WARNING: LEFT
VENTRICULAR DYSFUNCTION AND EMBRYO-FETAL TOXICITY
·
Left Ventricular Dysfunction: PERJETA can result in
subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF.
Evaluate cardiac function prior to and during treatment. Discontinue PERJETA
treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.1, 6.1)
·
Embryo-fetal Toxicity: Exposure to PERJETA can result in
embryo-fetal death and birth defects. Advise patients of these risks and the
need for effective contraception. (5.2, 8.1, 8.3)
Indications and
Usage for Perjeta Injection
Metastatic
Breast Cancer (MBC)
PERJETA is
indicated for use in combination with trastuzumab and docetaxel for the
treatment of patients with HER2-positive metastatic breast cancer who have not
received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Neoadjuvant
Treatment of Breast Cancer
PERJETA is
indicated for use in combination with trastuzumab and docetaxel for the
neoadjuvant treatment of patients with HER2-positive, locally advanced,
inflammatory, or early stage breast cancer (either greater than 2 cm in
diameter or node positive) as part of a complete treatment regimen for early
breast cancer. This indication is based on demonstration of an improvement in
pathological complete response rate. No data are available demonstrating
improvement in event-free survival or overall survival [see Clinical Studies
(14.2) and Dosage and
Administration (2.1)].
Limitations of
Use:
The
safety of PERJETA as part of a doxorubicin-containing regimen has not been
established.The
safety of PERJETA administered for greater than 6 cycles for early breast
cancer has not been established.
Perjeta
Injection Dosage and Administration
Recommended
Doses and Schedules
The initial dose
of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed
every 3 weeks by a dose of 420 mg administered as an intravenous infusion over
30 to 60 minutes.
When
administered with PERJETA, the recommended initial dose of trastuzumab is 8
mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks
by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90
minutes.
PERJETA, trastuzumab,
and docetaxel should be administered sequentially. PERJETA and trastuzumab can
be given in any order. Docetaxel should be administered after PERJETA and
trastuzumab. An observation period of 30 to 60 minutes is recommended after
each PERJETA infusion and before commencement of any subsequent infusion of
trastuzumab or docetaxel [see Warnings and
Precautions (5.3)].
Metastatic
Breast Cancer (MBC)
When
administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2administered as
an intravenous infusion. The dose may be escalated to 100 mg/m2 administered
every 3 weeks if the initial dose is well tolerated.
Neoadjuvant
Treatment of Breast Cancer
PERJETA should
be administered every 3 weeks for 3 to 6 cycles as part of one of the following
treatment regimens for early breast cancer [see Clinical Studies
(14.2)]:
Four
preoperative cycles of PERJETA in combination with trastuzumab and
docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin,
and cyclophosphamide (FEC) as given in Study 2Three
preoperative cycles of FEC alone followed by 3 preoperative cycles of
PERJETA in combination with docetaxel and trastuzumab as given in Study 3Six
preoperative cycles of PERJETA in combination with docetaxel, carboplatin,
and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended)
as given in Study 3
Following
surgery, patients should continue to receive trastuzumab to complete 1 year of
treatment. There is insufficient evidence to recommend continued use of PERJETA
for greater than 6 cycles for early breast cancer. There is insufficient
evidence to recommend concomitant administration of an anthracycline with
PERJETA, and there are no safety data to support sequential use of doxorubicin
with PERJETA.
Dose
Modification
For delayed or
missed doses, if the time between two sequential infusions is less than 6
weeks, the 420 mg dose of PERJETA should be administered. Do not wait until the
next planned dose. If the time between two sequential infusions is 6 weeks or
more, the initial dose of 840 mg PERJETA should be re-administered as a 60-minute
intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg
administered as an intravenous infusion over 30 to 60 minutes.
PERJETA should
be discontinued if trastuzumab treatment is discontinued.
Dose reductions
are not recommended for PERJETA.
For docetaxel
dose modifications, see relevant prescribing information.
Left Ventricular
Ejection Fraction (LVEF):
Withhold PERJETA
and trastuzumab dosing for at least 3 weeks for either:
a
drop in LVEF to less than 45% orLVEF
of 45% to 49% with a 10% or greater absolute decrease below pretreatment
values [see Warnings
and Precautions (5.1)]
PERJETA may be
resumed if the LVEF has recovered to greater than 49% or to 45% to 49%
associated with less than a 10% absolute decrease below pretreatment values.
If after a
repeat assessment within approximately 3 weeks, the LVEF has not improved, or
has declined further, PERJETA and trastuzumab should be discontinued, unless
the benefits for the individual patient are deemed to outweigh the risks [see Warnings and
Precautions (5.1)].
Infusion-Related
Reactions
The infusion
rate of PERJETA may be slowed or interrupted if the patient develops an
infusion-related reaction [see Warnings and
Precautions (5.3)].
Hypersensitivity
Reactions/Anaphylaxis
The infusion
should be discontinued immediately if the patient experiences a serious
hypersensitivity reaction [see Warnings and
Precautions (5.4)].
Preparation for
Administration
Administer as an
intravenous infusion only. Do not administer as an intravenous push or bolus.
Do not mix PERJETA with other drugs.
Preparation
Prepare the
solution for infusion, using aseptic technique, as follows:
Parenteral
drug products should be inspected visually for particulates and discoloration
prior to administration.Withdraw
the appropriate volume of PERJETA solution from the vial(s).Dilute
into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag.Mix
diluted solution by gentle inversion. Do not shake.Administer
immediately once prepared.If
the diluted infusion solution is not used immediately, it can be stored at
2°C to 8°C for up to 24 hours.Dilute
with 0.9% Sodium Chloride injection only. Do not use dextrose (5%)
solution.
Dosage Forms and
Strengths
PERJETA (pertuzumab)
420 mg/14 mL (30 mg/mL) in a single-use vial
Contraindications
PERJETA is
contraindicated in patients with known hypersensitivity to pertuzumab or to any
of its excipients.
Warnings and
Precautions
Left Ventricular
Dysfunction
Decreases in
LVEF have been reported with drugs that block HER2 activity, including PERJETA.
In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and
docetaxel was not associated with increases in the incidence of symptomatic
left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with
placebo in combination with trastuzumab and docetaxel [see Clinical Studies
(14.1)]. Left ventricular dysfunction occurred
in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the
placebo-treated group. Symptomatic left ventricular systolic dysfunction
(congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated
group and 1.8% of patients in the placebo-treated group [see Adverse
Reactions (6.1)]. Patients who have received prior
anthracyclines or prior radiotherapy to the chest area may be at higher risk of
decreased LVEF.
In patients
receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in
the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated
group. An increased incidence of LVEF declines was observed in patients treated
with PERJETA in combination with trastuzumab and docetaxel. In the overall
treatment period, LVEF decline > 10% and a drop to less than 50% occurred in
1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared
to 8.4% of patients treated with neoadjuvant PERJETA in combination with
trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients
treated with neoadjuvant PERJETA in combination with trastuzumab and no
patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.
In patients
receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF
decline > 10% and a drop to less than 50% occurred in 6.9% of patients
treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus
trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus
trastuzumab and docetaxel following FEC, and 10.5% of patients treated with
PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients
treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of
patients treated with PERJETA in combination with TCH, and none of the patients
treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus
trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.
PERJETA has not
been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior
history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy,
or conditions that could impair left ventricular function such as uncontrolled
hypertension, recent myocardial infarction, serious cardiac arrhythmia
requiring treatment or a cumulative prior anthracycline exposure to > 360
mg/m2 of doxorubicin or its equivalent.
Assess LVEF
prior to initiation of PERJETA and at regular intervals (e.g., every three
months in the metastatic setting and every six weeks in the neoadjuvant
setting) during treatment to ensure that LVEF is within the institution's
normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater
absolute decrease below the pretreatment value, withhold PERJETA and
trastuzumab and repeat LVEF assessment within approximately 3 weeks.
Discontinue PERJETA and trastuzumab if the LVEF has not improved or has
declined further, unless the benefits for the individual patient outweigh the
risks [see Dosage and
Administration (2.2)].
Embryo-Fetal
Toxicity
Based on its
mechanism of action and findings in animal studies, PERJETA can cause fetal
harm when administered to a pregnant woman. PERJETA is a HER2/neu receptor
antagonist. Cases of oligohydramnios and oligohydramnios sequence manifesting
as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been
reported with use of another HER2/neu receptor antagonist (trastuzumab) during
pregnancy. In an animal reproduction study, administration of pertuzumab to
pregnant cynomolgus monkeys during the period of organogenesis resulted in
oligohydramnios, delayed fetal kidney development, and embryo-fetal death at
exposures 2.5 to 20 times the exposure in humans at the recommended dose, based
on Cmax.
Verify the
pregnancy status of females of reproductive potential prior to the initiation
of PERJETA. Advise pregnant women and females of reproductive potential that
exposure to PERJETA in combination with trastuzumab during pregnancy or within
7 months prior to conception can result in fetal harm, including embryo-fetal
death or birth defects. Advise females of reproductive potential to use
effective contraception during treatment and for 7 months following the last
dose of PERJETA in combination with trastuzumab [see Use in Specific
Populations (8.1, 8.3)].
Infusion-Related
Reactions
PERJETA has been
associated with infusion reactions [see Adverse
Reactions (6.1)]. An infusion reaction was defined
in Study 1 as any event described as hypersensitivity, anaphylactic reaction,
acute infusion reaction, or cytokine release syndrome occurring during an
infusion or on the same day as the infusion. The initial dose of PERJETA was
given the day before trastuzumab and docetaxel to allow for the examination of
PERJETA-associated reactions. On the first day, when only PERJETA was
administered, the overall frequency of infusion reactions was 13.0% in the
PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were
Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills,
fatigue, headache, asthenia, hypersensitivity, and vomiting.
During the
second cycle when all drugs were administered on the same day, the most common
infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue,
dysgeusia, hypersensitivity, myalgia, and vomiting.
In Study 2 and
Study 3, PERJETA was administered on the same day as the other study treatment
drugs. Infusion reactions were consistent with those observed in Study 1, with
a majority of reactions being National Cancer Institute - Common Terminology
Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.
Observe patients
closely for 60 minutes after the first infusion and for 30 minutes after
subsequent infusions of PERJETA. If a significant infusion-related reaction
occurs, slow or interrupt the infusion, and administer appropriate medical
therapies. Monitor patients carefully until complete resolution of signs and
symptoms. Consider permanent discontinuation in patients with severe infusion
reactions [see Dosage and
Administration (2.2)].
Hypersensitivity
Reactions/Anaphylaxis
In Study 1, the
overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the
PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of
Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the
PERJETA-treated group and 2.5% in the placebo-treated group according to NCI -
CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the
placebo-treated group experienced anaphylaxis.
In Study 2 and
Study 3, hypersensitivity/anaphylaxis events were consistent with those
observed in Study 1. In Study 2, two patients in the PERJETA- and
docetaxel-treated group experienced anaphylaxis. In Study 3, the overall
frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH
treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.
Patients should
be observed closely for hypersensitivity reactions. Severe hypersensitivity,
including anaphylaxis, has been observed in clinical trials with treatment of
PERJETA [see Clinical Trials
Experience (6.1)]. Medications to treat such reactions,
as well as emergency equipment, should be available for immediate use. PERJETA
is contraindicated in patients with known hypersensitivity to pertuzumab or to
any of its excipients [see Contraindications
(4)].
HER2 Testing
Detection of
HER2 protein overexpression is necessary for selection of patients appropriate
for PERJETA therapy because these are the only patients studied and for whom
benefit has been shown [see Indications and
Usage (1) and Clinical Studies
(14)]. Patients with breast cancer were
required to have evidence of HER2 overexpression defined as 3+ IHC or FISH
amplification ratio ≥ 2.0 in the clinical studies. Only limited data were
available for patients whose breast cancer was positive by FISH, but did not
demonstrate protein overexpression by IHC.
Assessment of
HER2 status should be performed by laboratories using FDA-approved tests with
demonstrated proficiency in the specific technology being utilized. Improper
assay performance, including use of sub-optimally fixed tissue, failure to
utilize specified reagents, deviation from specific assay instructions, and
failure to include appropriate controls for assay validation, can lead to
unreliable results.
Adverse
Reactions
The following
adverse reactions are discussed in greater detail in other sections of the
label:
Left
Ventricular Dysfunction [see Warnings
and Precautions (5.1)]Embryo-Fetal
Toxicity [see Warnings
and Precautions (5.2)]Infusion-Related
Reactions [see Warnings
and Precautions (5.3)]Hypersensitivity
Reactions/Anaphylaxis [see Warnings
and Precautions (5.4)]
Clinical Trials
Experience
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 clinical practice.
Metastatic
Breast Cancer (MBC)
The adverse
reactions described in Table 1 were
identified in 804 patients with HER2-positive metastatic breast cancer treated
in Study 1. Patients were randomized to receive either PERJETA in combination
with trastuzumab and docetaxel or placebo in combination with trastuzumab and
docetaxel. The median duration of study treatment was 18.1 months for patients
in the PERJETA-treated group and 11.8 months for patients in the
placebo-treated group. No dose adjustment was permitted for PERJETA or
trastuzumab. The rates of adverse events resulting in permanent discontinuation
of all study therapy were 6.1% for patients in the PERJETA-treated group and
5.3% for patients in the placebo-treated group. Adverse events led to
discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated
group and 23.2% of patients in the placebo-treated group. Table 1 reports
the adverse reactions that occurred in at least 10% of patients in the
PERJETA-treated group. The safety profile of PERJETA remained unchanged with an
additional 2.75 years of follow-up (median total follow-up of 50 months) in
Study 1.
The most common
adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab
and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and
peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse
reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia,
diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased
incidence of febrile neutropenia was observed for Asian patients in both treatment
arms compared with patients of other races and from other geographic regions.
Among Asian patients, the incidence of febrile neutropenia was higher in the
pertuzumab-treated group (26%) compared with the placebo-treated group (12%).
Table 1 Summary of Adverse Reactions Occurring in ≥
10% of Patients on the PERJETA Treatment Arm in Study 1
|
|
Body System/
Adverse Reactions
|
PERJETA + trastuzumab +
docetaxel
n=407
Frequency rate %
|
Placebo + trastuzumab +
docetaxel
n=397
Frequency rate %
|
|
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
|
*
In this table
this denotes an adverse reaction that has been reported in association with a
fatal outcome
|
|
General disorders and
administration site conditions
|
|
|
Fatigue
|
37.6
|
2.2
|
36.8
|
3.3
|
|
Asthenia
|
26.0
|
2.5
|
30.2
|
1.5
|
|
Edema peripheral
|
23.1
|
0.5
|
30.0
|
0.8
|
|
Mucosal inflammation
|
27.8
|
1.5
|
19.9
|
1.0
|
|
Pyrexia
|
18.7
|
1.2
|
17.9
|
0.5
|
|
Skin and subcutaneous tissue
disorders
|
|
|
Alopecia
|
60.9
|
0.0
|
60.5
|
0.3
|
|
Rash
|
33.7
|
0.7
|
24.2
|
0.8
|
|
Nail disorder
|
22.9
|
1.2
|
22.9
|
0.3
|
|
Pruritus
|
14.0
|
0.0
|
10.1
|
0.0
|
|
Dry skin
|
10.6
|
0.0
|
4.3
|
0.0
|
|
Gastrointestinal disorders
|
|
|
Diarrhea
|
66.8
|
7.9
|
46.3
|
5.0
|
|
Nausea
|
42.3
|
1.2
|
41.6
|
0.5
|
|
Vomiting
|
24.1
|
1.5
|
23.9
|
1.5
|
|
Constipation
|
15.0
|
0.0
|
24.9
|
1.0
|
|
Stomatitis
|
18.9
|
0.5
|
15.4
|
0.3
|
|
Blood and lymphatic system
disorders
|
|
|
Neutropenia
|
52.8
|
48.9
|
49.6
|
45.8
|
|
Anemia
|
23.1
|
2.5
|
18.9
|
3.5
|
|
Leukopenia
|
18.2
|
12.3
|
20.4
|
14.6
|
|
Febrile neutropenia*
|
13.8
|
13.0
|
7.6
|
7.3
|
|
Nervous system disorders
|
|
|
Neuropathy peripheral
|
32.4
|
3.2
|
33.8
|
2.0
|
|
Headache
|
20.9
|
1.2
|
16.9
|
0.5
|
|
Dysgeusia
|
18.4
|
0.0
|
15.6
|
0.0
|
|
Dizziness
|
12.5
|
0.5
|
12.1
|
0.0
|
|
Musculoskeletal and
connective tissue disorders
|
|
|
Myalgia
|
22.9
|
1.0
|
23.9
|
0.8
|
|
Arthralgia
|
15.5
|
0.2
|
16.1
|
0.8
|
|
Infections and infestations
|
|
|
Upper respiratory tract infection
|
16.7
|
0.7
|
13.4
|
0.0
|
|
Nasopharyngitis
|
11.8
|
0.0
|
12.8
|
0.3
|
|
Respiratory, thoracic, and mediastinal
disorders
|
|
|
Dyspnea
|
14.0
|
1.0
|
15.6
|
2.0
|
|
Metabolism and nutrition
disorders
|
|
|
Decreased appetite
|
29.2
|
1.7
|
26.4
|
1.5
|
|
Eye disorders
|
|
|
Lacrimation increased
|
14.0
|
0.0
|
13.9
|
0.0
|
|
Psychiatric disorders
|
|
|
Insomnia
|
13.3
|
0.0
|
13.4
|
0.0
|
The following clinically
relevant adverse reactions were reported in < 10% of patients in the
PERJETA-treated group in Study 1:
Skin and
subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs.
3.5% in the placebo-treated group)
Respiratory,
thoracic and mediastinal disorders: Pleural effusion (5.2% in the
PERJETA-treated group vs. 5.8% in the placebo-treated group)
Cardiac
disorders: Left
ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the
placebo-treated group) including symptomatic left ventricular systolic
dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the
placebo-treated group)
Immune system
disorders: Hypersensitivity
(10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group)
Adverse Reactions
Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of
Docetaxel
In Study 1,
adverse reactions were reported less frequently after discontinuation of
docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment
group occurred in < 10% of patients with the exception of diarrhea (19.1%),
upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and
fatigue (11.1%).
Neoadjuvant
Treatment of Breast Cancer (Study 2)
In Study 2, the
most common adverse reactions seen with PERJETA in combination with trastuzumab
and docetaxel administered for 4 cycles were similar to those seen in the
PERJETA-treated group in Study 1. The most common adverse reactions (> 30%)
were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE
v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile
neutropenia, leukopenia, and diarrhea. In this group, one patient permanently
discontinued neoadjuvant treatment due to an adverse event. Table 2 reports
the adverse reactions that occurred in patients who received neoadjuvant
treatment with PERJETA for breast cancer in Study 2.
Table 2 Summary of Adverse Reactions Occurring in ≥
10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2
|
|
Body System/
Adverse Reactions
|
Trastuzumab + docetaxel
n=107
Frequency rate
%
|
PERJETA + trastuzumab +
docetaxel
n=107
Frequency rate
%
|
PERJETA + trastuzumab
n=108
Frequency rate
%
|
PERJETA + docetaxel
n=108
Frequency rate
%
|
|
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
|
General disorders and
administration site conditions
|
|
|
Fatigue
|
27.1
|
0.0
|
26.2
|
0.9
|
12.0
|
0.0
|
25.5
|
1.1
|
|
Asthenia
|
17.8
|
0.0
|
20.6
|
1.9
|
2.8
|
0.0
|
16.0
|
2.1
|
|
Edema peripheral
|
10.3
|
0.0
|
2.8
|
0.0
|
0.9
|
0.0
|
5.3
|
0.0
|
|
Mucosal inflammation
|
21.5
|
0.0
|
26.2
|
1.9
|
2.8
|
0.0
|
25.5
|
0.0
|
|
Pyrexia
|
10.3
|
0.0
|
16.8
|
0.0
|
8.3
|
0.0
|
8.5
|
0.0
|
|
Skin and subcutaneous tissue
disorders
|
|
|
Alopecia
|
66.4
|
0.0
|
65.4
|
0.0
|
2.8
|
0.0
|
67.0
|
0.0
|
|
Rash
|
21.5
|
1.9
|
26.2
|
0.9
|
11.1
|
0.0
|
28.7
|
1.1
|
|
Gastrointestinal disorders
|
|
|
Diarrhea
|
33.6
|
3.7
|
45.8
|
5.6
|
27.8
|
0.0
|
54.3
|
4.3
|
|
Nausea
|
36.4
|
0.0
|
39.3
|
0.0
|
13.9
|
0.0
|
36.2
|
1.1
|
|
Vomiting
|
12.1
|
0.0
|
13.1
|
0.0
|
4.6
|
0.0
|
16.0
|
2.1
|
|
Stomatitis
|
7.5
|
0.0
|
17.8
|
0.0
|
4.6
|
0.0
|
9.6
|
0.0
|
|
Blood and lymphatic system
disorders
|
|
|
Neutropenia
|
63.6
|
58.9
|
50.5
|
44.9
|
0.9
|
0.9
|
64.9
|
57.4
|
|
Leukopenia
|
21.5
|
11.2
|
9.3
|
4.7
|
0.0
|
0.0
|
13.8
|
8.5
|
|
Nervous system disorders
|
|
|
Headache
|
11.2
|
0.0
|
11.2
|
0.0
|
13.9
|
0.0
|
12.8
|
0.0
|
|
Dysgeusia
|
10.3
|
0.0
|
15.0
|
0.0
|
4.6
|
0.0
|
7.4
|
0.0
|
|
Peripheral Sensory Neuropathy
|
12.1
|
0.9
|
8.4
|
0.9
|
1.9
|
0.0
|
10.6
|
0.0
|
|
Musculoskeletal and
connective tissue disorders
|
|
|
Myalgia
|
22.4
|
0.0
|
22.4
|
0.0
|
9.3
|
0.0
|
21.3
|
0.0
|
|
Arthralgia
|
8.4
|
0.0
|
10.3
|
0.0
|
4.6
|
0.0
|
9.6
|
0.0
|
|
Metabolism and nutrition
disorders
|
|
|
Decreased appetite
|
6.5
|
0.0
|
14.0
|
0.0
|
1.9
|
0.0
|
14.9
|
0.0
|
|
Psychiatric disorders
|
|
|
Insomnia
|
11.2
|
0.0
|
8.4
|
0.0
|
3.7
|
0.0
|
8.5
|
0.0
|
The following
adverse reactions were reported in < 10% of patients receiving neoadjuvant
treatment and occurred more frequently in PERJETA-treated groups in Study 2:
(Ptz=pertuzumab; T=trastuzumab; D=docetaxel)
Blood and
lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D
arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia
(6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4%
in the Ptz+D arm)
Immune system
disorders: Hypersensitivity
(1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3%
in the Ptz+D arm)
Nervous system
disorders: Dizziness
(3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2%
in the Ptz+D arm)
Infections and
infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the
Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm)
Respiratory,
thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7%
in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm)
Cardiac
disorders: Left
ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in
the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left
ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm,
Ptz+T+D arm, and Ptz+D arm)
Eye disorders: Lacrimation
increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm,
and 4.3% in the Ptz+D arm)
Neoadjuvant
Treatment of Breast Cancer (Study 3)
In Study 3, when
PERJETA was administered in combination with trastuzumab and docetaxel for 3
cycles following 3 cycles of FEC, the most common adverse reactions (> 30%)
were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most
common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were
neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular
dysfunction, anemia, dyspnea, nausea, and vomiting.
Similarly, when
PERJETA was administered in combination with docetaxel, carboplatin, and
trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%)
were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and
thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions
(> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea,
thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and
hypersensitivity.
The rates of
adverse events resulting in permanent discontinuation of any component of neoadjuvant
treatment were 6.7% for patients receiving PERJETA in combination with
trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA
in combination with TCH. Table 3 reports
the adverse reactions that occurred in patients who received neoadjuvant
treatment with PERJETA for breast cancer in Study 3.
Table 3 Summary of Adverse Reactions Occurring in ≥
10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3
|
|
|
Body System/Adverse Reactions
|
PERJETA + trastuzumab + FEC
followed by PERJETA + trastuzumab + docetaxel
|
PERJETA + trastuzumab +
docetaxel following FEC
|
PERJETA + TCH
|
|
|
n=72
|
n=75
|
n=76
|
|
|
Frequency rate
%
|
Frequency rate
%
|
Frequency rate
%
|
|
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
All Grades
%
|
Grades 3 – 4
%
|
|
|
FEC=5-fluorouracil, epirubicin, cyclophosphamide,
TCH=docetaxel, carboplatin, trastuzumab
|
|
|
General disorders and
administration site conditions
|
|
|
|
Fatigue
|
36.1
|
0.0
|
36.0
|
0.0
|
42.1
|
3.9
|
|
|
Asthenia
|
9.7
|
0.0
|
14.7
|
1.3
|
13.2
|
1.3
|
|
|
Edema peripheral
|
11.1
|
0.0
|
4.0
|
0.0
|
9.2
|
0.0
|
|
|
Mucosal inflammation
|
23.6
|
0.0
|
20.0
|
0.0
|
17.1
|
1.3
|
|
|
Pyrexia
|
16.7
|
0.0
|
9.3
|
0.0
|
15.8
|
0.0
|
|
|
Skin and subcutaneous tissue
disorders
|
|
|
|
Alopecia
|
48.6
|
0.0
|
52.0
|
0.0
|
55.3
|
0.0
|
|
|
Rash
|
19.4
|
0.0
|
10.7
|
0.0
|
21.1
|
1.3
|
|
|
Dry skin
|
5.6
|
0.0
|
9.3
|
0.0
|
10.5
|
0.0
|
|
|
Palmar-Plantar Erythrodysaesthesia Syndrome
|
6.9
|
0.0
|
10.7
|
0.0
|
7.9
|
0.0
|
|
|
Gastrointestinal disorders
|
|
|
|
Diarrhea
|
61.1
|
4.2
|
61.3
|
5.3
|
72.4
|
11.8
|
|
|
Dyspepsia
|
25.0
|
1.4
|
8
|
0.0
|
22.4
|
0.0
|
|
|
Nausea
|
52.8
|
0.0
|
53.3
|
2.7
|
44.7
|
0.0
|
|
|
Vomiting
|
40.3
|
0.0
|
36.0
|
2.7
|
39.5
|
5.3
|
|
|
Constipation
|
18.1
|
0.0
|
22.7
|
0.0
|
15.8
|
0.0
|
|
|
Stomatitis
|
13.9
|
0.0
|
17.3
|
0.0
|
11.8
|
0.0
|
|
|
Blood and lymphatic system
disorders
|
|
|
|
Neutropenia
|
51.4
|
47.2
|
46.7
|
42.7
|
48.7
|
46.1
|
|
|
Anemia
|
19.4
|
1.4
|
9.3
|
4.0
|
38.2
|
17.1
|
|
|
Leukopenia
|
22.2
|
19.4
|
16.0
|
12.0
|
17.1
|
11.8
|
|
|
Febrile neutropenia
|
18.1
|
18.1
|
9.3
|
9.3
|
17.1
|
17.1
|
|
|
Thrombocytopenia
|
6.9
|
0.0
|
1.3
|
0.0
|
30.3
|
11.8
|
|
|
Immune system disorders
|
|
|
|
Hypersensitivity
|
9.7
|
2.8
|
1.3
|
0.0
|
11.8
|
2.6
|
|
|
Nervous system disorders
|
|
|
|
Neuropathy peripheral
|
5.6
|
0.0
|
1.3
|
0.0
|
10.5
|
0.0
|
|
|
Headache
|
22.2
|
0.0
|
14.7
|
0.0
|
17.1
|
0.0
|
|
|
Dysgeusia
|
11.1
|
0.0
|
13.3
|
0.0
|
21.1
|
0.0
|
|
|
Dizziness
|
8.3
|
0.0
|
8.0
|
1.3
|
15.8
|
0.0
|
|
|
Musculoskeletal and
connective tissue disorders
|
|
|
|
Myalgia
|
16.7
|
0.0
|
10.7
|
1.3
|
10.5
|
0.0
|
|
|
Arthralgia
|
11.1
|
0.0
|
12.0
|
0.0
|
6.6
|
0.0
|
|
|
Respiratory, thoracic, and
mediastinal disorders
|
|
|
|
Cough
|
9.7
|
0.0
|
5.3
|
0.0
|
11.8
|
0.0
|
|
|
Dyspnea
|
12.5
|
0.0
|
8.0
|
2.7
|
10.5
|
1.3
|
|
|
Epistaxis
|
11.1
|
0.0
|
10.7
|
0.0
|
15.8
|
1.3
|
|
|
Oropharyngeal pain
|
8.3
|
0.0
|
6.7
|
0.0
|
11.8
|
0.0
|
|
|
Metabolism and nutrition
disorders
|
|
|
|
Decreased appetite
|
20.8
|
0.0
|
10.7
|
0.0
|
21.1
|
0.0
|
|
|
Eye disorders
|
|
|
|
Lacrimation increased
|
12.5
|
0.0
|
5.3
|
0.0
|
7.9
|
0.0
|
|
|
Psychiatric disorders
|
|
|
|
Insomnia
|
11.1
|
0.0
|
13.3
|
0.0
|
21.1
|
0.0
|
|
|
Investigations
|
|
|
|
ALT increased
|
6.9
|
0.0
|
2.7
|
0.0
|
10.5
|
3.9
|
|
The following
selected adverse reactions were reported in < 10% of patients receiving
neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel;
FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel,
carboplatin, and trastuzumab)
Skin and
subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm,
6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in
the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms),
Pruritus (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and
3.9% in the Ptz+TCH arm)
Infections and
infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D
arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis
(6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in
the Ptz+TCH arm)
Respiratory,
thoracic, and mediastinal disorders: Pleural effusion (1.4% in the
Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm)
Cardiac
disorders: Left
ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the
FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left
ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in
the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)
Immunogenicity
As with all
therapeutic proteins, there is the potential for an immune response to PERJETA.
Patients in
Study 1 were tested at multiple time-points for antibodies to PERJETA.
Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2%
(23/372) of patients in the placebo-treated group tested positive for
anti-PERJETA antibodies. Of these 34 patients, none experienced
anaphylactic/hypersensitivity reactions that were clearly related to the
anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum
at the levels expected at the time of ATA sampling can interfere with the
ability of this assay to detect anti-pertuzumab antibodies. In addition, the
assay may be detecting antibodies to trastuzumab. As a result, data may not
accurately reflect the true incidence of anti-pertuzumab antibody development.
Immunogenicity data
are highly dependent on the sensitivity and specificity of the test methods
used. Additionally, the observed incidence of a positive result in a test
method may be influenced by several factors, including sample handling, timing
of sample collection, drug interference, concomitant medication, and the
underlying disease. For these reasons, comparison of the incidence of
antibodies to PERJETA with the incidence of antibodies to other products may be
misleading.
Drug
Interactions
No drug-drug
interactions were observed between pertuzumab and trastuzumab, or between
pertuzumab and docetaxel.
USE IN SPECIFIC
POPULATIONS
Pregnancy
Pregnancy
Exposure Registry and Pharmacovigilance Program
There is a
pregnancy exposure registry that monitors pregnancy outcomes in women exposed
to PERJETA during pregnancy. Encourage women who receive PERJETA in combination
with trastuzumab during pregnancy or within 7 months prior to conception, to
enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or
visiting http://www.motherpregnancyregistry.com/.
In addition,
there is a pregnancy pharmacovigilance program for PERJETA. If PERJETA is
administered during pregnancy, or if a patient becomes pregnant while receiving
PERJETA or within 7 months following the last dose of PERJETA in combination
with trastuzumab, health care providers and patients should immediately report
PERJETA exposure to Genentech at 1-888-835-2555.
Risk Summary
Based on its
mechanism of action and findings in animal studies, PERJETA can cause fetal
harm when administered to a pregnant woman. There are no available data on the
use of PERJETA in pregnant women. However, in post-marketing reports, use of
another HER2/neu receptor antagonist (trastuzumab) during pregnancy resulted in
cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary
hypoplasia, skeletal abnormalities, and neonatal death. In an animal
reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys
during the period of organogenesis resulted in oligohydramnios, delayed fetal
kidney development, and embryo-fetal deaths at clinically relevant exposures
that were 2.5 to 20-fold greater than exposures in humans receiving the
recommended dose, based on Cmax [see Data]. Apprise
the patient of the potential risks to a fetus. There are clinical
considerations if PERJETA in combination with trastuzumab is used during
pregnancy or within 7 months prior to conception [see Clinical
Considerations].
The estimated
background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Clinical
Considerations
Fetal/Neonatal
Adverse Reactions
Monitor women
who received PERJETA in combination with trastuzumab during pregnancy or within
7 months prior to conception for oligohydramnios. If oligohydramnios occurs,
perform fetal testing that is appropriate for gestational age and consistent
with community standards of care.
Data
Animal Data
Pregnant
cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of
30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg.
These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold
greater than exposures in humans receiving the recommended dose, based on Cmax. Intravenous
administration of pertuzumab from GD19 through GD50 (period of organogenesis)
was embryotoxic, with dose-dependent increases in embryo-fetal death between
GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams
treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively
(2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean
section on GD100, oligohydramnios, decreased relative lung and kidney weights,
and microscopic evidence of renal hypoplasia consistent with delayed renal
development were identified in all pertuzumab dose groups. Pertuzumab exposure
was reported in offspring from all treated groups, at levels of 29% to 40% of
maternal serum levels at GD100.
Lactation
Risk Summary
There is no
information regarding the presence of pertuzumab in human milk, the effects on
the breastfed infant or the effects on milk production. Published data suggest
that human IgG is present in human milk but does not enter the neonatal and
infant circulation in substantial amounts. Consider the developmental and
health benefits of breast feeding along with the mother's clinical need for
PERJETA treatment and any potential adverse effects on the breastfed child from
PERJETA or from the underlying maternal condition. This consideration should
also take into account the elimination half-life of pertuzumab and the
trastuzumab wash out period of 7 months.
Females and
Males of Reproductive Potential
Pregnancy
Testing
Verify the
pregnancy status of females of reproductive potential prior to the initiation
of PERJETA.
Contraception
Females
Based on the
mechanism of action and animal data, PERJETA can cause embryo-fetal harm when
administered during pregnancy. Advise females of reproductive potential to use
effective contraception during treatment and for 7 months following the last
dose of PERJETA in combination with trastuzumab [see Use in Specific
Populations (8.1)].
Pediatric Use
The safety and
effectiveness of PERJETA have not been established in pediatric patients.
Geriatric Use
Of 402 patients
who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5
patients (1%) were ≥ 75 years of age. No overall differences in efficacy and
safety of PERJETA were observed between these patients and younger patients.
Based on a
population pharmacokinetic analysis, no significant difference was observed in
the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and
patients ≥ 65 years (n=175).
Renal Impairment
Dose adjustments
of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60
to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose
adjustment can be recommended for patients with severe renal impairment (CLcr
less than 30 mL/min) because of the limited pharmacokinetic data
available [see Clinical
Pharmacology (12.3)].
Hepatic
Impairment
No clinical
studies have been conducted to evaluate the effect of hepatic impairment on the
pharmacokinetics of pertuzumab.
Overdosage
No drug
overdoses have been reported with PERJETA to date.
Perjeta
Injection Description
Pertuzumab is a
recombinant humanized monoclonal antibody that targets the extracellular
dimerization domain (Subdomain II) of the human epidermal growth factor
receptor 2 protein (HER2). Pertuzumab is produced by recombinant DNA technology
in a mammalian cell (Chinese Hamster Ovary) culture that may contain the
antibiotic, gentamicin. Gentamicin is not detectable in the final product.
Pertuzumab has an approximate molecular weight of 148 kDa.
PERJETA is a
sterile, clear to slightly opalescent, colorless to pale brown liquid for
intravenous infusion. Each single use vial contains 420 mg of pertuzumab at a
concentration of 30 mg/mL in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose
and 0.02% polysorbate 20.
Perjeta
Injection - Clinical Pharmacology
Mechanism of
Action
Pertuzumab
targets the extracellular dimerization domain (Subdomain II) of the human
epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks
ligand-dependent heterodimerization of HER2 with other HER family members,
including EGFR, HER3, and HER4. As a result, pertuzumab inhibits
ligand-initiated intracellular signaling through two major signal pathways,
mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K).
Inhibition of these signaling pathways can result in cell growth arrest and
apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent
cell-mediated cytotoxicity (ADCC).
While pertuzumab
alone inhibited the proliferation of human tumor cells, the combination of
pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing
xenograft models.
Pharmacokinetics
Pertuzumab
demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on
a population PK analysis that included 481 patients, the median clearance (CL)
of pertuzumab was 0.24 L/day and the median half-life was 18 days. With an
initial dose of 840 mg followed by a maintenance dose of 420 mg every three
weeks thereafter, the steady-state concentration of pertuzumab was reached
after the first maintenance dose.
The population
PK analysis suggested no PK differences based on age, gender, ethnicity
(Japanese vs. non-Japanese), or disease status (neoadjuvant versus metastatic
setting). Baseline serum albumin level and lean body weight as covariates only
exerted a minor influence on PK parameters. Therefore, no dose adjustments
based on body weight or baseline albumin level are needed.
No drug-drug
interactions were observed between pertuzumab and trastuzumab, or between
pertuzumab and docetaxel in a sub-study of 37 patients in Study 1.
No dedicated
renal impairment trial for PERJETA has been conducted. Based on the results of
the population pharmacokinetic analysis, pertuzumab exposure in patients with
mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60
mL/min, n=71) were similar to those in patients with normal renal function
(CLcr greater than 90 mL/min, n=200). No relationship between CLcr and
pertuzumab exposure was observed over the range of observed CLcr (27 to 244
mL/min).
Cardiac Electrophysiology
The effect of
pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420
mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients
with HER2-positive breast cancer in Study 1. No large changes in the mean QT
interval (i.e., greater than 20 ms) from placebo based on Fridericia correction
method were detected in the trial. A small increase in the mean QTc interval
(i.e., less than 10 ms) cannot be excluded because of the limitations of the
trial design.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Long-term
studies in animals have not been performed to evaluate the carcinogenic
potential of pertuzumab.
Studies have not
been performed to evaluate the mutagenic potential of pertuzumab.
No specific
fertility studies in animals have been performed to evaluate the effect of
pertuzumab. No adverse effects on male and female reproductive organs were
observed in repeat-dose toxicity studies of up to six months duration in
cynomolgus monkeys.
Clinical Studies
Metastatic
Breast Cancer
Study 1 was a
multicenter, double-blind, placebo-controlled trial of 808 patients with
HER2-positive metastatic breast cancer. HER2 overexpression was defined as a
score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by
a central laboratory. Patients were randomly allocated 1:1 to receive placebo
plus trastuzumab and docetaxel or PERJETA plus trastuzumab and docetaxel. Randomization
was stratified by prior treatment (prior or no prior adjuvant/neoadjuvant
anti-HER2 therapy or chemotherapy) and geographic region (Europe, North
America, South America, and Asia). Patients with prior adjuvant or neoadjuvant
therapy were required to have a disease-free interval of greater than 12 months
before trial enrollment.
PERJETA was
given intravenously at an initial dose of 840 mg, followed by 420 mg every 3
weeks thereafter. Trastuzumab was given intravenously at an initial dose of 8
mg/kg, followed by 6 mg/kg every 3 weeks thereafter. Patients were treated with
PERJETA and trastuzumab until progression of disease, withdrawal of consent, or
unacceptable toxicity. Docetaxel was given as an initial dose of 75 mg/m2 by
intravenous infusion every 3 weeks for at least 6 cycles. The docetaxel dose
could be escalated to 100 mg/m2 at the investigator's discretion
if the initial dose was well tolerated. At the time of the primary analysis,
the mean number of cycles of study treatment administered was 16.2 in the
placebo-treated group and 19.9 in the PERJETA-treated group.
The primary
endpoint of Study 1 was progression-free survival (PFS) as assessed by an
independent review facility (IRF). PFS was defined as the time from the date of
randomization to the date of disease progression or death (from any cause) if
the death occurred within 18 weeks of the last tumor assessment. Additional
endpoints included overall survival (OS), PFS (investigator-assessed),
objective response rate (ORR), and duration of response.
Patient
demographic and baseline characteristics were balanced between the treatment
arms. The median age was 54 (range 22 to 89 years), 59% were White, 32% were
Asian, and 4% were Black. All were women with the exception of 2 patients.
Seventeen percent of patients were enrolled in North America, 14% in South
America, 38% in Europe, and 31% in Asia. Tumor prognostic characteristics,
including hormone receptor status (positive 48%, negative 50%), presence of
visceral disease (78%) and non-visceral disease only (22%) were similar in the
study arms. Approximately half of the patients received prior adjuvant or
neoadjuvant anti-HER2 therapy or chemotherapy (placebo 47%, PERJETA 46%). Among
patients with hormone receptor positive tumors, 45% received prior adjuvant
hormonal therapy and 11% received hormonal therapy for metastatic disease.
Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab.
Study 1
demonstrated a statistically significant improvement in IRF-assessed PFS in the
PERJETA-treated group compared with the placebo-treated group [hazard ratio
(HR)=0.62 (95% CI: 0.51, 0.75), p < 0.0001] and an increase in median PFS of
6.1 months (median PFS of 18.5 months in the PERJETA-treated group vs. 12.4
months in the placebo-treated group) (see Figure 1). The results
for investigator-assessed PFS were comparable to those observed for
IRF-assessed PFS.
Consistent
results were observed across several patient subgroups including age (< 65
or ≥ 65 years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2
therapy or chemotherapy (yes or no), and prior adjuvant/neoadjuvant trastuzumab
(yes or no). In the subgroup of patients with hormone receptor-negative disease
(n=408), the hazard ratio was 0.55 (95% CI: 0.42, 0.72). In the subgroup of
patients with hormone receptor-positive disease (n=388), the hazard ratio was
0.72 (95% CI: 0.55, 0.95). In the subgroup of patients with disease limited to
non-visceral metastasis (n=178), the hazard ratio was 0.96 (95% CI: 0.61,
1.52).
At the time of
the final PFS analysis, 165 patients had died, and more deaths had occurred in
the placebo-treated group (23.6%) compared with the PERJETA-treated group
(17.2%); OS was not mature and interim OS analysis results did not meet the
pre-specified stopping boundary for statistical significance. The final
analysis of OS (Table 4, Figure 2) was performed
when 389 patients had died (221 in the placebo-treated group and 168 in the
PERJETA-treated group). A statistically significant OS improvement in favor of
the PERJETA-treated group was demonstrated [HR=0.68 (95% CI; 0.56, 0.84),
p=0.0002] with an increase in median OS of 15.7 months (median OS of 56.5
months in the PERJETA-treated group vs. 40.8 months in the placebo-treated
group). OS results in patient subgroups were consistent with those observed for
IRF-assessed PFS with the exception of the subgroup of patients with disease
limited to non-visceral metastasis [HR=1.11 (95% CI: 0.66, 1.85)].
Table 4 Summary of Efficacy from Study 1
|
|
Parameter
|
PERJETA + trastuzumab +
docetaxel
n=402
|
Placebo + trastuzumab +
docetaxel
n=406
|
HR
(95% CI)
|
p-value
|
|
CI=Confidence Interval
|
|
*
Final analysis
of overall survival, cutoff date Feb 2014
|
|
Progression-Free Survival
(independent review)
|
|
|
|
|
|
No. of patients with an
event
Median
months
|
191 (47.5%)
18.5
|
242 (59.6%)
12.4
|
0.62
(0.51, 0.75)
|
< 0.0001
|
|
Overall Survival* (final analysis)
|
|
|
|
|
|
No. of patients who died
Median
months
|
168 (41.8%)
56.5
|
221 (54.4%)
40.8
|
0.68
(0.56, 0.84)
|
0.0002
|
|
Objective Response Rate
(ORR, independent review)
No. of
patients analyzed
|
|
|
|
|
|
Objective response (CR + PR)
|
343
|
336
|
|
|
|
Complete response (CR)
|
275 (80.2%)
|
233 (69.3%)
|
|
|
|
Partial Response (PR)
|
19 (5.5%)
|
14 (4.2%)
|
|
|
|
Median Duration of Response
(months)
|
256 (74.6%)
20.2
|
219 (65.2%)
12.5
|
|
|
|
Difference in ORR
95% CI
|
10.8%
(4.2%, 17.5%)
|
|
0.0011
|
Figure 1
Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival for Study 1
Figure 2
Kaplan-Meier Curve of Overall Survival for Study 1 (Final Analysis)
Neoadjuvant
Treatment of Breast Cancer
Study 2
Study 2 was a
multicenter, randomized trial conducted in 417 patients with operable, locally
advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were
scheduled for neoadjuvant therapy. HER2 overexpression was defined as a score
of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a
central laboratory. Patients were randomly allocated to receive 1 of 4
neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel,
PERJETA plus trastuzumab and docetaxel, PERJETA plus trastuzumab, or PERJETA
plus docetaxel. Randomization was stratified by breast cancer type (operable,
locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone
receptor (PgR) positivity.
PERJETA was
given intravenously at an initial dose of 840 mg, followed by 420 mg every 3
weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8
mg/kg, followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as
an initial dose of 75 mg/m2 by intravenous infusion every 3
weeks for 4 cycles. The docetaxel dose could be escalated to 100 mg/m2 at the investigator's
discretion if the initial dose was well tolerated. Following surgery all
patients received 3 cycles of 5-fluorouracil (600 mg/m2), epirubicin
(90 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) given
intravenously every 3 weeks and trastuzumab administered intravenously every 3
weeks to complete 1 year of therapy. After surgery, patients in the PERJETA
plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to
FEC.
The primary
endpoint of the study was pathological complete response (pCR) rate in the
breast (ypT0/is). The FDA-preferred definition of pCR is the absence of
invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
Demographics
were well balanced (median age was 49 – 50 years old, the majority were
Caucasian (71%) and all were female. Overall, 7% of patients had inflammatory
cancer, 32% had locally advanced cancer, and 61% had operable cancer.
Approximately half the patients in each treatment group had hormone
receptor-positive disease (defined as ER-positive and/or PgR-positive).
The efficacy
results are summarized in Table 5. Statistically significant
improvements in pCR rates by both the study and FDA-preferred definitions were
observed in patients receiving PERJETA plus trastuzumab and docetaxel compared
to patients receiving trastuzumab plus docetaxel. The pCR rates and magnitude
of improvement with PERJETA were lower in the subgroup of patients with hormone
receptor-positive tumors compared to patients with hormone receptor-negative
tumors.
Table 5 Summary of Efficacy from Study 2
|
|
Endpoint/Study Population
|
H+T
|
Ptz+H+T
|
Ptz+H
|
Ptz+T
|
|
T=docetaxel, Ptz=PERJETA, H=trastuzumab
CI=Confidence Interval
|
|
*
ypT0/is ypN0 (absence of invasive cancer in the breast
and lymph nodes)
†
95% CI for one sample binomial using Pearson-Clopper
method.
‡
p-value from Cochran-Mantel-Haenszel (CMH) test, with
Simes multiplicity adjustment
§
One patient had
unknown hormone receptor status. The patient did not achieve a pCR.
|
|
Overall ITT
|
N=107
|
N=107
|
N=107
|
N=96
|
|
pCR*,
n
|
23
|
42
|
12
|
17
|
|
(%)
|
(21.5%)
|
(39.3%)
|
(11.2%)
|
(17.7%)
|
|
[95% CI]†
|
[14.1, 30.5]
|
[30.0, 49.2]
|
[5.9, 18.8]
|
[10.7, 26.8]
|
|
p-value (with Simes
correction for CMH test)‡
|
|
0.0063
(vs. H+T)
|
0.0223
(vs. H+T)
|
0.0018
(vs. Ptz+H+T)
|
|
Hormone receptor-positive
subgroup
|
N=50
|
N=50
|
N=51§
|
N=46
|
|
pCR*,
n
|
6
|
11
|
1
|
4
|
|
(%)
|
(12.0%)
|
(22.0%)
|
(2.0%)
|
(8.7%)
|
|
[95% CI]†
|
[4.5, 24.3]
|
[11.5, 36.0]
|
[0.1, 10.5]
|
[2.4, 20.8]
|
|
Hormone receptor-negative
subgroup
|
N=57
|
N=57
|
N=55§
|
N=50
|
|
pCR*,
n
|
17
|
31
|
11
|
13
|
|
(%)
|
(29.8%)
|
(54.4%)
|
(20.0%)
|
(26.0%)
|
|
[95% CI]†
|
[18.4, 43.4]
|
[40.7, 67.6]
|
[10.4, 33.0]
|
[14.6, 40.3]
|
Study 3
An additional
phase 2 neoadjuvant study was conducted in 225 patients with HER2-positive
locally advanced, operable, or inflammatory (T2-4d) breast cancer designed
primarily to assess cardiac safety in which all arms included PERJETA. HER2
overexpression was defined as a score of 3+ IHC or FISH amplification ratio of
2.0 or greater as determined by a central laboratory.
Patients were
randomly allocated to receive 1 of 3 neoadjuvant regimens prior to surgery as
follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination
with PERJETA and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of
docetaxel and trastuzumab in combination with PERJETA, or 6 cycles of
docetaxel, carboplatin, and trastuzumab (TCH) in combination with PERJETA.
Randomization was stratified by breast cancer type (operable, locally advanced,
or inflammatory) and ER and/or PgR positivity.
PERJETA was
given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg
every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose
of 8 mg/kg, followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m2), epirubicin
(100 mg/m2), and cyclophosphamide (600 mg/m2) were given
intravenously every 3 weeks for 3 cycles. In the PERJETA plus trastuzumab,
docetaxel, and FEC arms, docetaxel was given as an initial dose of 75 mg/m2 by
intravenous infusion every 3 weeks for 3 cycles with the option to escalate to
100 mg/m2 at the investigator's discretion if the initial
dose was well tolerated. However, in the PERJETA plus TCH arm, docetaxel was
given intravenously at 75 mg/m2 (no escalation was permitted) and
carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles.
Following surgery all patients received trastuzumab to complete 1 year of
therapy, which was administered intravenously every 3 weeks.
Demographics
were well balanced (median age was 49-50 years old, the majority were Caucasian
(76%)) and all were female. Overall 6% of patients had inflammatory cancer, 25%
had locally advanced cancer and 69% had operable cancer, with approximately
half the patients in each treatment group having ER-positive and/or
PgR-positive disease.
The pCR (ypT0/is
ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%, 66.2%),
and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with PERJETA plus
trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, PERJETA
plus trastuzumab and docetaxel following FEC, or PERJETA plus TCH, respectively. The pCR
rates were lower in the subgroups of patients with hormone receptor-positive
tumors: 41.0% (95% CI: 25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5%
(95% CI: 31.5%, 63.9%) than with hormone receptor-negative tumors: 73.5% (95%
CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%, 77.3%), and 81.1% (95% CI: 64.8%,
92.0%), respectively.
How
Supplied/Storage and Handling
How Supplied
PERJETA is
supplied as a 420 mg/14 mL (30 mg/mL) single-use vial containing
preservative-free solution. NDC 50242-145-01.
Store vials in a
refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.
Keep vial in the
outer carton in order to protect from light.
DO NOT FREEZE.
DO NOT SHAKE.
Patient
Counseling Information
Left Ventricular
Dysfunction
Advise
patients to contact a health care professional immediately for any of the
following: new onset or worsening shortness of breath, cough, swelling of
the ankles/legs, swelling of the face, palpitations, weight gain of more
than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings
and Precautions (5.1)].
Embryo-Fetal
Toxicity
Advise
pregnant women and females of reproductive potential that exposure to
PERJETA in combination with trastuzumab during pregnancy or within 7
months prior to conception can result in fetal harm. Advise female
patients to contact their healthcare provider with a known or suspected
pregnancy [see Use in
Specific Populations (8.1)].Advise
women who are exposed to PERJETA in combination with trastuzumab during
pregnancy or within 7 months prior to conception that there is a pregnancy
exposure registry and a pregnancy pharmacovigilance program that monitors
pregnancy outcomes. Encourage these patients to enroll in the MotHER
Pregnancy Registry and report their pregnancy to Genentech [see Use in
Specific Populations (8.1)].Advise
females of reproductive potential to use effective contraception during
treatment and for 7 months following the last dose of PERJETA in
combination with trastuzumab [see Use in
Specific Populations (8.3)].
PERJETA® (pertuzumab)
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
U.S. License No. 1048
PERJETA is a
registered trademark of Genentech, Inc.
©2017 Genentech, Inc.
Representative
sample of labeling (see the HOW SUPPLIED section
for complete listing):
PRINCIPAL
DISPLAY PANEL - 14 mL Vial Label
NDC 50242-145-01
Perjeta®
(Pertuzumab)
Injection
420 mg / 14 mL
(30 mg / mL)
Dilute Prior To
Use
For Intravenous Infusion Only
Single-Use Vial
Discard Unused Portion
No preservative.
Rx only
1 vial
Genentech
10157890
|
PERJETA pertuzumab
injection, solution, concentrate
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-145
|
|
Route of Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
Pertuzumab (Pertuzumab)
|
Pertuzumab
|
30 mg in 1 mL
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
histidine
|
|
|
acetic acid
|
|
|
sucrose
|
|
|
polysorbate 20
|
|
|
water
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-145-01
|
1 VIAL, SINGLE-USE in 1 CARTON
|
|
|
1
|
|
14 mL in 1 VIAL, SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
BLA
|
BLA125409
|
06/08/2012
|
|
|
|
Labeler - Genentech, Inc. (080129000)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (Vacaville)
|
|
004074162
|
API MANUFACTURE(50242-145), ANALYSIS(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Diagnostics GmbH
|
|
315028860
|
MANUFACTURE(50242-145), ANALYSIS(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
F. Hoffmann-La Roche Ltd
|
|
485244961
|
LABEL(50242-145), PACK(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (Hillsboro)
|
|
833220176
|
LABEL(50242-145), PACK(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (SSF)
|
|
080129000
|
ANALYSIS(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (Oceanside)
|
|
146373191
|
ANALYSIS(50242-145)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Singapore Technical Operations Pte. Ltd.
|
|
937189173
|
ANALYSIS(50242-145)
|
Revised: 11/2017
Genentech, Inc.
