KADCYLA

Trastuzumab emtansine, formerly called Trastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody drug conjugate (ADC) comprised of Genentech's trastuzumab antibody linked to ImmunoGen's cell-killing agent, DM1.

T-DM1 combines two strategies-

• anti-HER2 activity and targeted intracellular delivery of the potent anti-microtubule agent, DM1 (a maytansine derivative)--to produce cell cycle arrest and apoptosis.

Trastuzumab emtansine is marketed under the brand name Kadcyla and is indicated for use in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment.

FDA label has two precautions.

First that trastuzumab emtansine and trastuzumab cannot be interchanged.

Second that there is a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.

Used in

HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment.

Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models.

In the

Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth.

• resistant model, Herceptin alone had no effect on tumor growth.

In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice.

In this

• resistant model, tumor regrowth was observed after cessation of Trastuzumab.

• DM1 treatment, yet regression re-occurred when dosing was resumed.

The effect was specific for

HER2-positive tumors.

Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis.

The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered Intravenous.

The volume of distribution of trastuzumab emtansine is about 3.13 L.

Trastuzumab emtansine undergoes lysosomal degradation to

All of these products are detected at low levels in the plasma.

DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes.

The route of elimination has not yet been fully elucidated.

Trastuzumab emtansine has a long half life of about 4 days.

Intravenous infusion, trastuzumab emtansine has a clearance of 0.68 L/day.

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FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.

Do not substitute

KADCYLA for or with trastuzumab.

HER2 Testing: Perform using FDA-authorized tests by laboratories with demonstrated proficiency.

For intravenous infusion only.

Do not administer as an intravenous push or bolus.

Do not use

Dextrose (5%) solution.

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, or a total of 14 cycles for patients with EBC.

Do not administer

KADCYLA at doses greater than 3.6 mg/kg. Management of adverse reactions (infusion-related reactions, hepatotoxicity, left ventricular cardiac dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy) may require temporary interruption, dose reduction, or treatment discontinuation of KADCYLA. 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens.

Assessment of

HER2 protein overexpression and/or HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancers by laboratories with demonstrated proficiency.

Information on the FDA-authorized tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: 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. 2.2 Recommended Doses and Schedules Do not substitute trastuzumab for or with KADCYLA.

KADCYLA is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle).

KADCYLA at doses greater than 3.6 mg/kg.

Closely monitor the infusion site for possible subcutaneous infiltration during drug administration.

First infusion

Administer infusion over 90 minutes.

Observe patients during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions.

Subsequent infusions

Administer over 30 minutes if prior infusions were well tolerated.

Observe patients during the infusion and for at least 30 minutes after infusion.

Cancer (MBC) Patients with MBC should receive treatment until disease progression or unmanageable toxicity.

Cancer (EBC) Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity. 2.3 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.

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 and 2.

Table 1 Recommended Dose Reduction Schedule for Adverse Reactions 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 Table 2 Dose Modification Guidelines for KADCYLA ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, DILI = Drug Induced Liver Injury; LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal Dose Modifications for Patients with MBC Adverse reaction Severity Treatment modification Increased Transaminase (AST/ALT) Grade 2 (> 2.5 to ≤ 5× the ULN) Treat at the same dose level.

Grade 3 (> 5 to ≤ 20× the ULN) Do not administer KADCYLA until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level Grade 4 (> 20× the ULN) Discontinue KADCYLA Hyperbilirubinemia Grade 2 (> 1.5 to ≤ 3× the ULN) Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.

Grade 3 (> 3 to ≤ 10× the ULN) Do not administer KADCYLA until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.

Grade 4 (> 10× the ULN) Discontinue KADCYLA Drug Induced Liver Injury (DILI) Serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN Permanently discontinue KADCYLA in the absence of another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication Nodular Regenerative Hyperplasia (NRH) All Grades Permanently discontinue KADCYLA Thrombocytopenia Grade 3 (25,000 to < 50,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then treat at the same dose level Grade 4 (< 25,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then reduce one dose level Left Ventricular Dysfunction Symptomatic CHF Discontinue KADCYLA LVEF < 40% Do not administer KADCYLA Repeat LVEF assessment within 3 weeks.

If LVEF < 40% is confirmed, discontinue KADCYLA LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline Do not administer KADCYLA Repeat LVEF assessment within 3 weeks.

If the

LVEF has not recovered to within 10% points from baseline, discontinue KADCYLA LVEF 40% to ≤ 45% and decrease is < 10% points from baseline Continue treatment with KADCYLA.

LVEF assessment within 3 weeks.

LVEF > 45% Continue treatment with KADCYLA.

Interstitial lung disease (ILD) or pneumonitis Permanently discontinue KADCYLA Peripheral Neuropathy Grade 3-4 Do not administer KADCYLA until resolution Grade ≤ 2 Dose Modification Guidelines for EBC Adverse reaction Severity Treatment modification Increased Alanine Transaminase (ALT) Grade 2-3 (> 3.0 to ≤ 20 × ULN on day of scheduled treatment) Do not administer KADCYLA until ALT recovers to Grade ≤ 1, and then reduce one dose level Grade 4 (> 20 × ULN at any time) Discontinue KADCYLA Increased Aspartate Transaminase (AST) Grade 2 (> 3.0 to ≤ 5 × ULN on day of scheduled treatment) Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then treat at the same dose level Grade 3 (> 5 to ≤ 20 × ULN on day of scheduled treatment) Do not administer KADCYLA until AST recovers to Grade ≤ 1, and then reduce one dose level Grade 4 (> 20 × ULN at any time) Discontinue KADCYLA Hyperbilirubinemia TBILI > 1.0 to ≤ 2.0 × the ULN on day of scheduled treatment Do not administer KADCYLA until total bilirubin recovers to ≤ 1.0 × ULN, and then reduce one dose level TBILI > 2 × ULN at any time Discontinue KADCYLA Nodular Regenerative Hyperplasia (NRH) All Grades Permanently discontinue KADCYLA Thrombocytopenia Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm 3 ) Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then treat at the same dose level.

If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.

Grade at any time < 25,000/mm 3 Do not administer KADCYLA until platelet count recovers to Grade ≤ 1 (≥ 75,000/mm 3 ), and then reduce one dose level.

LVEF < 45% Do not administer KADCYLA Repeat LVEF assessment within 3 weeks.

If LVEF < 45% is confirmed, discontinue KADCYLA.

LVEF 45% to < 50% and decrease is ≥ 10% points from baseline Prior to starting KADCYLA treatment Do not administer KADCYLA Repeat LVEF assessment within 3 weeks.

LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue KADCYLA.

LVEF 45% to < 50% and decrease is < 10% points from baseline Continue treatment with KADCYLA.

LVEF ≥ 50% Continue treatment with KADCYLA.

CHF, Grade 3-4 LVSD or Grade 3-4 heart failure, or Grade 2 heart failure accompanied by LVEF < 45% Discontinue KADCYLA Peripheral Neuropathy Grade 3-4 Do not administer KADCYLA until resolution Grade ≤ 2 Pulmonary Toxicity Interstitial lung disease (ILD) or pneumonitis Permanently discontinue KADCYLA Radiotherapy-Related Pneumonitis Grade 2 Discontinue KADCYLA if not resolving with standard treatment Grade 3-4 Discontinue KADCYLA 2.4 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.

Administer KADCYLA as an intravenous infusion only with a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter.

Do not mix

KADCYLA, or administer as an infusion, with other medicinal products.

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 or 0.45% Sodium Chloride Injection into the 100 mg KADCYLA vial, or 8 mL of Sterile Water for Injection or 0.45% Sodium Chloride 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 or 0.45% Sodium Chloride Injection.

If not used immediately, the reconstituted KADCYLA vials can be stored for up to 120 hours (5 days) in a refrigerator at 2°C to 8°C (36°F to 46°F); discard unused KADCYLA after 120 hours (5 days) if stored at 2°C to 8°C (36°F to 46°F).

Do not freeze.

The reconstituted product contains no preservative and is intended for single-dose only.

Determine the correct dose (mg) of KADCYLA.

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.

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.

Supplied/Storage KADCYLA (ado-trastuzumab emtansine) is supplied as: Carton Contents NDC One 100 mg vial, single-dose vial NDC 50242-088-01 One 160 mg vial, single-dose 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. 16.2 Special Handling Follow procedures for proper handling and disposal of anticancer drugs.

Supplied/Storage KADCYLA (ado-trastuzumab emtansine) is supplied as: Carton Contents NDC One 100 mg vial, single-dose vial NDC 50242-088-01 One 160 mg vial, single-dose 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.

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.

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.

Based on its mechanism of action, the DM1 component of KADCYLA can also cause embryo-fetal harm when administered to a pregnant woman.

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.

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.

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.

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 to 50) and late (Gestation Days 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.

Safety and effectiveness of

KADCYLA have not been established in pediatric patients.

Of the 495 patients who were randomized to KADCYLA in EMILIA, 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.

No overall differences in the safety of KADCYLA were observed in patients aged ≥ 65 compared to patients < 65 years of age.

EMILIA did not include sufficient numbers of patients aged ≥ 75 years to draw conclusions on the safety or effectiveness of KADCYLA in this.

Of the 743 patients who were randomized to KADCYLA in KATHERINE, 58 patients (8%) were ≥ 65 years of age and 2 patients (0.3%) were ≥ 75 years of age.

No overall differences in the safety or effectiveness of KADCYLA were observed in patients aged ≥ 65 compared to patients < 65 years of age.

KATHERINE did not include sufficient numbers of patients aged ≥ 75 years to draw conclusions on the safety or effectiveness of KADCYLA in this.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.