Article2 - Kadcyla eMagazine

1. Indications and Usage

The Indications and Usage section of the KADCYLA Prescribing Information is organized by clinical setting: Subsection 1.1 describes the indication for metastatic breast cancer(MBC), and Subsection 1.2 describes the indication for early breast cancer (EBC), which is defined as cancer that has not spread beyond the breast or axillary lymph nodes.

Metastatic Breast Cancer (MBC)

KADCYLA, as a single agent, is indicated for the treatment of patients with HER2+ 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 6 months of completing adjuvant therapy

Patients should be selected for therapy based on an FDA-approved companion diagnostic for KADCYLA.

Early Breast Cancer (EBC)

KADCYLA, as a single agent, is indicated for the adjuvant treatment of patients with HER2+ early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy. Patients should be selected for therapy based on an FDA-approved companion diagnostic for KADCYLA.

Select the icons below for more information.

KADCYLA indications as listed in the PI.

Which clinical trials support the indications for KADCYLA?

Selected NCCN Guidelines: HER2+ EBC

PERJETA (pertuzumab) is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2+ MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Pertuzumab is also indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer; and as adjuvant treatment for patients with HER2+ EBC at high risk of recurrence.

According to National Comprehensive Cancer Center (NCCN) guidelines, patients with HER2+ EBC should be treated with neoadjuvant systemic therapy incorporating trastuzumab. A pertuzumab-containing neoadjuvant regimen may be administered to patients with ≥T2 (ie, 2–5 cm) or node-positive, HER2+ EBC.

NCCN guidelines also recommend that patients who receive neoadjuvant therapy (with or without pertuzumab) then receive HER2-directed therapy in the adjuvant setting, with the choice of therapy directed according to their response to neoadjuvant treatment.

No residual disease–patients with pathologic complete response (pCR) should continue adjuvant trastuzumab, with or without pertuzumab, to complete 1 year of HER2-directed therapy
Residual disease–patients with residual disease should receive treatment with KADCYLA for 14 cycles. No further chemotherapy is administered with or after KADCYLA.

Selection of Adjuvant Systemic Therapy After Neoadjuvant Systemic Therapy

*Following neoadjuvant taxane and trastuzumab-based treatment.

†Or until disease recurrence or unmanageable toxicity.

‡Patients who begin PERJETA and Herceptin in the neoadjuvant setting should receive 3-6 cycles before surgery and should continue treatment after surgery, every 3 weeks, to complete 1 year (up to 18 cycles). Patients who begin treatment in the adjuvant setting should receive a total of 1 year (up to 18 cycles) of PERJETA and Herceptin-based therapy, every 3 weeks, starting on day 1 of the first taxane-containing cycle.

^§Based on the Prescribing Information, PERJETA + Herceptin remains an option for patients with residual invasive disease following neoadjuvant treatment with PERJETA + Herceptin-based therapy. In the adjuvant setting, there have been no studies that compare KADCYLA to PERJETA + Herceptin-based therapy.

2. Dosage and Administration

The Dosage and Administration section of the Prescribing Information is divided into four subsections that describe: how patients should be selected for treatment with KADCYLA, the recommended dosing schedules for each of the FDA-approved breast cancer indications, dose modification guidelines for different clinical situations, and steps for preparing KADCYLA for administration.

2.1 Patient Selection

Patients should be selected for treatment with KADCYLA 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-approved tests specific for breast cancers by laboratories with demonstrated proficiency. 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.

Select the icon to learn more.

Which tests are FDA-approved for determining HER2 status?

2.2 Recommended Doses and Schedules

Trastuzumab should not be substituted for or with KADCYLA.

The recommended dose of KADCYLA is 3.6 mg/kg given as an intravenous infusion every three weeks (21-day cycle). KADCYLA should not be administered at doses greater than 3.6 mg/kg. Health care providers should closely monitor the infusion site for possible subcutaneous infiltration during drug administration.

Although the dose of KADCLYA is the same for both of its indications, the treatment duration differs depending on the indication. Select each tab to learn more.

MBC Dosing Schedule

EBC Dosing Schedule

2.3 Dose Modifications

The dose of KADCYLA should not be re-escalated after a dose reduction is made. If a planned dose is delayed or missed, it should be administered as soon as possible, rather than waiting until the next planned cycle. The administration schedule should then be adjusted to maintain a three-week interval between doses. The infusion should be administered at the dose and rate the patient tolerated in the most recent infusion.

If a patient develops an infusion-related reaction, the rate of KADCYLA infusion should be slowed or interrupted. If the patient develops a life-threatening infusion-related reaction, KADCYLA should be permanently discontinued.

To manage increased serum transaminases, hyperbilirubinemia, left ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy, providers may need to temporarily interrupt treatment, reduce the dose, or discontinue treatment with KADCYLA as per the guidelines provided in the tables below (ie, Tables 1 and 2 in the PI).

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

Dosing modification guidelines for patients with MBC

Select each row of the table for details on dosing modifications in 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, eg, liver metastasis or concomitant medication.
Nodular Regenerative Hyperplasia (NRH)
	All Grades	Permanently discontinue KADCYLA.
Thrombocytopenia
	Grade 3 (25,000 to <50,000/mm³)	Do not administer KADCYLA until platelet count recovers to Grade ≤1 (≥75,000/mm³), and then treat at the same dose level.
	Grade 4 (< 25,000/mm³)	Do not administer KADCYLA until platelet count recovers to Grade ≤1 (≥75,000/mm³), and then treat at the same 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. Repeat LVEF assessment within 3 weeks.
	LVEF >45%	Continue treatment with KADCYLA.
Pulmonary Toxicity
	Interstitial lung disease (ILD) or pneumonitis	Permanently discontinue KADCYLA.
Peripheral Neuropathy
	Grade 3-4	Do not administer KADCYLA until resolution Grade ≤2

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

Dosing Modification Guidelines for Patients With EBC

Now select each row of the table for details on dosing modifications in patients with 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 on 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/mm³)	Do not administer KADCYLA until platelet count recovers to Grade ≤1 (≥75,000/mm³), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.
	Grade 4 at any time (<25,000/mm³)	Do not administer KADCYLA until platelet count recovers to Grade ≤1 (≥75,000/mm³), and then reduce one dose level.
Left Ventricular Dysfunction
	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*	Do not administer KADCYLA. Repeat LVEF assessment within 3 weeks. If the 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. Repeat LVEF assessment within 3 weeks.
	LVEF ≥50%	Continue treatment with KADCYLA.
Heart Failure
	Symptomatic 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

It is important that health care providers check the KADCYLA vial labels before reconstitution to ensure that the drug being prepared and administered is KADCYLA (ado-trastuzumab emtansine) and not trastuzumab.

Select the arrows to learn more about KADCYLA administration, reconstitution, and dilution.

Administration

Administer KADCYLA as an intravenous infusion only with a 0.2 or 0.22 micro 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.

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 2°C to 8°C (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-dose only.

Dilution

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. 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 and Contraindications

Select the headings below for information on KADCYLA dosage forms and strengths and the contraindications.

Dosage Forms and Strengths

Lyophilized powder in single-dose vials: 100 mg per vial or 160 mg per vial of ado-trastuzumab emtansine

Contraindications

There are no known contraindications for KADCYLA.

Increased transaminase (Grade 3)	C. Do not administer KADCYLA until AST/ALT recovers to Grade ≤2, and then reduce one dose level.
Hyperbilirubinemia (Grade 3)	D. Do not administer KADCYLA until total bilirubin recovers to Grade ≤1, and then reduce one dose level.
Thrombocytopenia (Grade 4)	A. Do not administer KADCYLA until platelet count recovers to Grade ≤1 (≥ 75,000/mm3), and then reduce one dose level.
Interstitial lung disease or pneumonitis	E. Permanently discontinue KADCYLA.
Peripheral neuropathy (Grade 3-4)	B. Do not administer KADCYLA until resolution Grade ≤2.

Test	Company
FoundationOne CDx	Foundation Medicine, Inc
PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody	Ventana Medical Systems, Inc.
INFORM HER2 Dual ISH DNA Probe Cocktail	Ventana Medical Systems, Inc
HercepTest	Dako Denmark A/S
HER2 FISH pharmDx Kit	Dako Denmark A/S