HannaH

HannaH was a randomized, open-label study to compare the pharmacokinetics, efficacy, and safety of HERCEPTIN HYLECTA compared to intravenous trastuzumab in women with HER2-positive breast cancer. Patients randomized to the HERCEPTIN HYLECTA arm received a dose of 600 mg HERCEPTIN HYLECTA every 3 weeks throughout the treatment phase. Patients were treated for 8 cycles in combination with chemotherapy (docetaxel followed by 5FU, epirubicin and cyclophosphamide), then underwent surgery, and continued HERCEPTIN HYLECTA to complete 18 cycles of therapy. The median age of patients was 50 (range: 25-81 years), all patients were female, and a majority of patients were white (67%). The median number of HERCEPTIN HYLECTA cycles received was 18 (range 1-18).

The most common adverse reactions of any grade (occurring in ≥10% of patients) with HERCEPTIN HYLECTA were alopecia (63%), nausea (49%), ARRs (48%), neutropenia (44%), diarrhea (34%), asthenia (25%), fatigue (24%), vomiting (23%), myalgia (21%), decreased appetite (20%), stomatitis (19%), arthralgia (18%), headache (17%), rash (16%), constipation (14%), radiation skin injury (14%), pyrexia (12%), cough (12%), anemia (11%), dyspnea (11%), incision site pain (11%), peripheral sensory neuropathy (11%), leukopenia (10%), mucosal inflammation (10%), hot flush (10%), upper respiratory tract infection (10%).

The most common Grade ≥3 adverse reactions (occurring in >1% of patients) in the HERCEPTIN HYLECTA arm were neutropenia (30%), febrile neutropenia (6%), leukopenia (4%), diarrhea (3%), hypertension (2%), irregular menstruation (2%), alopecia (1%), nausea (1%), granulocytopenia (1%), vomiting (1%), amenorrhea (1%), and cellulitis (1%). Adverse reactions leading to interruption of any study drug in the HERCEPTIN HYLECTA arm occurred in 34% of patients; 31% of patients had these events during the neoadjuvant phase of the study with concurrent chemotherapy and 9% of patients had these events during the adjuvant phase. Overall, the most common (≥ 1%) were neutropenia (21%), leukopenia (2.4%), ALT increase (1.7%), pyrexia (1.7%), anemia (1%), bronchitis (1%), and left ventricular dysfunction (1%). Adverse reactions that led to discontinuation of any study drug in the HERCEPTIN HYLECTA arm (>1 patient) were left ventricular dysfunction (2%).

The incidence of ARRs in the HERCEPTIN HYLECTA arm was 48% and was 37% in the intravenous trastuzumab arm. Five (2%) patients in the HERCEPTIN HYLECTA arm experienced a Grade 3 ARR. Three of the events in the HERCEPTIN HYLECTA arm occurred on the day of study drug administration when docetaxel treatment was administered concurrently. The most commonly reported ARRs in the HERCEPTIN HYLECTA arm (≥5% of patients) were rash, pruritus, erythema, cough and dyspnea. Grade 1 and 2 injection-site reactions (ISRs) occurred in 10% of patients in the HERCEPTIN HYLECTA arm. The most common ISRs were injection-site pain and injection-site erythema.

The data in Table 3 were obtained from the HannaH trial for adverse reactions that occurred in ≥ 5% of the patients treated with HERCEPTIN HYLECTA.

SafeHER

SafeHER was a prospective, two-cohort, non-randomized, multi-center, multinational, open-label study to assess the safety of HERCEPTIN HYLECTA in patients with operable HER2-positive breast cancer. In SafeHER, 1864 patients were enrolled and treated with 600 mg of HERCEPTIN HYLECTA administered subcutaneously once every three weeks for 18 cycles.

The median age of patients was 54 (range: 20-88 years), 99.8% were female, and a majority were white (76%). A majority of the patients received HERCEPTIN HYLECTA concurrently with a chemotherapy regimen (58%). The median number of HERCEPTIN HYLECTA cycles administered was 18 and the median duration of HERCEPTIN HYLECTA exposure was 11.8 months. The median duration of follow-up was 23.7 months.

During the treatment period, the most common adverse reactions of any grade (occurring in ≥10% of patients) were ARRs (39%), diarrhea (21%), fatigue (21%), arthralgia (21%), nausea (15%), myalgia (14%), headache (13%), asthenia (12%), pain in extremity (11%), cough (11%), pyrexia (11%), hot flush (10%), and rash (10%). The most common Grade ≥3 adverse reactions (occurring in >1% of patients) were neutropenia (4%), febrile neutropenia (2%), hypertension (2%), leukopenia (1%), and diarrhea (1%). Adverse reactions that led to study drug discontinuation (≥0.5% of patients) were ejection fraction decreased (2%) and left ventricular dysfunction (1%).

The incidence of ARRs was 39%, with Grade ≥3 ARRs reported in 1% of patients treated with HERCEPTIN HYLECTA. The most frequently reported Grade ≥3 ARRs were dyspnea (<1%), cough (<1%), erythema (<1%), rash (<1%), and drug hypersensitivity (<1%). ISRs were reported in 20% of patients treated with HERCEPTIN HYLECTA. The most common ISRs were injection-site erythema (7%) and injection-site pain (6%). All ISRs were Grade 1 or 2, except for one (<1%) Grade 3 injection site discomfort.

The data in Table 4 were obtained from the SafeHER trial for adverse reactions that occurred in ≥5% of the patients treated with HERCEPTIN HYLECTA.

Fetal/Neonatal Adverse Reactions

Monitor women who received HERCEPTIN HYLECTA during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing that is appropriate for gestational age and consistent with community standards of care.

Human Data

In post-marketing reports and published literature, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal manifestations included pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In most reported cases, amniotic fluid index increased after use of trastuzumab was stopped. In reported cases where Herceptin therapy was resumed after amniotic index improved, oligohydramnios recurred.

Animal Data

HERCEPTIN HYLECTA for subcutaneous injection contains trastuzumab and hyaluronidase [see Description (11)].

Females

HERCEPTIN HYLECTA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with HERCEPTIN HYLECTA and for 7 months following the last dose of HERCEPTIN HYLECTA [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy.

Docetaxel and carboplatin: When intravenous trastuzumab was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered.

Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in Study BO18255, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with intravenous trastuzumab.

HannaH

The HannaH study (NCT00950300) was a randomized, multicenter, open-label, clinical trial in 596 patients with HER2-positive operable or locally advanced breast cancer (LABC), including inflammatory breast cancer. HER2-positivity was defined as IHC 3+ or ISH+. Patients were randomized to receive 8 cycles of either HERCEPTIN HYLECTA or intravenous trastuzumab concurrently with chemotherapy (docetaxel followed by 5FU, epirubicin and cyclophosphamide), followed by surgery and continued therapy with HERCEPTIN HYLECTA or intravenous trastuzumab as treated prior to surgery, for an additional 10 cycles, to complete 18 cycles of therapy. HannaH was designed to demonstrate non-inferiority of treatment with HERCEPTIN HYLECTA versus intravenous trastuzumab based on co-primary PK and efficacy outcomes (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, respectively) [see Clinical Pharmacology 12.3]. EFS and OS were among other outcomes evaluated in this study. The majority of patients were white (69%) and the median age was 50 years (range: 24-81).

The analysis of the efficacy co-primary outcome, pCR, defined as absence of invasive neoplastic cells in the breast, resulted in rates of 45.4% (95% CI: 39.2, 51.7) in the HERCEPTIN HYLECTA arm and 40.7% (95% CI: 34.7, 46.9) in the intravenous trastuzumab arm.

With a median follow-up exceeding 70 months, no difference in EFS and OS was observed in the final analysis between patients who received intravenous trastuzumab and those who received HERCEPTIN HYLECTA.

SafeHER

The SafeHER study (NCT01566721) was a prospective, two-cohort, non-randomized, multinational, open-label study designed to assess the overall safety and tolerability of HERCEPTIN HYLECTA with chemotherapy in 1864 patients with HER2-positive breast cancer. The secondary objectives include the evaluation of DFS and OS. HER2-positivity was defined as IHC 3+ or ISH+. Patients received a fixed dose of 600 mg HERCEPTIN HYLECTA every 3 weeks for a total of 18 cycles throughout the study. HERCEPTIN HYLECTA treatment was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neoadjuvant chemotherapy followed by trastuzumab therapy. The majority of treated patients were white (76%) and the median age was 54 years (range: 20-88).

In the primary safety analysis (median follow-up 23.7 months), no new safety signals were identified for HERCEPTIN HYLECTA. Safety and tolerability results, including in lower weight patients, were consistent with the known safety profile for HERCEPTIN HYLECTA and intravenous trastuzumab.

In the ITT population (n=1867), 126 patients (7%) had a DFS event (recurrence, contralateral invasive breast cancer or death) and 28 patients (1.5%) had an OS event at the time of clinical cut-off.

Studies NSABP B31 and NCCTG N9831

In Studies 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 (Study NCCTG N9831) or was required to be performed at a reference laboratory (Study 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 intravenous trastuzumab (AC→paclitaxel + intravenous 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 Study NSABP B31; paclitaxel was administered only by the weekly schedule in Study NCCTG N9831. Intravenous 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. Intravenous trastuzumab treatment was permanently discontinued in patients who developed congestive heart failure, or persistent/recurrent LVEF decline [see Dosage and Administration (2.3)]. 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 of the combined efficacy analysis was 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 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 + intravenous 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 + intravenous trastuzumab arm. The data from both arms in Study NSABP B31 and two of the three study arms in Study NCCTG N9831 were pooled for efficacy analyses. The patients included in the DFS analysis had a median age of 49 years (range, 22–80 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 Study

In the HERA Study, 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 4 cycles of chemotherapy to receive no additional treatment, or 1 year of intravenous trastuzumab treatment or 2 years of intravenous 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. Intravenous trastuzumab was administered with an initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every 3 weeks. The major efficacy outcome measure was DFS, defined as in Studies NSABP B31 and NCCTG N9831.

HERA was designed to compare 1 and 2 years of three-weekly intravenous 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 intravenous trastuzumab treatment to observation was performed at a median follow-up duration of 12.6 months in the intravenous trastuzumab. Among the 3386 patients randomized to the observation (n = 1693) and intravenous trastuzumab one-year (n = 1693) treatment arms, the median age was 49 years (range 21–80), 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 > 2 cm, Grade 2–3, 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 intravenous trastuzumab treatment were disclosed, a prospectively planned analysis that included comparison of one year versus two years of intravenous trastuzumab treatment at a median follow-up duration of 8 years was performed. Based on this analysis, extending intravenous trastuzumab treatment for a duration of two years did not show additional benefit over treatment for one year [Hazard Ratios of two-years intravenous trastuzumab versus one-year intravenous trastuzumab treatment in the ITT population for DFS = 0.99 (95% CI: 0.87, 1.13), p = 0.90 and OS = 0.98 (0.83, 1.15); p = 0.78].

BCIRG006 Study

In the BCIRG006 Study, 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 intravenous trastuzumab (AC-TH), or docetaxel and carboplatin plus intravenous 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. Intravenous 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. 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 Studies NSABP B31 and NCCTG N9831, HERA, and BCIRG006 and OS results for the integrated analysis of Studies NSABP B31 and NCCTG N9831, and HERA are presented in Table 9. For Studies 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 1, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm is presented in Figure 2. The duration of DFS for BCIRG006 is presented in Figure 3. For Studies 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 Studies 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 1 Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (Studies NSABP B31 and NCCTG N9831)

Figure 2 Duration of Overall Survival in Patients with Adjuvant Treatment of Breast Cancer (Studies NSABP B31 and NCCTG N9831)

Figure 3 Duration of 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 Study NCCTG N9831 and HERA, where central laboratory testing data were available. The results are shown in Table 10. The number of events in Study 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. 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 intravenous 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 intravenous 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 intravenous trastuzumab and chemotherapy experienced a significantly longer time to disease progression (TTP), a higher overall response rate (ORR), and a longer median duration of response as compared with patients randomized to chemotherapy alone. Patients randomized to intravenous trastuzumab and chemotherapy also had a longer median overall survival (OS) (see Table 11). These treatment effects were observed both in patients who received intravenous trastuzumab plus paclitaxel and in those who received intravenous 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 (Study H0649g)

Intravenous trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical trial (Study H0649g) in patients with HER2 overexpressing MBC 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%.