IHC unknown / FISH (+)	—	—	724	0.59 (0.38, 0.93)

Figure 4

Figure 5

Figure 6

]

. 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

14.1 Adjuvant Breast Cancer

NSABP B31 and NCCTG N9831

[see

Dosage and Administration (2.5)

]

HERA

BCIRG006

Table 9: Efficacy Results from Adjuvant Treatment of Breast Cancer (NSABP B31 and NCCTG N9831, HERA, and BCIRG006)
CI = confidence interval.
	DFS events	DFS Hazard ratio (95% CI) p-value	Deaths (OS events)	OS Hazard ratio p-value
NSABP B31 and NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).
AC→TH (n = 1872)Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH arm. (n = 2031)Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the AC→TH arm).	133	0.48 Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes, and hormone receptor status. (0.39, 0.59) p< 0.0001stratified log-rank test.	289	0.64 (0.55, 0.74) p< 0.0001
AC→T (n = 1880) (n = 2032)	261		418
HERA At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm.
Chemo→ Trastuzumab (n = 1693)	127	0.54 (0.44, 0.67) p< 0.0001log-rank test.	31	0.75 p = NSNS = non-significant.
Chemo→ Observation (n = 1693)	219		40
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1075)	134	0.67 (0.54 – 0.84) p=0.0006 A two-sided alpha level of 0.025 for each comparison.	56
AC→TH (n = 1074)	121	0.60 (0.48 – 0.76) p< 0.0001	49
AC→T (n = 1073)	180		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)

Table 10: DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or Amplification
	NCCTG N9831		HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
HER2 Assay Result IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a central laboratory.	Number of Patients	Hazard Ratio DFS (95% CI)	Number of Patients	Hazard Ratio DFS (95% CI)
IHC 3+
FISH (+)	1170	0.42 (0.27, 0.64)	91	0.56 (0.13, 2.50)
FISH (−)	51	0.71 (0.04, 11.79)	8	—
FISH Unknown	51	0.69 (0.09, 5.14)	2258	0.53 (0.41, 0.69)
IHC < 3+ / FISH (+)	174	1.01 (0.18, 5.65)	299All cases in this category in HERA were IHC 2+.	0.53 (0.20, 1.42)
IHC unknown / FISH (+)	—	—	724	0.59 (0.38, 0.93)

Figure 4

Figure 5

Figure 6

]

. 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.

Table 4: Adverse ReactionsData for trastuzumab single agent were from 4 studies, including 213 patients from H0649g. (≥ 5%) in the Trastuzumab Arms in H0648g and H0649g
	Trastuzumab n = 352 %	Trastuzumab + Paclitaxel n = 91 %	Paclitaxel n = 95 %	Trastuzumab + AC Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. n = 143 %	AC n = 135 %
General
Pain	47	61	62	57	42
Asthenia	42	62	57	54	55
Fever	36	49	23	56	34
Chills	32	41	4	35	11
Headache	26	36	28	44	31
Abdominal pain	22	34	22	23	18
Back pain	22	34	30	27	15
Infection	20	47	27	47	31
Flu syndrome	10	12	5	12	6
Accidental injury	6	13	3	9	4
Allergic reaction	3	8	2	4	2
Gastrointestinal
Nausea	33	51	9	76	77
Diarrhea	25	45	29	45	26
Vomiting	23	37	28	53	49
Anorexia	14	24	16	31	26
Nausea and vomiting	8	14	11	18	9
Respiratory
Cough increased	26	41	22	43	29
Dyspnea	22	27	26	42	25
Rhinitis	14	22	5	22	16
Pharyngitis	12	22	14	30	18
Sinusitis	9	21	7	13	6
Skin
Rash	18	38	18	27	17
Herpes simplex	2	12	3	7	9
Acne	2	11	3	3	< 1
Nervous
Insomnia	14	25	13	29	15
Dizziness	13	22	24	24	18
Paresthesia	9	48	39	17	11
Depression	6	12	13	20	12
Peripheral neuritis	2	23	16	2	2
Neuropathy	1	13	5	4	4
Metabolic
Peripheral edema	10	22	20	20	17
Edema	8	10	8	11	5
Cardiovascular
Congestive heart failure	7	11	1	28	7
Tachycardia	5	12	4	10	5
Musculoskeletal
Bone pain	7	24	18	7	7
Arthralgia	6	37	21	8	9
Urogenital
Urinary tract infection	5	18	14	13	7
Blood and Lymphatic
Anemia	4	14	9	36	26
Leukopenia	3	24	17	52	34

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

14.3 Metastatic Gastric Cancer

The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma (ToGA). In this open-label, multi-center trial, 594 patients were randomized 1:1 to trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), and fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) or HER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function (e.g., LVEF > 50%).

On the trastuzumab-containing arm, trastuzumab was administered as an IV infusion at an initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms cisplatin was administered at a dose of 80 mg/m²Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both study arms, capecitabine was administered at 1000 mg/m²dose 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 median age of the study population was 60 years (range: 21 to 83); 76% were male; 53% were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy.

The main outcome measure of ToGA was overall survival (OS), analyzed by the unstratified log-rank test. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final and the updated analyses are summarized in Table 13 and Figure 7.

Table 12: Overall Survival in ToGA (ITT Population)
	FC FC = capecitabine vs. 5-fluorouracil. + Trastuzumab Arm N = 298	FC Arm N = 296
Overall Survival (interim analysis)
N (%)	167 (56.0%)	184 (62.2%)
Median (months)	13.5	11.0
95% CI	(11.7, 15.7)	(9.4, 12.5)
Hazard Ratio	0.73
95% CI	(0.60, 0.91)
p-valueTwo sided p-value comparing with the nominal significance level of 0.0193.	0.0038
Overall Survival (updated)
N (%)	221 (74.2%)	227 (76.7%)
Median (months)	13.1	11.7
95% CI	(11.9, 15.1)	(10.3, 13.0)
Hazard Ratio	0.80
95% CI	(0.67, 0.97)


Figure 7
Updated Overall Survival in Patients with Metastatic Gastric Cancer (ToGA)

An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression (IHC) testing is summarized in Table 14.

Table 13: Exploratory Analyses by HER2 Status Using Updated Overall Survival Results
	FC (N = 296) Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory subgroup analyses.	FC + H (N = 298) Five patients on the trastuzumab-containing arm who were FISH+, but IHC status unknown were excluded from the exploratory subgroup analyses.
FISH+ / IHC 0, 1+ subgroup (N=133)
No. Deaths / n (%)	57/71 (80%)	56/62 (90%)
Median OS Duration (mos.)	8.8	8.3
95% CI (mos.)	(6.4, 11.7)	(6.2, 10.7)
Hazard ratio (95% CI)	1.33 (0.92, 1.92)
FISH+ / IHC2+ subgroup (N=160)
No. Deaths / n (%)	65/80 (81%)	64/80 (80%)
Median OS Duration (mos.)	10.8	12.3
95% CI (mos.)	(6.8, 12.8)	(9.5, 15.7)
Hazard ratio (95% CI)	0.78 (0.55, 1.10)
FISH+ or FISH- / IHC3+Includes 6 patients on chemotherapy arm, 10 patients on trastuzumab arm with FISH-, IHC3+ and 8 patients on chemotherapy arm, 8 patients on trastuzumab arm with FISH status unknown, IHC 3+.subgroup (N=294)
No. Deaths / n (%)	104/143 (73%)	96/151 (64%)
Median OS Duration (mos.)	13.2	18.0
95% CI (mos.)	(11.5, 15.2)	(15.5, 21.2)
Hazard ratio (95% CI)	0.66 (0.50, 0.87)

Figure 7

]

. 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.

Table 5: Adverse Reactions (All Grades ≥ 5% or Grade 3-4 ≥ 1% between Arms) in ToGA
Adverse Reactions	Trastuzumab + FC (N = 294) %		FC (N = 290) %
Adverse Reactions	All Grades	Grades 3-4	All Grades	Grades 3-4
Investigations
Neutropenia	78	34	73	29
Hypokalemia	28	10	24	6
Anemia	28	12	21	10
Thrombocytopenia	16	5	11	3
Blood and Lymphatic System Disorders
Febrile Neutropenia	—	5	—	3
Gastrointestinal Disorders
Diarrhea	37	9	28	4
Stomatitis	24	1	15	2
Dysphagia	6	2	3	< 1
General
Fatigue	35	4	28	2
Fever	18	1	12	0
Mucosal Inflammation	13	2	6	1
Chills	8	< 1	0	0
Metabolism and Nutrition Disorders
Weight Decrease	23	2	14	2
Infections and Infestations
Upper Respiratory Tract Infections	19	0	10	0
Nasopharyngitis	13	0	6	0
Renal and Urinary Disorders
Renal Failure and Impairment	18	3	15	2
Nervous System Disorders
Dysgeusia	10	0	5	0

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: Myocardial Dysfunction (by LVEF) in NSABP B31, NCCTG N9831, HERA and BCIRG006For NSABP B31, NCCTG N9831 and HERA, events are counted from the beginning of trastuzumab treatment. For BCIRG006, events are counted from the date of randomization.
Study and Arm	LVEF < 50% and Decrease from Baseline			LVEF Decrease
Study and Arm	LVEF < 50%	≥ 10% decrease	≥ 16% decrease	< 20% and ≥ 10%	≥ 20%
NSABP B31 & NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→TH arm.
AC→TH (n = 1856)	23.1% (428)	18.5% (344)	11.2% (208)	37.9% (703)	8.9% (166)
AC→T (n = 1170)	11.7% (137)	7.0% (82)	3.0% (35)	22.1% (259)	3.4% (40)
HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
Trastuzumab (n = 1678)	8.6% (144)	7.0% (118)	3.8% (64)	22.4% (376)	3.5% (59)
Observation (n = 1708)	2.7% (46)	2.0% (35)	1.2% (20)	11.9% (204)	1.2% (21)
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1056)	8.5% (90)	5.9% (62)	3.3% (35)	34.5% (364)	6.3% (67)
AC→TH (n = 1068)	17% (182)	13.3% (142)	9.8% (105)	44.3% (473)	13.2% (141)
AC→T (n = 1050)	9.5% (100)	6.6% (69)	3.3% (35)	34% (357)	5.5% (58)

Figure 1

and

Figure 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.

Table 6: Myocardial Dysfunction (by LVEF) in NSABP B31, NCCTG N9831, HERA and BCIRG006For NSABP B31, NCCTG N9831 and HERA, events are counted from the beginning of trastuzumab treatment. For BCIRG006, events are counted from the date of randomization.
Study and Arm	LVEF < 50% and Decrease from Baseline			LVEF Decrease
Study and Arm	LVEF < 50%	≥ 10% decrease	≥ 16% decrease	< 20% and ≥ 10%	≥ 20%
NSABP B31 & NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (AC→TH).Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→TH arm.
AC→TH (n = 1856)	23.1% (428)	18.5% (344)	11.2% (208)	37.9% (703)	8.9% (166)
AC→T (n = 1170)	11.7% (137)	7.0% (82)	3.0% (35)	22.1% (259)	3.4% (40)
HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
Trastuzumab (n = 1678)	8.6% (144)	7.0% (118)	3.8% (64)	22.4% (376)	3.5% (59)
Observation (n = 1708)	2.7% (46)	2.0% (35)	1.2% (20)	11.9% (204)	1.2% (21)
BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
TCH (n = 1056)	8.5% (90)	5.9% (62)	3.3% (35)	34.5% (364)	6.3% (67)
AC→TH (n = 1068)	17% (182)	13.3% (142)	9.8% (105)	44.3% (473)	13.2% (141)
AC→T (n = 1050)	9.5% (100)	6.6% (69)	3.3% (35)	34% (357)	5.5% (58)

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–IV, where IV is the most severe level of cardiac failure) (see

Table 2: Incidence of Cardiac DysfunctionCongestive heart failure or significant asymptomatic decrease in LVEF.in Metastatic Breast Cancer Studies
		Incidence
		NYHA I–IV		NYHA III–IV
Study	Event	Trastuzumab	Control	Trastuzumab	Control
H0648g (AC)Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.	Cardiac Dysfunction	28%	7%	19%	3%
H0648g (paclitaxel)	Cardiac Dysfunction	11%	1%	4%	1%
H0649g	Cardiac DysfunctionIncludes 1 patient with fatal cardiomyopathy.	7%	N/A	5%	N/A

). 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 to 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

Adjuvant Breast Cancer

Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2 to 5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected NCI-CTC Grade 3 to 5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [NCCTG N9831]) was higher in patients receiving trastuzumab and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2 to 5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2 to 5: 2.4% vs. 0.2% [NCCTG N9831]).

Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving trastuzumab, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone.

In HERA, there were 4 cases of interstitial pneumonitis in the one-year trastuzumab treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months.

Metastatic Breast Cancer

Among women receiving trastuzumab for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see

5.4 Pulmonary Toxicity

Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity 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

[seeWarnings and Precautions (5.2)]

. 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.

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 to 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.

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