WARNING:
HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY
·
Do Not Substitute Kadcyla for or with trastuzumab. (2.1)
·
Hepatotoxicity: Serious hepatotoxicity has been reported,
including liver failure and death in patients treated with Kadcyla. Monitor
serum transaminases and bilirubin prior to initiation of Kadcyla treatment and
prior to each Kadcyla dose. Reduce dose or discontinue Kadcyla as appropriate
in cases of increased serum transaminases or total bilirubin. (2.2, 5.1)
·
Cardiac Toxicity: Kadcyla administration may lead to
reductions in left ventricular ejection fraction (LVEF). Evaluate left
ventricular function in all patients prior to and during treatment with
Kadcyla. Withhold treatment for clinically significant decrease in left
ventricular function. (2.2, 5.2)
·
Embryo-Fetal Toxicity: Exposure to Kadcyla during
pregnancy can result in embryo-fetal harm. Advise patients of these risks and
the need for effective contraception (5.3, 8.1, 8.3).
Indications and
Usage for Kadcyla
Kadcyla®, as a single
agent, is indicated for the treatment of patients with HER2-positive,
metastatic breast cancer who previously received trastuzumab and a taxane,
separately or in combination. Patients should have either:
·
Received prior therapy for metastatic disease, or
·
Developed disease recurrence during or within six months
of completing adjuvant therapy.
Kadcyla Dosage
and Administration
Recommended
Doses and Schedules
The recommended
dose of Kadcyla is 3.6 mg/kg given as an intravenous infusion every 3 weeks
(21-day cycle) until disease progression or unacceptable toxicity. Do not
administer Kadcyla at doses greater than 3.6 mg/kg. Do not
substitute Kadcyla for or with trastuzumab.
Closely monitor the
infusion site for possible subcutaneous infiltration during drug
administration [see Warnings and Precautions (5.10)].
First infusion:
Administer infusion over 90 minutes. Patients should be observed during the
infusion and for at least 90 minutes following the initial dose for fever,
chills, or other infusion-related reactions [see Warnings and
Precautions (5.5)].
Subsequent
infusions: Administer over 30 minutes if prior infusions were well tolerated.
Patients should be observed during the infusion and for at least 30 minutes
after infusion.
Dose
Modifications
Do not
re-escalate the Kadcyla dose after a dose reduction is made.
If a planned
dose is delayed or missed, administer as soon as possible; do not wait until
the next planned cycle. Adjust the schedule of administration to maintain a
3-week interval between doses. Administer the infusion at the dose and rate the
patient tolerated in the most recent infusion.
Slow or
interrupt the infusion rate of Kadcyla if the patient develops an
infusion-related reaction. Permanently discontinue Kadcyla for life-threatening
infusion-related reactions [see Warnings and Precautions (5.5)].
Management of
increased serum transaminases, hyperbilirubinemia, left ventricular
dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may
require temporary interruption, dose reduction or treatment discontinuation of
Kadcyla as per guidelines provided in Tables 1 to 5.
Table 1 Recommended Dose Reduction Schedule for
Adverse Events
|
|
Dose Reduction Schedule
|
Dose Level
|
|
Starting dose
|
3.6 mg/kg
|
|
First dose reduction
|
3 mg/kg
|
|
Second dose reduction
|
2.4 mg/kg
|
|
Requirement for further dose reduction
|
Discontinue treatment
|
Hepatotoxicity
[see Warnings and Precautions (5.1)]
Reduce the dose
of Kadcyla in the case of hepatotoxicity exhibited as increases in serum
transaminases and/or hyperbilirubinemia (see Tables 2 and 3).
Table 2 Dose Modification Guidelines for Increased
Serum Transaminases (AST/ALT)
|
|
Grade 2
(> 2.5 to ≤ 5 × ULN)
|
Grade 3
(> 5 to ≤ 20 × ULN)
|
Grade 4
(> 20 × ULN)
|
|
ALT = alanine transaminase; AST = aspartate
transaminase; ULN = upper limit of normal.
|
|
Treat at same dose level.
|
Do not administer Kadcyla until AST/ALT recovers to
Grade ≤ 2, and then reduce one dose level.
|
Permanently discontinue Kadcyla.
|
Table 3 Dose Modification Guidelines for
Hyperbilirubinemia
|
|
Grade 2
(> 1.5 to ≤ 3 × ULN)
|
Grade 3
(> 3 to ≤ 10 × ULN)
|
Grade 4
(> 10 × ULN)
|
|
Do not administer Kadcyla until total bilirubin
recovers to Grade ≤ 1, and then treat at same dose level.
|
Do not administer Kadcyla until total bilirubin
recovers to Grade ≤ 1, and then reduce one dose level.
|
Permanently discontinue Kadcyla.
|
Permanently
discontinue Kadcyla treatment in patients with serum transaminases > 3 × ULN
and concomitant total bilirubin > 2 × ULN.
Permanently
discontinue Kadcyla in patients diagnosed with nodular regenerative hyperplasia
(NRH).
Left Ventricular
Dysfunction [see Warnings and Precautions (5.2)]
Table 4 Dose Modifications for Left Ventricular Dysfunction
|
|
Symptomatic CHF
|
LVEF < 40%
|
LVEF 40% to ≤ 45% and decrease
is ≥ 10% points from baseline
|
LVEF 40% to ≤ 45% and decrease
is < 10% points from baseline
|
LVEF > 45%
|
|
CHF = Congestive Heart Failure; LVEF = Left Ventricular
Ejection Fraction
|
|
Discontinue Kadcyla
|
Do not administer Kadcyla.
|
Do not administer Kadcyla.
|
Continue treatment with Kadcyla.
|
Continue treatment with Kadcyla.
|
|
|
Repeat LVEF assessment within 3 weeks. If LVEF < 40%
is confirmed, discontinue Kadcyla.
|
Repeat LVEF assessment within 3 weeks. If the LVEF has
not recovered to within 10% points from baseline, discontinue Kadcyla.
|
Repeat LVEF assessment within 3 weeks.
|
|
Thrombocytopenia
[see Warnings and Precautions (5.7)]
Reduce the dose
in the case of Grade 4 thrombocytopenia (platelets < 25,000/mm3) (see Table 5).
Table 5 Dose Modification Guidelines for
Thrombocytopenia
|
|
Grade 3
|
Grade 4
|
|
PLT 25,000/mm3 to < 50,000/mm3
|
PLT < 25,000/mm3
|
|
PLT = Platelets
|
|
Do not administer Kadcyla until platelet count recovers
to ≤ Grade 1 (≥ 75,000/mm3), and then treat at same dose
level.
|
Do not administer Kadcyla until platelet count recovers
to ≤ Grade 1 (≥ 75,000/mm3), and then reduce one dose
level.
|
Pulmonary
Toxicity [see Warnings and Precautions (5.4)]
Permanently
discontinue Kadcyla in patients diagnosed with interstitial lung disease (ILD)
or pneumonitis.
Peripheral
Neuropathy [see Warnings and Precautions (5.8)]
Temporarily
discontinue Kadcyla in patients experiencing Grade 3 or 4 peripheral neuropathy
until resolution to ≤ Grade 2.
Preparation for
Administration
In order to
prevent medication errors it is important to check the vial labels to ensure
that the drug being prepared and administered is Kadcyla (ado-trastuzumab
emtansine) and not trastuzumab.
Administration:
·
Administer Kadcyla as an intravenous
infusion only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter.
Do not administer as an intravenous push or bolus.
·
Do not mix Kadcyla, or administer as an infusion, with
other medicinal products.
·
In order to improve traceability of biological medicinal
products, the tradename and the batch number of the administered product should
be clearly recorded (or stated) in the patient file.
Reconstitution:
·
Use aseptic technique for reconstitution and preparation
of dosing solution. Appropriate procedures for the preparation of
chemotherapeutic drugs should be used.
·
Using a sterile syringe, slowly inject 5 mL of Sterile
Water for Injection into the 100 mg Kadcyla vial, or 8 mL of Sterile Water for
Injection into the 160 mg Kadcyla vial to yield a solution containing 20 mg/mL.
Swirl the vial gently until completely dissolved. Do not shake. Inspect
the reconstituted solution for particulates and discoloration.
·
The reconstituted solution should be clear to slightly
opalescent and free of visible particulates. The color of the reconstituted
solution should be colorless to pale brown. Do not use if the reconstituted
solution contains visible particulates or is cloudy or discolored.
·
The reconstituted lyophilized vials should be used
immediately following reconstitution with Sterile Water for Injection. If not
used immediately, the reconstituted Kadcyla vials can be stored for up to 24
hours in a refrigerator at 2ºC to 8ºC (36°F to 46°F); discard unused Kadcyla
after 24 hours. Do not freeze.
·
The reconstituted product contains no preservative and is
intended for single-use only.
Dilution:
Determine the
correct dose (mg) of Kadcyla [see Dosage and Administration (2.1)].
·
Calculate the volume of the 20 mg/mL reconstituted
Kadcyla solution needed.
·
Withdraw this amount from the vial and add it to an
infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Do not use
Dextrose (5%) solution.
·
Gently invert the bag to mix the solution in order to
avoid foaming.
·
The diluted Kadcyla infusion solution should be used
immediately. If not used immediately, the solution may be stored in a
refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. This
storage time is additional to the time allowed for the reconstituted
vials. Do not freeze or shake.
Dosage Forms and
Strengths
Lyophilized
powder in single-use vials: 100 mg per vial or 160 mg per vial of
ado-trastuzumab emtansine.
Contraindications
None.
Warnings and
Precautions
Hepatotoxicity
Hepatotoxicity,
predominantly in the form of asymptomatic, transient increases in the
concentrations of serum transaminases, has been observed in clinical trials
with Kadcyla [see Adverse Reactions (6.1)]. Serious
hepatobiliary disorders, including at least two fatal cases of severe
drug-induced liver injury and associated hepatic encephalopathy, have been
reported in clinical trials with Kadcyla. Some of the observed cases may have
been confounded by comorbidities and/or concomitant medications with known
hepatotoxic potential.
Monitor serum
transaminases and bilirubin prior to initiation of Kadcyla treatment and prior
to each Kadcyla dose. Patients with known active hepatitis B virus or hepatitis
C virus were excluded from Study 1 [see Clinical Studies
(14.1)]. Reduce the dose or discontinue Kadcyla
as appropriate in cases of increased serum transaminases and/or total
bilirubin [see Dosage and Administration (2.2)]. Permanently
discontinue Kadcyla treatment in patients with serum transaminases > 3 × ULN
and concomitant total bilirubin > 2 × ULN. Kadcyla has not been studied in
patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × ULN
prior to the initiation of treatment.
In clinical
trials of Kadcyla, cases of nodular regenerative hyperplasia (NRH) of the liver
have been identified from liver biopsies (3 cases out of 884 treated patients,
one of which was fatal). Two of these three cases of NRH were observed in the
randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare
liver condition characterized by widespread benign transformation of hepatic
parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic
portal hypertension. The diagnosis of NRH can be confirmed only by
histopathology. NRH should be considered in all patients with clinical symptoms
of portal hypertension and/or cirrhosis-like pattern seen on the computed
tomography (CT) scan of the liver but with normal transaminases and no other
manifestations of cirrhosis. Upon diagnosis of NRH, Kadcyla treatment must be
permanently discontinued.
Left Ventricular
Dysfunction
Patients treated
with Kadcyla are at increased risk of developing left ventricular dysfunction.
A decrease of LVEF to < 40% has been observed in patients treated with
Kadcyla. In the randomized trial (Study 1), left ventricular dysfunction
occurred in 1.8% of patients in the Kadcyla-treated group and 3.3% of patients
in the lapatinib plus capecitabine-treated group [see Adverse
Reactions (6.1)].
Assess LVEF
prior to initiation of Kadcyla and at regular intervals (e.g. every three
months) during treatment to ensure the LVEF is within the institution's normal
limits. Treatment with Kadcyla has not been studied in patients with LVEF <
50% prior to initiation of treatment. If, at routine monitoring, LVEF is <
40%, or is 40% to 45% with a 10% or greater absolute decrease below the
pretreatment value, withhold Kadcyla and repeat LVEF assessment within
approximately 3 weeks. Permanently discontinue Kadcyla if the LVEF has not
improved or has declined further [see Dosage and
Administration (2.2)]. Patients with a history of symptomatic
congestive heart failure (CHF), serious cardiac arrhythmia, or history of
myocardial infarction or unstable angina within 6 months were excluded from
Study 1 [see Clinical Studies (14.1)].
Embryo-Fetal
Toxicity
Kadcyla can
cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios,
and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal
abnormalities and neonatal death were observed in the postmarketing setting in
patients treated with trastuzumab, the antibody component of Kadcyla. DM1, the
cytotoxic component of Kadcyla, can cause embryo-fetal toxicity based on its
mechanism of action.
Verify the
pregnancy status of females of reproductive potential prior to the initiation
of Kadcyla. Advise pregnant women and females of reproductive potential that
exposure to Kadcyla during pregnancy or within 7 months prior to conception can
result in fetal harm. Advise females of reproductive potential to use effective
contraception during treatment and for 7 months following the last dose of
Kadcyla [see Use in Specific Populations (8.1, 8.3)].
Pulmonary
Toxicity
Cases of
interstitial lung disease (ILD), including pneumonitis, some leading to acute
respiratory distress syndrome or fatal outcome have been reported in clinical
trials with Kadcyla. Pneumonitis at an incidence of 0.8% (7 out of 884 treated
patients) has been reported, with one case of grade 3 pneumonitis. Signs and
symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These
events may or may not occur as sequelae of infusion reactions. In the
randomized trial (Study 1), the overall frequency of pneumonitis was 1.2% [see Adverse
Reactions (6.1)].
Permanently
discontinue treatment with Kadcyla in patients diagnosed with ILD or
pneumonitis.
Patients with
dyspnea at rest due to complications of advanced malignancy and co-morbidities
may be at increased risk of pulmonary toxicity.
Infusion-Related
Reactions, Hypersensitivity Reactions
Treatment with
Kadcyla has not been studied in patients who had trastuzumab permanently
discontinued due to infusion-related reactions (IRR) and/or hypersensitivity;
treatment with Kadcyla is not recommended for these patients.
Infusion-related
reactions, characterized by one or more of the following symptoms − flushing,
chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia
have been reported in clinical trials of Kadcyla. In the randomized trial
(Study 1), the overall frequency of IRRs in patients treated with Kadcyla was
1.4% [see Adverse Reactions (6.1)]. In most
patients, these reactions resolved over the course of several hours to a day
after the infusion was terminated. Kadcyla treatment should be interrupted in
patients with severe IRR. Kadcyla treatment should be permanently discontinued
in the event of a life-threatening IRR [see Dosage and
Administration (2.2)]. Patients should be observed closely
for IRR reactions, especially during the first infusion.
One case of a
serious, allergic/anaphylactic-like reaction has been observed in clinical
trials of single-agent Kadcyla. Medications to treat such reactions, as well as
emergency equipment, should be available for immediate use.
Hemorrhage
Cases of
hemorrhagic events, including central nervous system, respiratory, and
gastrointestinal hemorrhage, have been reported in clinical trials with
Kadcyla. Some of these bleeding events resulted in fatal outcomes. In the
randomized trial (Study 1), the overall frequency of hemorrhage was 32.2% in
the Kadcyla-treated group and 16.4% in the lapatinib plus capecitabine-treated
group. The incidence of ≥ Grade 3 hemorrhage was 1.8% in the Kadcyla-treated
group and 0.8% in the lapatinib plus capecitabine-treated group [see Adverse
Reactions (6.1)]. Although, in some of the observed
cases the patients were also receiving anti-coagulation therapy, antiplatelet
therapy, or had thrombocytopenia, in others there were no known additional risk
factors. Use caution with these agents and consider additional monitoring when
concomitant use is medically necessary.
Thrombocytopenia
Thrombocytopenia,
or decreased platelet count, was reported in clinical trials of Kadcyla (103 of
884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any
Grade). The majority of these patients had Grade 1 or 2 events (< LLN to ≥
50,000/mm3) with the nadir occurring by day 8 and generally
improving to Grade 0 or 1 (≥ 75,000 /mm3) by the next
scheduled dose. In clinical trials of Kadcyla, the incidence and severity of
thrombocytopenia were higher in Asian patients.
In the
randomized trial (Study 1), the overall frequency of thrombocytopenia was 31.2%
in the Kadcyla-treated group and 3.3% in the lapatinib plus
capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence
of ≥ Grade 3 thrombocytopenia was 14.5% in the Kadcyla-treated group and 0.4%
in the lapatinib plus capecitabine-treated group. In Asian patients, the
incidence of > Grade 3 thrombocytopenia was 45.1%
in the Kadcyla-treated group and 1.3% in the lapatinib plus
capecitabine-treated group.
Monitor platelet
counts prior to initiation of Kadcyla and prior to each Kadcyla dose [see Dosage and
Administration (2.2)]. Kadcyla has not been studied in
patients with platelet counts <100,000/mm3 prior to
initiation of treatment. In the event of decreased platelet count to Grade 3 or
greater (< 50,000/mm3) do not administer Kadcyla until
platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and
Administration (2.2)]. Patients with thrombocytopenia (<
100,000/mm3) and patients on anti-coagulant treatment should be
closely monitored during treatment with Kadcyla.
Neurotoxicity
Peripheral
neuropathy, mainly as Grade 1 and predominantly sensory, was reported in
clinical trials of Kadcyla (14 of 884 treated patients with ≥ Grade 3; 196 of
884 treated patients with any Grade). In the randomized trial (Study 1), the
overall frequency of peripheral neuropathy was 21.2% in the Kadcyla-treated
group and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse
Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral
neuropathy was 2.2% in the Kadcyla-treated group and 0.2% in the lapatinib plus
capecitabine-treated group.
Kadcyla should
be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral
neuropathy until resolution to ≤ Grade 2. Patients should be clinically
monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical
Toxicology (13.2)].
HER2 Testing
Detection of
HER2 protein overexpression or gene amplification is necessary for selection of
patients appropriate for Kadcyla therapy because these are the only patients
studied for whom benefit has been shown [see Indications and
Usage (1), Clinical Studies (14.1)]. In the
randomized study (Study 1), patients with breast cancer were required to have
evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or
evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by
Dako HER2 FISH PharmDx™ test kit. Only limited data were
available for patients whose breast cancer was positive by FISH and 0 or 1+ by
IHC.
Assessment of
HER2 status should be performed by laboratories 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.
Extravasation
In Kadcyla
clinical studies, reactions secondary to extravasation have been observed.
These reactions, observed more frequently within 24 hours of infusion, were
usually mild and comprised erythema, tenderness, skin irritation, pain, or
swelling at the infusion site. Specific treatment for Kadcyla extravasation is
unknown. The infusion site should be closely monitored for possible
subcutaneous infiltration during drug administration.
Adverse
Reactions
The following
adverse reactions are discussed in greater detail in other sections of the
label:
·
Hepatotoxicity [See Warnings and
Precautions (5.1)]
·
Left Ventricular Dysfunction [See Warnings and
Precautions (5.2)]
·
Embryo-Fetal Toxicity [See Warnings and
Precautions (5.3)]
·
Pulmonary Toxicity [See Warnings and
Precautions (5.4)]
·
Infusion-Related Reactions, Hypersensitivity
Reactions [See Warnings and Precautions (5.5)]
·
Hemorrhage [See Warnings and
Precautions (5.6)]
·
Thrombocytopenia [See Warnings and
Precautions (5.7)]
·
Neurotoxicity [See Warnings and
Precautions (5.8)]
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 practice.
In clinical
trials, Kadcyla has been evaluated as single-agent in 884 patients with
HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%)
adverse drug reactions (ADRs) seen in 884 patients treated with Kadcyla were
fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache,
increased transaminases, constipation and epistaxis.
The ADRs
described in Table 6 were
identified in patients with HER2-positive metastatic breast cancer treated in a
randomized trial (Study 1) [see Clinical Studies (14.1)]. Patients were
randomized to receive Kadcyla or lapatinib plus capecitabine. The median
duration of study treatment was 7.6 months for patients in the Kadcyla-treated
group and 5.5 months and 5.3 months for patients treated with lapatinib and
capecitabine, respectively. Two hundred and eleven (43.1%) patients experienced
≥ Grade 3 adverse events in the Kadcyla-treated group compared with 289 (59.2%)
patients in the lapatinib plus capecitabine-treated group. Dose adjustments for
Kadcyla were permitted [see Dosage and Administration (2.2)]. Thirty-two
patients (6.5%) discontinued Kadcyla due to an adverse event, compared with 41
patients (8.4%) who discontinued lapatinib, and 51 patients (10.5%) who
discontinued capecitabine due to an adverse event. The most common adverse
events leading to Kadcyla withdrawal were thrombocytopenia and increased
transaminases. Eighty patients (16.3%) treated with Kadcyla had adverse events
leading to dose reductions. The most frequent adverse events leading to dose
reduction of Kadcyla (in ≥ 1% of patients) included thrombocytopenia, increased
transaminases, and peripheral neuropathy. Adverse events that led to dose
delays occurred in 116 (23.7%) of Kadcyla treated patients. The most frequent
adverse events leading to a dose delay of Kadcyla (in ≥ 1% of patients) were neutropenia,
thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia.
Table 6 reports
the ADRs that occurred in patients in the Kadcyla-treated group (n=490) of the randomized
trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most
common ADRs seen with Kadcyla in the randomized trial (frequency > 25%) were
nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased
transaminases, headache, and constipation. The most common NCI–CTCAE (version
3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased
transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.
Table 6 Summary of Adverse Drug Reactions Occurring in
Patients on the Kadcyla Treatment Arm in the Randomized Trial (Study 1)
|
|
|
Adverse Drug Reactions
(MedDRA)
System Organ Class
|
Kadcyla
(3.6 mg/kg)
n=490
Frequency rate %
|
Lapatinib (1250 mg) +
Capecitabine (2000 mg/m2)
n=488
Frequency rate %
|
|
|
|
All grades (%)
|
Grade 3 – 4 (%)
|
All grades (%)
|
Grade 3 – 4 (%)
|
|
|
ND = Not determined
|
|
|
*
Nodular
Regenerative Hyperplasia and Portal Hypertension occurred in the same
patient.
|
|
|
Blood and Lymphatic System
Disorders
|
|
|
Neutropenia
|
6.7
|
2.0
|
9.0
|
4.3
|
|
|
Anemia
|
14.3
|
4.1
|
10.5
|
2.5
|
|
|
Thrombocytopenia
|
31.2
|
14.5
|
3.3
|
0.4
|
|
|
Cardiac Disorders
|
|
|
Left ventricular dysfunction
|
1.8
|
0.2
|
3.3
|
0.4
|
|
|
Eye Disorders
|
|
|
Lacrimation increased
|
3.3
|
0
|
2.5
|
0
|
|
|
Dry eye
|
3.9
|
0
|
3.1
|
0
|
|
|
Vision blurred
|
4.5
|
0
|
0.8
|
0
|
|
|
Conjunctivitis
|
3.9
|
0
|
2.3
|
0
|
|
|
Gastrointestinal Disorders
|
|
|
Dyspepsia
|
9.2
|
0
|
11.5
|
0.4
|
|
|
Stomatitis
|
14.1
|
0.2
|
32.6
|
2.5
|
|
|
Dry Mouth
|
16.7
|
0
|
4.9
|
0.2
|
|
|
Abdominal pain
|
18.6
|
0.8
|
17.6
|
1.6
|
|
|
Vomiting
|
19.2
|
0.8
|
29.9
|
4.5
|
|
|
Diarrhea
|
24.1
|
1.6
|
79.7
|
20.7
|
|
|
Constipation
|
26.5
|
0.4
|
11.1
|
0
|
|
|
Nausea
|
39.8
|
0.8
|
45.1
|
2.5
|
|
|
General Disorders and
Administration
|
|
|
Peripheral edema
|
7.1
|
0
|
8.2
|
0.2
|
|
|
Chills
|
7.6
|
0
|
3.1
|
0
|
|
|
Pyrexia
|
18.6
|
0.2
|
8.4
|
0.4
|
|
|
Asthenia
|
17.8
|
0.4
|
17.6
|
1.6
|
|
|
Fatigue
|
36.3
|
2.5
|
28.3
|
3.5
|
|
|
Hepatobiliary Disorders*
|
|
|
Nodular regenerative hyperplasia*
|
0.4
|
ND
|
0
|
0
|
|
|
Portal hypertension*
|
0.4
|
0.2
|
0
|
0
|
|
|
Immune System Disorders
|
|
|
Drug hypersensitivity
|
2.2
|
0
|
0.8
|
0
|
|
|
Injury, Poisoning, and
Procedural
|
|
|
Infusion-related reaction
|
1.4
|
0
|
0.2
|
0
|
|
|
Infections and Infestations
|
|
|
Urinary tract infection
|
9.4
|
0.6
|
3.9
|
0
|
|
|
Investigations
|
|
|
Blood alkaline phosphatase increased
|
4.7
|
0.4
|
3.7
|
0.4
|
|
|
Increased transaminases
|
28.8
|
8.0
|
14.3
|
2.5
|
|
|
Metabolism and Nutrition
Disorders
|
|
|
Hypokalemia
|
10.2
|
2.7
|
9.4
|
4.7
|
|
|
Musculoskeletal and
Connective Tissue Disorders
|
|
|
Myalgia
|
14.1
|
0.6
|
3.7
|
0
|
|
|
Arthralgia
|
19.2
|
0.6
|
8.4
|
0
|
|
|
Musculoskeletal pain
|
36.1
|
1.8
|
30.5
|
1.4
|
|
|
Nervous System Disorders
|
|
|
Dysgeusia
|
8.0
|
0
|
4.1
|
0.2
|
|
|
Dizziness
|
10.2
|
0.4
|
10.7
|
0.2
|
|
|
Peripheral neuropathy
|
21.2
|
2.2
|
13.5
|
0.2
|
|
|
Headache
|
28.2
|
0.8
|
14.5
|
0.8
|
|
|
Psychiatric Disorders
|
|
|
Insomnia
|
12.0
|
0.4
|
8.6
|
0.2
|
|
|
Respiratory, Thoracic, and
Mediastinal Disorders
|
|
|
Pneumonitis
|
1.2
|
0
|
0
|
0
|
|
|
Dyspnea
|
12.0
|
0.8
|
8.0
|
0.4
|
|
|
Cough
|
18.2
|
0.2
|
13.1
|
0.2
|
|
|
Epistaxis
|
22.5
|
0.2
|
8.4
|
0
|
|
|
Skin and Subcutaneous Tissue
Disorders
|
|
|
Pruritus
|
5.5
|
0.2
|
9.2
|
0
|
|
|
Rash
|
11.6
|
0
|
27.5
|
1.8
|
|
|
Vascular Disorders
|
|
|
Hemorrhage
|
32.2
|
1.8
|
16.4
|
0.8
|
|
|
Hypertension
|
5.1
|
1.2
|
2.3
|
0.4
|
|
Table 7 Selected Laboratory Abnormalities
|
|
|
Parameter
|
Kadcyla
(3.6 mg/kg)
|
Lapatinib (1250 mg) +
Capecitabine (2000 mg/m2)
|
|
|
All Grade %
|
Grade 3 %
|
Grade 4 %
|
All Grade %
|
Grade 3 %
|
Grade 4 %
|
|
|
Increased bilirubin
|
17
|
<1
|
0
|
57
|
2
|
0
|
|
|
Increased AST
|
98
|
7
|
<1
|
65
|
3
|
0
|
|
|
Increased ALT
|
82
|
5
|
<1
|
54
|
3
|
0
|
|
|
Decreased platelet count
|
83
|
14
|
3
|
21
|
<1
|
<1
|
|
|
Decreased hemoglobin
|
60
|
4
|
1
|
64
|
3
|
<1
|
|
|
Decreased neutrophils
|
39
|
3
|
<1
|
38
|
6
|
2
|
|
|
Decreased potassium
|
33
|
3
|
0
|
31
|
6
|
<1
|
|
|
|
|
|
|
|
|
|
|
|
Hepatic failure
has been observed in two patients (0.2%) with HER2-positive metastatic breast
cancer in clinical trials (n=884) with Kadcyla as single-agent.
Immunogenicity
As with all
therapeutic proteins, there is the potential for an immune response to Kadcyla.
A total of 836
patients from six clinical studies were tested at multiple time points for
anti-therapeutic antibody (ATA) responses to Kadcyla. Following Kadcyla dosing,
5.3% (44/836) of patients tested positive for anti-Kadcyla antibodies at one or
more post-dose time points. The presence of Kadcyla in patient serum at the
time of ATA sampling may interfere with the ability of this assay to detect
anti-Kadcyla antibodies. As a result, data may not accurately reflect the true
incidence of anti-Kadcyla antibody development. In addition, neutralizing
activity of anti-Kadcyla antibodies has not been assessed.
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. Therefore, comparison of the incidence of antibodies to
Kadcyla with the incidence of antibodies to other products may be misleading.
Clinical significance of anti-Kadcyla antibodies is not yet known.
Drug
Interactions
No formal
drug-drug interaction studies with Kadcyla have been conducted. In vitro studies
indicate that DM1, the cytotoxic component of Kadcyla, is metabolized mainly by
CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and
voriconazole) with Kadcyla should be avoided due to the potential for an
increase in DM1 exposure and toxicity. Consider an alternate medication with no
or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4
inhibitors is unavoidable, consider delaying Kadcyla treatment until the strong
CYP3A4 inhibitors have cleared from the circulation (approximately 3
elimination half-lives of the inhibitors) when possible. If a strong CYP3A4
inhibitor is coadministered and Kadcyla treatment cannot be delayed, patients
should be closely monitored for adverse reactions.
USE IN SPECIFIC
POPULATIONS
Pregnancy
Pregnancy
Exposure Registry and Pregnancy Pharmacovigilance Program
There is a
pregnancy exposure registry that monitors pregnancy outcomes in women exposed
to Kadcyla during pregnancy. Encourage women who receive Kadcyla 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 Kadcyla. If Kadcyla is
administered during pregnancy, or if a patient becomes pregnant while receiving
Kadcyla or within 7 months following the last dose of Kadcyla, health care
providers and patients should immediately report Kadcyla exposure to Genentech
at 1-888-835-2555.
Risk Summary
Kadcyla can
cause fetal harm when administered to a pregnant woman. There are no available
data on the use of Kadcyla in pregnant women. Cases of oligohydramnios and
oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal
abnormalities, and neonatal death were observed in the postmarketing setting in
patients treated with trastuzumab, the antibody component of Kadcyla [see Data]. Based on its
mechanism of action, the DM1 component of Kadcyla can also cause embryo-fetal
harm when administered to a pregnant woman [see Data]. Apprise the
patient of the potential risks to a fetus. There are clinical considerations if
Kadcyla is used in a pregnant woman, or if a patient becomes pregnant within 7
months following the last dose of Kadcyla [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 Kadcyla 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
Human Data
There are no
available data on the use of Kadcyla in pregnant women. In the post-marketing
setting, cases of oligohydramnios, and of oligohydramnios sequence, manifesting
in the fetus as pulmonary hypoplasia, skeletal abnormalities and neonatal death
were observed after treatment with trastuzumab during pregnancy. These case
reports described oligohydramnios in pregnant women who received trastuzumab
either alone or in combination with chemotherapy. In some case reports,
amniotic fluid index increased after trastuzumab was stopped. In one case,
trastuzumab therapy resumed after amniotic index improved, and oligohydramnios
recurred.
Animal Data
There were no
reproductive and developmental toxicology studies conducted with ado-trastuzumab
emtansine. DM1, the cytotoxic component of Kadcyla, disrupts microtubule
function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic,
suggesting it has the potential to cause embryotoxicity and teratogenicity. In
studies where trastuzumab was administered to pregnant cynomolgus monkeys
during the period of organogenesis at doses up to 25 mg/kg given twice weekly
(about 7 times the clinical dose), trastuzumab crossed the placental barrier
during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150)
phases of gestation. The resulting concentrations of trastuzumab in fetal serum
and amniotic fluid were approximately 33% and 25%, respectively, of those
present in the maternal serum but were not associated with adverse
developmental effects.
Lactation
Risk Summary
There is no
information regarding the presence of ado-trastuzumab emtansine in human milk,
the effects on the breastfed infant, or the effects on milk production. DM1,
the cytotoxic component of Kadcyla, may cause serious adverse reactions in
breastfed infants based on its mechanism of action [see Data]. Advise women
not to breastfeed during treatment and for 7 months following the last dose of
Kadcyla.
Data
There were no
animal lactation studies conducted with ado-trastuzumab emtansine or the
cytotoxic component of Kadcyla (DM1). In lactating cynomolgus monkeys,
trastuzumab was present in breast milk at about 0.3% of maternal serum
concentrations after pre- (beginning Gestation Day 120) and post-partum
(through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (about
7 times the clinical dose of Kadcyla). Infant monkeys with detectable serum
levels of trastuzumab did not exhibit any adverse effects on growth or
development from birth to 1 month of age.
Females and
Males of Reproductive Potential
Pregnancy
Testing
Verify the
pregnancy status of females of reproductive potential prior to the initiation
of Kadcyla.
Contraception
Females
Kadcyla 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 Kadcyla [see Use in Specific
Populations (8.1)].
Males
Because of the
potential for genotoxicity, advise male patients with female partners of reproductive
potential to use effective contraception during treatment with Kadcyla and for
4 months following the last dose.
Infertility
Based on results
from animal toxicity studies, Kadcyla may impair fertility in females and males
of reproductive potential. It is not known if the effects are reversible [see Nonclinical
Toxicology (13.1)].
Pediatric Use
Safety and
effectiveness of Kadcyla have not been established in pediatric patients.
Geriatric Use
Of 495 patients
who were randomized to Kadcyla in the randomized trial (Study 1) [see Clinical Studies
(14.1)], 65 patients (13%) were ≥ 65 years of
age and 11 patients (2%) were ≥ 75 years of age. In patients ≥ 65 years old
(n=138 across both treatment arms) the hazard ratios for progression-free
survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and
1.05 (95% CI: 0.58, 1.91), respectively.
Population
pharmacokinetic analysis indicates that age does not have a clinically
meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine [see Clinical
Pharmacology (12.3)].
Renal Impairment
No dedicated
renal impairment trial for Kadcyla has been conducted. Based on the population
pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug
reactions and dose modifications, dose adjustments of Kadcyla are not needed in
patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate
(CLcr 30 to 59 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 data available [see Clinical Pharmacology (12.3)].
Hepatic
Impairment
No adjustment to
the starting dose is required for patients with mild or moderate hepatic
impairment [see Clinical Pharmacology (12.3)]. Kadcyla was
not studied in patients with severe hepatic impairment. Closely monitor
patients with hepatic impairment due to known hepatotoxicity observed with
Kadcyla [see Warnings and Precautions, Hepatotoxicity
(5.1)].
Overdosage
There is no
known antidote for overdose of Kadcyla. In clinical trials, overdose of Kadcyla
has been reported at approximately two times the recommended dose which
resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In
the fatal case, the patient incorrectly received Kadcyla at 6 mg/kg and died
approximately 3 weeks following the overdose; a cause of death and a causal
relationship to Kadcyla were not established.
Kadcyla
Description
Kadcyla
(ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate (ADC)
which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to
the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable
thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate).
Emtansine refers to the MCC-DM1 complex.
The antibody
trastuzumab, is a well characterized recombinant monoclonal antibody product
produced by mammalian (Chinese hamster ovary) cells, and the small molecule
components (DM1 and MCC) are produced by chemical synthesis. Ado-trastuzumab
emtansine contains an average of 3.5 DM1 molecules per antibody.
Ado-trastuzumab emtansine has the following chemical structure:
Note: The
bracketed structure is DM1 plus MCC which represents the emtansine component.
The n is, on average, 3.5 DM1 molecules per trastuzumab (Mab) molecule.
Kadcyla
(ado-trastuzumab emtansine) is a sterile, white to off-white preservative free
lyophilized powder in single-use vials. Each vial contains 100 mg or 160 mg
ado-trastuzumab emtansine. Following reconstitution, each single-use vial
contains ado-trastuzumab emtansine (20 mg/mL), polysorbate 20 [0.02% (w/v)],
sodium succinate (10 mM), and sucrose [6% (w/v)] with a pH of 5.0 and density
of 1.026 g/mL. The resulting solution containing 20 mg/mL ado-trastuzumab
emtansine is administered by intravenous infusion following dilution.
Kadcyla -
Clinical Pharmacology
Mechanism of
Action
Ado-trastuzumab
emtansine is a HER2-targeted antibody-drug conjugate. The antibody is the
humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a
microtubule inhibitor. Upon binding to sub-domain IV of the HER2 receptor,
ado-trastuzumab emtansine undergoes receptor-mediated internalization and
subsequent lysosomal degradation, resulting in intracellular release of
DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts
microtubule networks in the cell, which results in cell cycle arrest and
apoptotic cell death. In addition, in vitrostudies have
shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2
receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and
inhibits shedding of the HER2 extracellular domain in human breast cancer cells
that overexpress HER2.
Pharmacokinetics
The
pharmacokinetics of Kadcyla was evaluated in a phase 1 study and in a
population pharmacokinetic analysis for the ado-trastuzumab emtansine conjugate
(ADC) using pooled data from 5 trials in patients with breast cancer. A linear
two-compartment model with first-order elimination from the central compartment
adequately describes the ADC concentration-time profile. In addition to ADC,
the pharmacokinetics of total antibody (conjugated and unconjugated
trastuzumab), DM1 were also determined. The pharmacokinetics of Kadcyla are
summarized below.
Distribution
Maximum
concentrations (Cmax) of ADC and DM1 were observed close to the end of
infusion. In Study 1, mean (SD) ADC and DM1 Cycle 1 Cmax following
Kadcyla administration was 83.4 (16.5) mg/mL and 4.61 (1.61) ng/mL,
respectively.
In vitro, the mean
binding of DM1 to human plasma proteins was 93%. In vitro, DM1 was a
substrate of P-glycoprotein (P-gp).
Based on
population pharmacokinetic analysis, the central volume of distribution of ADC
was 3.13 L.
Metabolism
In vitro studies
indicate that DM1, the small molecule component of Kadcyla, undergoes
metabolism by CYP3A4/5. DM1 did not inhibit or induce major CYP450
enzymes in vitro. In human plasma, ado-trastuzumab emtansine
catabolites MCC-DM1, Lys-MCC-DM1, and DM1 were detected at low levels.
Elimination
Based on
population pharmacokinetic analysis, following intravenous infusion of Kadcyla,
the clearance of the ADC was 0.68 L/day and the elimination half-life (t1/2) was
approximately 4 days. No accumulation of Kadcyla was observed after repeated
dosing of intravenous infusion every 3 weeks.
Based on
population pharmacokinetic analysis (n=671), body weight, sum of longest
diameter of target lesions by RECIST, HER2 extracellular domain (ECD)
concentrations, AST, albumin, and baseline trastuzumab concentrations were
identified as statistically significant covariates for ado-trastuzumab
emtansine clearance. However, the magnitude of effect of these covariates on
ado-trastuzumab emtansine exposure suggests that, with the exception of body
weight, these covariates are unlikely to have a clinically meaningful effect on
Kadcyla exposure. Therefore, the body weight based dose of 3.6 mg/kg every 3
weeks without correction for other covariates is considered appropriate.
Effect of Renal
Impairment
Based on
population pharmacokinetic analysis in 668 patients, including moderate (CLcr 30 - 59
mL/min, n=53) and mild (CLcr 60 - 89 mL/min, n=254) renal
impairment, indicate that pharmacokinetics of the ADC is not affected by mild
to moderate renal impairment as compared to normal renal function (CLcr ≥ 90
mL/min, n=361). Data from only one patient with severe renal impairment (CLcr < 30
mL/min) is available [see Use in Specific Populations (8.7)].
Effect of
Hepatic Impairment
The liver is a
primary organ for eliminating DM1 and DM1-containing catabolites. The
pharmacokinetics of trastuzumab emtasine and DM1-containing catabolites were
evaluated after the administration of 3.6 mg/kg of Kadcyla to metastatic
HER2-positive breast cancer patients with normal hepatic function (n=10), mild
(Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.
–
Plasma
concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1)
were low and comparable between patients with and without hepatic impairment.
–
Systemic
exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and
moderate hepatic impairment were approximately 38% and 67% lower than that of
patients with normal hepatic function, respectively. Trastuzumab emtansine
exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or
moderate hepatic dysfunction was within the range observed in patients with
normal hepatic function.
Kadcyla has not
been studied in patients with severe hepatic impairment (Child-Pugh class C).
Effects of Age and Race
Based on
population pharmacokinetic analysis, age (< 65 (n=577); 65 - 75 (n=78); >
75 (n=16)) and race (Asian (n=73); non-Asian (n=598)) do not have a clinically
meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.
Cardiac Electrophysiology
The effect of
multiple doses of Kadcyla (3.6 mg/kg every 3 weeks) on the QTc interval was
evaluated in an open label, single arm study in 51 patients with HER2-positive
metastatic breast cancer. No large changes in the mean QT interval (i.e., >
20 ms) were detected in the study.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
studies have not been conducted with ado-trastuzumab emtansine.
DM1 was
aneugenic or clastogenic in an in vivo single-dose
rat bone marrow micronucleus assay at exposures that were comparable to mean
maximum concentrations of DM1 measured in humans administered Kadcyla. DM1 was
not mutagenic in an in vitro bacterial reverse mutation (Ames)
assay.
Based on results
from animal toxicity studies, Kadcyla may impair fertility in humans. In a
single-dose toxicity study of ado-trastuzumab emtansine in rats, degeneration
of seminiferous tubules with hemorrhage in the testes associated with increased
weights of testes and epididymides at a severely toxic dose level (60 mg/kg;
about 4 times the clinical exposure based on AUC) were observed. The same dose
in female rats resulted in signs of hemorrhage and necrosis of the corpus
luteum in ovaries. In monkeys dosed with ado-trastuzumab emtansine once every
three weeks for 12 weeks (four doses), at up to 30 mg/kg (about 7 times the clinical
exposure based on AUC), there were decreases in the weights of epididymides,
prostate, testes, seminal vesicles and uterus, although the interpretation of
these effects is unclear due to the varied sexual maturity of enrolled animals.
Animal Toxicology and/or Pharmacology
In monkeys,
treatment with doses of ado-trastuzumab emtansine up to 30 mg/kg (about 7 times
the clinical exposure based on AUC) caused dose dependent axonal degeneration
in the sciatic nerve with hypertrophy or hyperplasia of the Schwann cells, and
axonal degeneration of the dorsal funiculus in the spinal cord. Based on the
mechanism of action of the cytotoxic component DM1, there is clinical potential
for neurotoxicity [see Warnings and Precautions (5.8)].
Clinical Studies
Metastatic Breast Cancer
The efficacy of
Kadcyla was evaluated in a randomized, multicenter, open-label trial of 991
patients with HER2-positive, unresectable locally advanced or metastatic breast
cancer. Prior taxane and trastuzumab-based therapy was required before trial
enrollment. Patients with only prior adjuvant therapy were required to have
disease recurrence during or within six months of completing adjuvant therapy.
Breast tumor samples were required to show HER2 overexpression defined as 3+
IHC or FISH amplification ratio ≥ 2.0 determined at a central laboratory.
Patients were randomly allocated (1:1) to receive lapatinib plus capecitabine
or Kadcyla. Randomization was stratified by world region (United States,
Western Europe, other), number of prior chemotherapy regimens for unresectable
locally advanced or metastatic disease (0–1, >1) and visceral versus
non-visceral disease as determined by the investigators.
Kadcyla was
given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Lapatinib was
administered at 1250 mg/day orally once per day of a 21-day cycle and
capecitabine was administered at 1000 mg/m2orally twice
daily on Days 1−14 of a 21-day cycle. Patients were treated with Kadcyla or
lapatinib plus capecitabine until progression of disease, withdrawal of
consent, or unacceptable toxicity. At the time of the primary analysis, median
time on study drug was 5.7 months (range: 0–28.4) for Kadcyla, 4.9 months
(range: 0–30.8) for lapatinib, and 4.8 months (range: 0–30.4) for capecitabine.
The co-primary
efficacy endpoints of the study were progression-free survival (PFS) based on
tumor response assessments by an independent review committee (IRC), and
overall survival (OS). PFS was defined as the time from the date of
randomization to the date of disease progression or death from any cause
(whichever occurred earlier). Overall survival was defined as the time from the
date of randomization to the date of death from any cause. Additional endpoints
included PFS (based on investigator tumor response assessments), objective
response rate (ORR), duration of response and time to symptom progression.
Patient
demographics and baseline tumor characteristics were balanced between treatment
arms. All patients had metastatic disease at study entry. The median age was
approximately 53 years (range 24-84 years), 74% were White, 18% were Asian and
5% were Black. All but 5 patients were women. Twenty-seven percent of patients
were enrolled in United States, 32% in Europe and 16% in Asia. Tumor prognostic
characteristics including hormone receptor status (positive: 55%, negative:
43%), presence of visceral disease (68%) and non-visceral disease only (33%)
and the number of metastatic sites (< 3: 61%, ≥ 3: 37%) were similar in the
study arms.
The majority of
patients (88%) had received prior systemic treatment in the metastatic setting.
Twelve percent of patients had prior treatment only in the neoadjuvant or
adjuvant setting and had disease relapse within 6 months of treatment. All but
one patient received trastuzumab prior to study entry; approximately 85% of
patients received prior trastuzumab in the metastatic setting. Over 99% percent
of patients had received a taxane, and 61% of patients had received an
anthracycline prior to study entry. Overall, patients received a median of 3
systemic agents in the metastatic setting. Among patients with hormone
receptor-positive tumors, 44.4% received prior adjuvant hormonal therapy and
44.8% received hormonal therapy for locally advanced/metastatic disease.
The randomized
trial demonstrated a statistically significant improvement in IRC-assessed PFS
in the Kadcyla-treated group compared with the lapatinib plus
capecitabine-treated group [hazard ratio (HR) = 0.65, 95% CI: 0.55, 0.77, p
< 0.0001], and an increase in median PFS of 3.2 months (median PFS of 9.6
months in the Kadcyla-treated group vs. 6.4 months in the lapatinib plus
capecitabine group). See Table 8 and Figure 1. The results
for investigator-assessed PFS were similar to those observed for IRC-assessed
PFS.
At the time of
PFS analysis, 223 patients had died. More deaths occurred in the lapatinib plus
capecitabine arm (26%) compared with the Kadcyla arm (19%), however the results
of this interim OS analysis did not meet the pre-specified stopping boundary
for statistical significance. At the time of the second interim OS analysis,
331 events had occurred. The co-primary endpoint of OS was met; OS was
significantly improved in patients receiving Kadcyla (HR = 0.68, 95% CI: 0.55,
0.85, p = 0.0006). This result crossed the pre-specified efficacy stopping boundary
(HR = 0.73 or p = 0.0037). The median duration of survival was 30.9 months in
the Kadcyla arm vs. 25.1 months in the lapatinib plus capecitabine arm.
See Table 8 and Figure 2.
A treatment
benefit with Kadcyla in terms of PFS and OS was observed in patient subgroups
based on stratification factors, key baseline demographic and disease
characteristics, and prior treatments. In the subgroup of patients with hormone
receptor-negative disease (n=426), the hazard ratios for PFS and OS were 0.56
(95% CI: 0.44, 0.72) and 0.75 (95% CI: 0.54, 1.03), respectively. In the
subgroup of patients with hormone receptor-positive disease (n=545), the hazard
ratios for PFS and OS were 0.72 (95% CI: 0.58, 0.91) and 0.62 (95% CI: 0.46,
0.85), respectively. In the subgroup of patients with non-measurable disease
(n=205), based on IRC assessments, the hazard ratios for PFS and OS were 0.91
(95% CI: 0.59, 1.42) and 0.96 (95% CI: 0.54, 1.68), respectively; in patients
with measurable disease the hazard ratios were 0.62 (95% CI: 0.52, 0.75) and
0.65 (95% CI: 0.51, 0.82), respectively. The PFS and OS hazard ratios in
patients who were younger than 65 years old (n=853) were 0.62 (95% CI: 0.52,
0.74) and 0.66 (95% CI: 0.52, 0.83), respectively. In patients ≥ 65 years old
(n=138), the hazard ratios for PFS and OS were 1.06 (95% CI: 0.68, 1.66) and
1.05 (95% CI: 0.58, 1.91), respectively.
Table 8 Summary of Efficacy from Study 1
|
|
|
Kadcyla
N= 495
|
|
Lapatinib +Capecitabine
N= 496
|
|
PFS: progression-free survival; OR: objective response
|
|
*
Stratified by world region (United States, Western
Europe, other), number of prior chemotherapeutic regimens for locally advanced
or metastatic disease (0-1 vs. >1), and visceral vs. non-visceral disease.
†
The second
interim analysis for OS was conducted when 331 events were observed and the
results are presented in this table.
|
|
Progression-Free Survival
(independent review)
|
|
|
Number (%) of patients with event
|
265 (53.5%)
|
|
304 (61.3%)
|
|
Median duration of PFS (months)
|
9.6
|
|
6.4
|
|
Hazard Ratio (stratified*)
|
|
0.650
|
|
|
95% CI for Hazard Ratio
|
|
(0.549, 0.771)
|
|
|
p-value (Log-Rank test, stratified*)
|
|
<0.0001
|
|
|
Overall Survival †
|
|
|
Number (%) of patients who died
|
149 (30.1%)
|
|
182 (36.7%)
|
|
Median duration of survival (months)
|
30.9
|
|
25.1
|
|
Hazard Ratio (stratified*)
|
|
0.682
|
|
|
95% CI for Hazard Ratio
|
|
(0.548, 0.849)
|
|
|
p-value (Log-Rank test*)
|
|
0.0006
|
|
|
Objective Response Rate
|
|
|
(independent
review)
|
|
|
Patients with measurable disease
|
397
|
|
389
|
|
Number of patients with OR (%)
|
173 (43.6%)
|
|
120 (30.8%)
|
|
Difference (95% CI)
|
|
12.7% (6.0, 19.4)
|
|
|
Duration of Objective
Response (months)
|
|
|
Number of patients with OR
|
173
|
|
120
|
|
Median duration (95% CI)
|
12.6 (8.4, 20.8)
|
|
6.5 (5.5, 7.2)
|
Figure 1 Kaplan-Meier Curve of IRC-Assessed
Progression-Free Survival for Study 1
Figure 2 Kaplan-Meier Curve of Overall Survival for Study
1
REFERENCES
1. OSHA Hazardous
Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
How Supplied/Storage and Handling
How Supplied/Storage
Kadcyla
(ado-trastuzumab emtansine) is supplied as:
|
Carton Contents
|
NDC
|
|
One 100 mg vial, single use vial
|
NDC 50242-088-01
|
|
One 160 mg vial, single use vial
|
NDC 50242-087-01
|
Store vials in a
refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution. Do not freeze or
shake.
Special Handling
Follow
procedures for proper handling and disposal of anticancer drugs1.
Patient Counseling Information
·
Inform patients of the possibility of severe liver injury
and advise patients to immediately seek medical attention if they experience
symptoms of acute hepatitis such as nausea, vomiting, abdominal pain
(especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus,
anorexia, etc. [see Warnings and Precautions (5.1)].
·
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, palpitations, weight gain of more
than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and
Precautions (5.2)].
Embryo-Fetal Toxicity
·
Advise pregnant women and females of reproductive
potential that Kadcyla exposure 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, 8.3)].
·
Advise women who are exposed to Kadcyla during pregnancy
or who become pregnant within 7 months following the last dose of Kadcyla 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
Kadcyla [see Use in Specific Populations (8.1, 8.3)].
·
Advise male patients with female partners of reproductive
potential to use effective contraception during treatment and for 4 months
following the last dose of Kadcyla [see Use in Specific
Populations (8.3)].
Lactation
·
Advise women not to breastfeed during treatment and for 7
months after the last dose of Kadcyla [see Use in Specific
Populations (8.2)].
Kadcyla® [ado-trastuzumab
emtansine]
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
U.S. License No: 1048
Initial U.S.
Approval: February 2013
Kadcyla is a
trademark of Genentech, Inc.
©2016 Genentech, Inc.
Representative
sample of labeling (see the HOW SUPPLIED section
for complete listing):
PRINCIPAL DISPLAY PANEL - 100 mg Vial Carton
NDC 50242-088-01
Kadcyla®
(ado-trastuzumab
emtansine)
For Injection
100 mg per vial
For Intravenous Infusion Only
Reconstitute and Dilute prior
to administration
Single-Dose Vial –
Discard Unused Portion
KEEP REFRIGERATED
Rx only
1 vial
Genentech
10165748
PRINCIPAL DISPLAY PANEL - 160 mg Vial Carton
NDC 50242-087-01
Kadcyla®
(ado-trastuzumab
emtansine)
For Injection
160 mg per vial
For Intravenous Infusion Only
Reconstitute and Dilute prior
to administration
Single-Dose Vial –
Discard Unused Portion
KEEP REFRIGERATED
Rx only
1 vial
Genentech
10165750
|
Kadcyla ado-trastuzumab
emtansine injection, powder, lyophilized, for solution
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-088
|
|
Route of Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
ADO-TRASTUZUMAB EMTANSINE (ADO-TRASTUZUMAB EMTANSINE)
|
ADO-TRASTUZUMAB EMTANSINE
|
20 mg in 1 mL
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
SUCROSE
|
60 mg in 1 mL
|
|
SUCCINIC ACID
|
1.18 mg in 1 mL
|
|
SODIUM HYDROXIDE
|
0.45 mg in 1 mL
|
|
POLYSORBATE 20
|
0.2 mg in 1 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-088-01
|
1 VIAL, SINGLE-USE in 1 CARTON
|
|
|
1
|
|
5 mL in 1 VIAL, SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
BLA
|
BLA125427
|
02/22/2013
|
|
|
|
Kadcyla ado-trastuzumab
emtansine injection, powder, lyophilized, for solution
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-087
|
|
Route of Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
ADO-TRASTUZUMAB EMTANSINE (ADO-TRASTUZUMAB EMTANSINE)
|
ADO-TRASTUZUMAB EMTANSINE
|
20 mg in 1 mL
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
SUCROSE
|
60 mg in 1 mL
|
|
SUCCINIC ACID
|
1.18 mg in 1 mL
|
|
SODIUM HYDROXIDE
|
0.45 mg in 1 mL
|
|
POLYSORBATE 20
|
0.2 mg in 1 mL
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-087-01
|
1 VIAL, SINGLE-USE in 1 CARTON
|
|
|
1
|
|
8 mL in 1 VIAL, SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
BLA
|
BLA125427
|
02/22/2013
|
|
|
|
Labeler - Genentech, Inc. (080129000)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (Hillsboro)
|
|
833220176
|
LABEL(50242-088, 50242-087), PACK(50242-088, 50242-087)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Genentech, Inc. (Vacaville)
|
|
004074162
|
API MANUFACTURE(50242-088, 50242-087),
ANALYSIS(50242-088, 50242-087)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Singapore Technical Operations Pte. Ltd.
|
|
937189173
|
API MANUFACTURE(50242-088, 50242-087),
ANALYSIS(50242-088, 50242-087)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
F. Hoffmann-La Roche Ltd
|
|
485244961
|
PACK(50242-088, 50242-087)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Pharma AG
|
|
315009878
|
ANALYSIS(50242-088, 50242-087)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Diagnostics GmbH
|
|
315028860
|
ANALYSIS(50242-088, 50242-087)
|
Revised: 07/2017
Genentech, Inc.
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