CLINICAL PHARMACOLOGY
Mechanism Of Action
The HER2 (or c-erbB2)
proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is
structurally related to the epidermal growth factor receptor. Trastuzumab has
been shown, in both in vitro assays and in animals, to inhibit the
proliferation of human tumor cells that overexpress HER2.
Trastuzumab is a mediator of
antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab-mediated
ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer
cells compared with cancer cells that do not overexpress HER2.
Hyaluronan is a polysaccharide
found in the extracellular matrix of the subcutaneous tissue. It is
depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the
stable structural components of the interstitial matrix, hyaluronan has a
half-life of approximately 0.5 days. Hyaluronidase increases permeability of
the subcutaneous tissue by depolymerizing hyaluronan. In the doses
administered, hyaluronidase in HERCEPTIN HYLECTA acts transiently and locally.
The effects of hyaluronidase are reversible and
permeability of the subcutaneous tissue is restored within 24 to 48 hours.
Hyaluronidase has been shown to increase the absorption
rate of a trastuzumab product into the systemic circulation when given in the
subcutis of Göttingen Minipigs.
Pharmacodynamics
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.
Pharmacokinetics
Trastuzumab exposure following subcutaneous
administration of HERCEPTIN HYLECTA 600 mg every 3 weeks as compared to
intravenous trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance every 3 weeks
in the HannaH Study is shown in Table 6. The pharmacokinetic (PK) results for
the co-primary endpoint, Ctrough predose Cycle 8, showed non-inferiority of
HERCEPTIN HYLECTA (78.7 mcg/mL) compared to intravenous trastuzumab (57.8
mcg/mL), with a geometric mean ratio of 1.3 (90% CI: 1.2–1.4).
A population PK model with parallel linear and nonlinear
elimination from the central compartment was constructed using pooled HERCEPTIN
HYLECTA and intravenous trastuzumab pharmacokinetic (PK) data from HannaH to
describe the observed trastuzumab PK concentrations following HERCEPTIN HYLECTA
subcutaneous administration and intravenous trastuzumab administration.
Population PK predicted trastuzumab exposure are shown in Table 6.
Following subcutaneous administration of HERCEPTIN
HYLECTA, trastuzumab concentrations were approximately at steady-state after
the Cycle 7 dose with < 15% increase in concentration up to Cycle 13. The
mean Ctrough at the pre-dose Cycle 18 in HERCEPTIN HYLECTA arm is similar to
that of Cycle 13, suggesting no further increase after Cycle 13. The mean Cmax was
32% lower, and the mean AUC0-21 days following the Cycle 7 dose and Cycle 12
dose was approximately 10% and 20% higher, respectively, in the HERCEPTIN
HYLECTA arm than in the intravenous trastuzumab arm.
Table 6 : Trastuzumab Exposure (median with 5th-95th Percentiles)
following Subcutaneous Administration of HERCEPTIN HYLECTA or Intravenous
Trastuzumab
Trastuzumab Exposure |
|
HERCEPTIN HYLECTA |
Intravenous Trastuzumab |
Ctrough (mcg/mL) |
Cycle 1 |
28.2 (14.8-40.9) |
29.4 (5.8-59.5) |
Cycle 7 |
75.0 (35.1-123) |
47.4 (5-114.7) |
Cmax (mcg/mL) |
Cycle 1 |
79.3 (56.1-109) |
178 (117-291) |
Cycle 7 |
149 (86.1-214) |
179 (107-309) |
AUC0-21 days (mcg/mL•day) |
Cycle 1 |
1065 (718-1504) |
1373 (736-2245) |
Cycle 7 |
2337 (1258-3478) |
1794 (673-3618) |
General PK parameters of
trastuzumab following subcutaneous administration of HERCEPTIN HYLECTA are
shown in Table 7. Trastuzumab is estimated to reach concentrations that are <
1 mcg/mL by 7 months in at least 95% patients.
Table 7 : PK parameters of Trastuzumab following
Subcutaneous Administration of HERCEPTIN HYLECTA *
Absorption |
|
Absolute Bioavailability |
0.77 (13) |
First-order absorption rate, ka (day-1) |
0.4 (2.92) † |
Tmax (day) |
3 (1-14)‡ |
Distribution |
Volume of Central Compartment (L) |
2.9 (19.1) |
Elimination |
Linear Elimination Clearance (L/day) |
0.11 (30) |
Non-linear Elimination Vmax (mg/day) |
11.9 (19.9) † |
Non-linear Elimination Km (mg/L) |
33.9 (38.6) † |
* Parameters represented as geometric mean (%CV) unless
otherwise specified
† Residual standard error
‡ Median (range) |
Specific Populations
Body weight showed a
statistically significant influence on PK. In patients with a body weight <
51 kg, mean steady state AUC of trastuzumab was about 80% higher after
HERCEPTIN HYLECTA than after intravenous trastuzumab treatment, whereas in the
highest BW group (> 90 kg) AUC was 20% lower after HERCEPTIN HYLECTA than
after intravenous trastuzumab treatment. However, no body weight based dose adjustments
are needed, as the exposure changes are not considered clinically relevant.
Drug Interaction Studies
There have been no formal drug
interaction studies performed with trastuzumab in humans. Clinically
significant interactions between trastuzumab and concomitant medications used
in clinical trials have not been observed.
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.
Clinical Studies
The comparability between HERCEPTIN HYLECTA administered
subcutaneously and intravenous trastuzumab was established in the HannaH study.
The HannaH study was conducted in patients with HER2 overexpressing breast
cancer in the neoadjuvant and adjuvant settings with co-primary endpoints of
pathological complete response (pCR) and the PK endpoint of Ctrough at cycle 7 [see
CLINICAL PHARMACOLOGY].
Adjuvant Breast Cancer
HERCEPTIN HYLECTA
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. HER2positivity 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]. 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.
Table 8: Summary of Pathological Complete Response
(pCR) (HannaH)
|
HERCEPTIN HYLECTA
(n=260) |
Intravenous Trastuzumab
(n=263) |
pCR (absence of invasive neoplastic cells in breast [ypT0/is]) |
118 (45.4%) |
107 (40.7%) |
Exact 95% CI for pCR Rate * |
(39.2; 51.7) |
(34.7; 46.9) |
Difference in pCR (SC minus IV arm) |
4.70 |
95% CI for Difference in pCR† |
(-4.0; 13.4) |
* CI for one sample binomial using Pearson-Clopper method
†Approximate 95% CI for difference of two rates using Hauck-Anderson method |
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.
Intravenous Trastuzumab
The safety and efficacy of
intravenous trastuzumab in women receiving adjuvant chemotherapy for HER2
overexpressing breast cancer were evaluated in an integrated analysis of two
randomized, open-label, clinical trials (Studies 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 Study) with a
total of 3386 women at definitive DFS analysis for 1-year intravenous
trastuzumab treatment versus observation, and a fourth randomized, open-label
clinical trial with a total of 3222 patients (Study BCIRG006).
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].
Radiation therapy, if administered, was initiated after the completion of
chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal therapy.
The primary endpoint 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. The secondary endpoint was OS.
A total of 3752 patients were included in the joint
efficacy analysis of the primary endpoint 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 primary 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. Similar demographic and baseline characteristics were reported for
the efficacy evaluable population, after 8.3 years of median follow-up in the
AC→paclitaxel + intravenous trastuzumab arm.
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.
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). 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 main outcome measure was
DFS, defined as in Studies NSABP B31 and NCCTG N9831.
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 arm and
formed the basis for the definitive DFS results from this study. 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 Caucasian, 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 definitive 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 main outcome measure.
Among the 3222 patients randomized, 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. Across all four studies, at the time of definitive
DFS analysis, there were insufficient numbers of patients within each of the
following subgroups to determine if the treatment effect was different from
that of the overall patient population: patients with low tumor grade, patients
within specific ethnic/racial subgroups (Black, Hispanic, Asian/Pacific
Islander patients), and patients>65 years of age. 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).
Table 9 : Efficacy Results from Adjuvant Treatment of
Breast Cancer (Studies NSABP B31, NCCTG N9831, HERA, and BCIRG006)
|
DFS events |
DFS Hazard ratio (95% CI) p-value |
Deaths (OS events) |
OS Hazard ratio p-value |
Studies NSABP B31 and NCCTG N9831* |
AC→TH (n = 1872)† (n = 2031)‡ |
133† |
0.48†,§
(0.39, 0.59)
p< 0.0001Δ |
289‡ |
0.64‡,§
(0.55, 0.74)
p< 0.0001Δ |
AC→T (n = 1880)† (n = 2032)‡ |
261† |
|
418‡ |
|
HERA# |
Chemo→ Intravenous trastuzumab (n = 1693) |
127 |
0.54
(0.44, 0.67)
p< 0.0001Þ |
31 |
0.75 p = NSβ |
Chemo→Observation (n = 1693) |
219 |
|
40 |
|
BCIRG006a |
TCH (n = 1075) |
134 |
0.67 (0.54 - 0.84)
p=0.0006 Δ,e |
56 |
|
AC→TH (n = 1074) |
121 |
0.60
(0.48 - 0.76)
p< 0.0001Δ,a |
49 |
|
AC→T (n = 1073) |
180 |
|
80 |
|
CI = confidence interval.
* Studies NSABP B31 and NCCTG N9831 regimens:
doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or
paclitaxel plus intravenous trastuzumab (AC→TH).
† Efficacy evaluable population, for the primary DFS analysis, following a
median follow-up of 2.0 years in the AC→TH arm.
‡ Efficacy evaluable population, for the final OS analysis, following
707 deaths (8.3 years of median follow-up in the AC→TH arm).
§ Hazard ratio estimated by Cox regression stratified by clinical trial,
intended paclitaxel schedule, number of positive nodes, and hormone receptor
status.
Δ stratified log-rank test.
# At definitive DFS analysis with median duration of follow-up of 12.6 months
in the one-year intravenous trastuzumab treatment arm.
Þ log-rank test.
β NS = non-significant.
a BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel
(AC→T) or docetaxel plus intravenous trastuzumab (AC→TH); docetaxel
and carboplatin plus intravenous trastuzumab (TCH).
e A two-sided alpha level of 0.025 for each comparison. |
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.
Table 10 : Treatment
Outcomes in Study NCCTG N9831and HERA as a Function of HER2 Overexpression or
Amplification
HER2 Assay Result† |
Study NCCTG N9831 |
HERA* |
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) |
299* |
0.53
(0.20, 1.42) |
IHC unknown / FISH (+) |
— |
— |
724 |
0.59
(0.38, 0.93) |
* Median follow-up duration of 12.6 months in the one-year
intravenous trastuzumab treatment arm.
† IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as
performed at a central laboratory.
‡ All cases in this
category in HERA were IHC 2+. |
Metastatic Breast Cancer
Intravenous Trastuzumab
The safety and efficacy of
intravenous trastuzumab in the treatment of women with metastatic breast cancer
were studied in a randomized, controlled clinical trial in combination with
chemotherapy (H0648g, n=469 patients) and an open-label single agent clinical
trial (H0649g, n=222 patients). Both trials studied patients with metastatic
breast cancer whose tumors overexpress the HER2 protein. Patients were eligible
if they had level 2 or 3 overexpression (based on a 0 to 3 scale) by
immunohistochemical assessment of tumor tissue performed by a central testing
lab.
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, 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 survival (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.
Table 11: H0648g: Efficacy
Results in First-Line Treatment for Metastatic Breast Cancer
|
Combined Results |
Paclitaxel Subgroup |
AC Subgroup |
Intravenous Trastuzumab + All Chemotherapy
(n=235) |
All Chemotherapy
(n=234) |
Intravenous Trastuzumab + Paclitaxel
(n=92) |
Paclitaxel
(n=96) |
Intravenous Trastuzumab + AC *
(n=143) |
AC
(n=138) |
Primary Endpoint |
|
Median TTP (mos)†,‡ |
7.2 |
4.5 |
6.7 |
2.5 |
7.6 |
5.7 |
95% CI |
7, 8 |
4, 5 |
5, 10 |
2, 4 |
7, 9 |
5, 7 |
p-value § |
< 0.0001 |
< 0.0001 |
0.002 |
Secondary Endpoints |
Overall Response Rate † |
45 |
29 |
38 |
15 |
50 |
38 |
95% CI |
39, 51 |
23, 35 |
28, 48 |
8, 22 |
42, 58 |
30, 46 |
p-value Δ |
< 0.001 |
< 0.001 |
0.10 |
Median Resp Duration (mos) †,‡ |
8.3 |
5.8 |
8.3 |
4.3 |
8.4 |
6.4 |
25%, 75% Quartile |
6 ,15 |
4, 8 |
5, 11 |
4, 7 |
6, 15 |
4, 8 |
Med Survival (mos)‡ |
25. 1 |
20.3 |
22.1 |
18.4 |
26.8 |
21.4 |
95% CI |
22, 30 |
17, 24 |
17, 29 |
13, 24 |
23, 33 |
18, 27 |
p-value § |
0.05 |
0.17 |
0.16 |
* AC=Anthracycline (doxorubicin or epirubicin) and
cyclophosphamide.
† Assessed by an independent Response Evaluation Committee.
‡ Kaplan-Meier Estimate.
§ log-rank test.
Δ χ2-test. |
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).
Table 12: Treatment Effects in H0648g as a Function of
HER2 Overexpression or Amplification
HER2 Assay Result |
Number of Patients (N) |
Relative Risk * for Time to Disease Progression (95% CI) |
Relative Risk * for Mortality (95% CI) |
CTA 2+ or 3+ |
469 |
0.49 (0.40, 0.61) |
0.80 (0.64, 1.00) |
FISH (+)† |
325 |
0.44 (0.34, 0.57) |
0.70 (0.53, 0.91) |
FISH (-)† |
126 |
0.62 (0.42, 0.94) |
1.06 (0.70, 1.63) |
CTA 2+ |
120 |
0.76 (0.50, 1.15) |
1.26 (0.82, 1.94) |
FISH (+) |
32 |
0.54 (0.21, 1.35) |
1.31 (0.53, 3.27) |
FISH (-) |
83 |
0.77 (0.48, 1.25) |
1.11 (0.68, 1.82) |
CTA 3+ |
349 |
0.42 (0.33, 0.54) |
0.70 (0.51, 0.90) |
FISH (+) |
293 |
0.42 (0.32, 0.55) |
0.67 (0.51, 0.89) |
FISH (-) |
43 |
0.43 (0.20, 0.94) |
0.88 (0.39, 1.98) |
*The relative risk represents the risk of progression or
death in the trastuzumab plus chemotherapy arm versus the chemotherapy arm.
† FISH testing results were available for 451 of the 469 patients enrolled on
study. |
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 MBCwho 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%.
Patient Experience
The PrefHER study (NCT01401166)
was a randomized, multi-center, two-arm, cross-over trial conducted in 240
patients with HER2-positive breast cancer undergoing neoadjuvant or adjuvant
treatment. One hundred twenty-one patients in arm A received 4 cycles of HERCEPTIN
HYLECTA followed by 4 cycles of intravenous trastuzumab and 119 patients in arm
B received 4 cycles of intravenous trastuzumab followed by 4 cycles of
HERCEPTIN HYLECTA. Both arms received a total of 18 cycles. After Cycle 8, 199
of 231 patients (86%) reported preferring subcutaneous administration of
HERCEPTIN HYLECTA over intravenous trastuzumab and the most common reason cited
was administration required less time (179/231) in the clinic. After Cycle 8,
29 out of 231 patients (13%) reported preferring intravenous trastuzumab over
HERCEPTIN HYLECTA and the most common reason was fewer local injection
reactions. Three out of 231 patients (1%) had no preference for the route of
administration. Nine out of 240 (3.8%) withdrew from treatment prior to
completion of Cycle 8 and did not complete the post-study preference
questionnaire.