Cycle length: 21 days.
Duration of therapy: 14 cycles for adjuvant treatment for residual disease. Until progression or unacceptable toxicity for metastatic disease. |
| Drug | Dose and route | Administration | Given on days |
| Ado-trastuzumab emtansine | 3.6 mg/kg IV | Dilute in 250 mL NS and administer over 90 minutes for the first dose and over 30 minutes for subsequent doses. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. Administer through a 0.2- or 0.22-micron inline polyethersulfone filter. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (30 to 90% frequency of emesis).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
|
| Prophylaxis for infusion reactions | - Most clinicians do not routinely premedicate prior to the first ado-trastuzumab emtansine dose. Patients may be instructed to self-administer acetaminophen or a NSAID if flu-like symptoms develop within 24 hours of drug administration.[3]
- Refer to UpToDate topics on infusion reactions to therapeutic monoclonal antibodies used for cancer therapy.
|
| Vesicant/irritant properties | - Irritant with vesicant-like properties; avoid extravasation. Ensure proper needle or catheter position prior to administration. Closely monitor infusion site during administration.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Dose adjustment for baseline liver or kidney dysfunction | |
| Cardiac issues | - Ado-trastuzumab emtansine is associated with cardiotoxicity; evaluate left ventricular function (prior to and at least every 3 months during treatment; more frequently for decreased LVEF).[3]
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
|
| Embryo-fetal | - Exposure to ado-trastuzumab emtansine during pregnancy can result in embryo-fetal harm.[3] Advise patients of these risks and the need for effective contraception.
|
| Drug-drug interactions | - Ado-trastuzumab emtansine is a CYP3A4 substrate and is associated with significant drug-drug interactions. Review medication history prior to initiation of therapy to identify specific concerns.[3]
|
| Monitoring parameters: |
- Monitor patient during infusion for signs of infusion-related reactions; monitor for at least 90 minutes following initial infusion and (if tolerated) for at least 30 minutes following subsequent infusions.
|
- Assess LVEF at baseline and periodically during treatment.
|
- Signs and symptoms of interstitial lung disease or pneumonitis.
|
- Signs and symptoms of neurotoxicity.
|
- Review serum transaminases and bilirubin prior to initiation and prior to each dose.
|
- CBC with differential at baseline and prior to each cycle.
|
- Monitor the infusion site for possible subcutaneous infiltration.
|
- Evaluate pregnancy status (obtain pregnancy test prior to each cycle).
|
| Suggested dose modifications for toxicity:¶ |
| Thrombocytopenia | - Ado-trastuzumab emtansine should not be initiated if platelets <100,000/mm3.
- Grade 2/3 – Hold until recovery to ≤grade 1 (platelets ≥75,000/mm3), then resume at the same dose level. If 2 dose delays are required, consider reducing by 1 dose level.[3]
- Grade 4 – Hold until recovery to ≤grade 1 (platelets ≥75,000/mm3), then resume with 1 dose level reduction.[3]
|
| | - Grade 3 (platelets 25,000/mm3 to <50,000/mm3) – Withhold treatment until platelet count recovers to ≤grade 1 (platelets ≥75,000/mm3), then resume at the same dose level.[3]
- Grade 4 – Hold until recovery to ≤grade 1 (platelets ≥75,000/mm3), then resume with 1 dose level reduction.[3]
|
| Cardiotoxicity | - Patients with LVEF <50% were excluded from clinical trials of ado-trastuzumab emtansine in early-stage breast cancer.
- If LVEF drops to 45 to 50% with a less than 10% decrease from baseline, continue treatment and repeat LVEF assessment within 3 weeks.[3]
- If LVEF drops to 45 to 50% with a greater than 10% decrease from baseline, hold treatment and repeat LVEF assessment within 3 weeks; if LVEF remains <50% and has not recovered to <10% from baseline, discontinue treatment.[3]
- If LVEF drops to <45%, hold treatment and repeat LVEF assessment within 3 weeks; if repeat LVEF <45% is confirmed, discontinue treatment.
- For patients who develop symptomatic heart failure, grade 3 to 4 left ventricular systolic dysfunction, grade 3 to 4 failure, or grade 2 heart failure with LVEF <45%; discontinue treatment.[3]
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER-2 targeted agents.
|
| | - LVEF >45% – Continue ado-trastuzumab emtansine.[3]
- LVEF 40 to ≤45% and decrease is <10% points from baseline – Continue ado-trastuzumab emtansine. Repeat LVEF assessment within 3 weeks.[3]
- LVEF 40 to ≤45% and decrease is ≥ 10% points from baseline – Hold treatment with ado-trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue ado-trastuzumab emtansine.[3]
- LVEF <40% – Hold treatment with ado-trastuzumab emtansine. Repeat LVEF assessment within 3 weeks. If LVEF <40% is confirmed, discontinue ado-trastuzumab emtansine.[3]
- Symptomatic congestive heart failure – Discontinue ado-trastuzumab emtansine.[3]
|
| Nodular regenerative hyperplasia | - Permanently discontinue ado-trastuzumab emtansine.[3]
|
| Pulmonary toxicity | - Discontinue ado-trastuzumab for serious pulmonary toxicity.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
|
| Radiotherapy-related pneumonitis | - Grade 2 – Discontinue ado-trastuzumab emtansine if not resolving with standard treatment.[3]
- Grade 3 to 4 – Discontinue ado-trastuzumab emtansine.[3]
|
| Hepatotoxicity | - Dose adjustments of ado-trastuzumab may be necessary in the setting of liver toxicity and may vary based on elevations in transaminases versus bilirubin.[3]
- Grades 2 to 3 ALT elevations (>3 to ≤20 × ULN on the day of scheduled treatment) – Withhold until ALT recovers to ≤grade 1, then resume with 1 dose level reduction.[3]
- Grade 2 AST elevations (>3 to ≤5 × ULN on the day of scheduled treatment) – Withhold until AST recovers to ≤grade 1, then resume at the same dose level.[3]
- Grade 3 AST elevations (>5 to ≤20 × ULN on the day of scheduled treatment) – Withhold until AST recovers to ≤grade 1, then resume with 1 dose level reduction.[3]
- Grade 4 ALT or AST elevations (>20 × ULN at any time) – Discontinue treatment.[3]
- Total bilirubin >1 to ≤2 × ULN on the day of scheduled treatment – Withhold until bilirubin recovers to ≤1 × ULN, then resume with 1 dose level reduction.[3]
- Total bilirubin >2 × ULN at any time – Discontinue treatment.[3]
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
|
| | - Grade 2 AST/ALT elevations (>2.5 to ≤5 × the ULN) – Treat at the same dose.[3]
- Grade 3 AST/ALT elevations (>5 to ≤20 × the ULN) – Hold treatment with ado-trastuzumab emtansine until AST/ALT recovers to grade ≤2, and then reduce 1 dose level.[3]
- Grade 4 AST/ALT elevations (>20 × the ULN) – Discontinue ado-trastuzumab emtansine.[3]
- Grade 2 total bilirubin (>1.5 to ≤3 × the ULN) – Hold treatment with ado-trastuzumab emtansine until total bilirubin recovers to grade ≤1, and then resume at the same dose level.[3]
- Grade 3 total bilirubin (>3 to ≤10 × the ULN) – Hold treatment ado-trastuzumab emtansine until total bilirubin recovers to grade ≤1 and then reduce 1 dose level.[3]
- Grade 4 total bilirubin (>10 × the ULN) – Discontinue ado-trastuzumab emtansine.[3]
- Drug induced liver injury: serum transaminases >3 × ULN and concomitant total bilirubin >2 × ULN – Permanently discontinue ado-trastuzumab emtansine, in the absence of another likely cause for the elevation of liver enzymes and bilirubin (eg, liver metastasis or concomitant medication).[3]
|
| Neurotoxicity | - For grade 3/4 peripheral neuropathy, hold therapy until resolution to ≤grade 2, then resume at the same dose level.[3]
|
| Infusion reaction | - Slow or stop the infusion for infusion related reaction. Permanently discontinue for life threatening reaction.[3]
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
