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Breast metastatic trastuzumab deruxtecan

 This protocol is currently under review:

Information will be updated once the protocol has been reviewed by the reference committee.

Note: The updated Cancer Council Australia clinical practice guidelines on the prevention, early detection, and management of colorectal cancer: risk and screening based on family history opens in a new tab or window are not yet incorporated in this protocol.

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

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Cycle 1 and further cycles

Drug Dose Route Day
Trastuzumab deruxtecan 5.4 mg/kg IV infusion 1
Frequency:
21 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Drug status:

Trastuzumab deruxtecan is PBS authority opens in a new tab or window 

Cost:
~ $10,520 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy. Note: the full dose of dexamethasone on Day 1 may not be required and may be reduced to 8mg at the clinicians discretion *
Trastuzumab deruxtecan 5.4 mg/kg (IV infusion) in 100 mL glucose 5%

over 90 minutes (1st dose); if first dose is well tolerated, subsequent doses may be administered over 30 minutes
Day 2 to 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2, 3 and 4 may not be required and may be reduced or omitted at the clinicians discretion.*

*Link to ID 7 Prevention of anti-cancer therapy induced nausea and vomiting

Frequency:
21 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Cycle 1 and further cycles

Drug Dose Route Day
Trastuzumab deruxtecan 5.4 mg/kg IV infusion 1
Frequency:
21 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Drug status:

Trastuzumab deruxtecan is PBS authority opens in a new tab or window 

Cost:
~ $10,520 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy. Note: the full dose of dexamethasone on Day 1 may not be required and may be reduced to 8mg at the clinicians discretion *
Trastuzumab deruxtecan 5.4 mg/kg (IV infusion) in 100 mL glucose 5%

over 90 minutes (1st dose); if first dose is well tolerated, subsequent doses may be administered over 30 minutes
Day 2 to 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2, 3 and 4 may not be required and may be reduced or omitted at the clinicians discretion.*

*Link to ID 7 Prevention of anti-cancer therapy induced nausea and vomiting

Frequency:
21 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Indications:

  • HER-2 positive unresectable or metastatic (stage IV) breast cancer in patients whose disease has progressed:
    • following prior HER-2 based treatment for metastatic disease, or
    • during or within six months of completing HER-2 based (neo)adjuvant therapy.

Cautions:

  • Left ventricular ejection fraction (LVEF) of 50% or less.
  • History of symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment.
  • History of myocardial infarction or unstable angina within 6 months.
  • Pre-existing pulmonary disease.
  • History of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids.
  • Current or suspected ILD/pneumonitis.
  • Active CNS metastases or spinal cord compression.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Emetogenicity HIGH

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Cardiac toxicity associated with HER-2 directed agents

Patients receiving HER-2 directed agents are at an increased risk of cardiotoxicity e.g. asymptomatic decrease in the left ventricular ejection fraction (LVEF) and congestive heart failure (CHF).

In patients with a  LVEF less than 45% and/or symptomatic heart failure HER-2 directed therapy should be avoided, except in the metastatic setting when breast cancer is life-threatening and where a cardiologist is also involved.

Concurrent anthracycline and HER-2 directed therapy is not recommended for extended periods of time.

Baseline and 3 monthly cardiac function tests are required during treatment. In the metastatic setting, after the first 12 months of therapy, if there are no cardiac complications, the frequency of cardiac assessments may be reduced at the discretion of the treating clinician unless there has been recent exposure to anthracyclines.

Read more about cardiac toxicity associated with HER-2 targeted agents
Pulmonary toxicity

Interstitial lung disease (ILD), including pneumonitis, sometimes leading to acute respiratory distress syndrome or fatality, has been reported with this treatment. Monitor patients for signs and symptoms (e.g. cough, dyspnoea, fever, not otherwise explained fatigue, decrease in oxygen saturation, and/or any other new or worsening respiratory symptoms). Consider CT scans to monitor for ILD/pneumonitis. Withhold treatment in the event of Grade 1 ILD/pneumonitis and initiate prompt investigation and management. Treatment should be permanently discontinued in patients diagnosed with ≥ Grade 2/symptomatic ILD or pneumonitis.

Read more about pulmonary toxicity associated with anti-cancer drugs and management of adverse events associated with trastuzumab deruxtecan treatment opens in a new tab or window
Blood tests

FBC, EUC, eGFR and LFTs at baseline and prior to each treatment.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact of cancer treatment on fertility opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note:

  • The dose modifications below are based on a combination of the product information, clinical trial, Rugo et al review and reference committee consensus.1, 2
  • The dose should not be re-escalated after a dose reduction has been made.
  • If further dose reduction below 3.2 mg/kg is required, discontinue trastuzumab deruxtecan.
Trastuzumab deruxtecan dose reduction schedule
Recommended dose 5.4 mg/kg
First dose reduction  4.4 mg/kg
Second dose reduction 3.2 mg/kg
Haematological toxicity
ANC x 109/L
0.5 to less than 1.0 Delay treatment until recovery (ANC is greater than or equal to 1.0) then resume trastuzumab deruxtecan at the same dose
less than 0.5 Delay treatment until recovery (ANC is greater than or equal to 1.0) then resume trastuzumab deruxtecan at the next lower dose level.
Febrile neutropenia Delay treatment until recovery (ANC is greater than or equal to 1.0) then resume trastuzumab deruxtecan at the next lower dose level.
Platelets x 109/L
25 to less than 50 Delay treatment until recovery (platelets are greater than or equal to 75) then resume trastuzumab deruxtecan as follows:
Recovery within 7 days: resume trastuzumab deruxtecan at the same dose
Recovery longer than 7 days: resume trastuzumab deruxtecan at the next lower dose level
less than 25 Delay treatment until recovery (platelets are greater than or equal to 75) then resume trastuzumab deruxtecan at the next lower dose level.
Kidney dosing recommendations 
eGFR (mL/min/1.73m2) Recommended dose
≥ 30 No dose modification necessary
< 30 This drug has not been studied in patients with severe kidney dysfunction
Hepatic impairment
Pre-existing hepatic dysfunction
Mild No dose modifications necessary
Moderate to severe Insufficient data in patients with moderate to severe hepatic impairment
Trastuzumab deruxtecan induced hepatotoxicity
Increased serum transaminases (ALT / AST)
Grade 2 No dose modifications necessary
Grade 3 OR without liver metastases OR with liver metastases and baseline AST or ALT ≤ 3 x ULN

Delay treatment until recovery to Grade ≤ 1 if baseline ≤ 3 x ULN, otherwise until recovery to ≤ baseline, then resume trastuzumab deruxtecan as follows:

Recovery within 7 days: at the same dose

Recovery longer than 7 days: at the next lower dose level
AST or ALT > 8.0 to 20.0 × ULN if baseline was normal OR > 8.0 to 20.0 × baseline if baseline was abnormal OR with liver metastases and baseline > 3 × ULN

Delay treatment until recovery to ≤ baseline, then resume trastuzumab deruxtecan as follows:

Recovery within 7 days: at the same dose

Recovery longer than 7 days: at the next lower dose level
Grade 4 Permanently discontinue trastuzumab deruxtecan
Hyperbilirubinaemia
Grade 2

No dose modifications necessary if there is Gilbert's syndrome or liver metastases at baseline

If no Gilbert's syndrome or liver metastases at baseline, delay treatment until recovery to Grade ≤ 1 then resume trastuzumab deruxtecan as follows:

Recovery within 7 days: at the same dose

Recovery longer than 7 days: at the next lower dose level
Grade 3

If no Gilbert's syndrome or liver metastases at baseline, delay treatment until recovery to Grade ≤ 1 then:

Recovery within 7 days: resume trastuzumab deruxtecan at the next lower dose level

Recovery longer than 7 days: discontinue trastuzumab deruxtecan

If there is Gilbert's syndrome or liver metastases at baseline, delay treatment until recovery to Grade < 2 then:

Recovery within 7 days: resume trastuzumab deruxtecan at the next lower dose level

Recovery longer than 7 days: discontinue trastuzumab deruxtecan
Grade 4 Permanently discontinue trastuzumab deruxtecan
Increased serum transaminases (ALT / AST) with hyperbilirubinaemia
ALT / AST ≥ 3 x ULN and bilirubin > 2 x ULN Delay treatment. If drug-induced liver injury is excluded, consider resuming trastuzumab deruxtecan. If drug-induced liver injury cannot be excluded, permanently discontinue trastuzumab deruxtecan
Cardiac toxicity
Consider referral to a cardiologist if any of the following occur
LVEF 40% to 45% AND 10% to 20% absolute decline from baseline

Delay treatment, repeat LVEF assessment within 3 weeks

If LVEF recovers to within 10% from baseline, resume trastuzumab deruxtecan at the same dose
Discontinue trastuzumab deruxtecan if LVEF has not recovered to within 10% from baseline
LVEF less than 40% OR 20% or greater absolute decline from baseline Delay treatment, repeat LVEF assessment within 3 weeks
Discontinue trastuzumab deruxtecan if LVEF less than 40% OR absolute decrease from baseline greater than 20% is confirmed
Symptomatic Congestive Heart Failure (CHF) Permanently discontinue trastuzumab deruxtecan
Interstitial lung disease (ILD)/pneumonitis
Grade 1 asymptomatic ILD/pneumonitis

Consider initiating corticosteroids as appropriate

Delay treatment until recovery to Grade 0 then resume trastuzumab deruxtecan as follows:
Recovery within 28 days: at the same dose
Recovery longer than 28 days: at the next lower dose level
Grade ≥ 2 symptomatic ILD/pneumonitis

Initiate corticosteroids as appropriate

Permanently discontinue trastuzumab deruxtecan
Missed doses of trastuzumab deruxtecan
If a planned dose is delayed or missed, administer as soon as possible at the most recently tolerated infusion rate; do not wait until the next planned cycle
Following a delayed or missed dose, adjust administration schedule to maintain a 3 week dosing interval.

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

Trastuzumab deruxtecan
  Interaction Clinical management
Cardiotoxic drugs (e.g. anthracyclines cyclophosphamide) Additive cardiotoxicity Monitor cardiac function closely in patients who have previously been treated with cumulatively cardiotoxic drugs
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update opens in a new tab or window

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 2.5 hours (initial); 90 minutes (subsequent) 

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Anti-cancer drug patient assessment tool prior to each day of treatment.

Prime IV line(s) with glucose 5%.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Trastuzumab deruxtecan

  • Trastuzumab deruxtecan is incompatible with sodium chloride solutions.
  • A 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter is required.
Initial infusion - administer trastuzumab deruxtecan:
  • via IV infusion over 90 minutes
  • protect from light
  • flush with ~50 mL of glucose 5%
  • observe patient for hypersensitivity reaction
  • stop infusion at first sign of reaction:
    • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
    • for severe reactions seek medical assistance immediately and do not restart infusion.
Subsequent infusions - administer trastuzumab deruxtecan:
  • if no previous hypersensitivity reaction administer via IV infusion over 30 minutes
  • protect from light
  • flush with ~50 mL of glucose 5%
  • observe patient for hypersensitivity reaction
  • stop infusion at first sign of reaction:
    • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
    • for severe reactions seek medical assistance immediately and do not restart infusion.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s).

Discharge information

Antiemetics - as/if prescribed.

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
Constipation
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, radiation therapy to the head, neck or oesophagus, and high-dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis and stomatitis
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Hypokalaemia

Abnormally low levels of potassium in the blood.
Ocular changes

Symptoms may include dry eyes.

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia - partial

Hair thinning and/or patchy hair loss. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia and scalp cooling
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

Delayed (onset months to years)
Cardiotoxicity

Cardiotoxicity is a well recognised complication of HER-2 directed agents (e.g. trastuzumab, trastuzumab emtansine, pertuzumab). Mechanistically distinct from anthracycline-induced cardiotoxicity, it typically manifests as an asymptomatic decrease in the left ventricular ejection fraction (LVEF) and less commonly as congestive heart failure (CHF).

Read more about cardiac toxicity associated with HER-2 targeted agents

The evidence supporting this protocol is provided by the DESTINY-Breast03 Trial.1 In this phase III, randomised, multicentre, international trial, 524 patients with HER-2 positive unresectable or metastatic breast cancer who had progressed on trastuzumab and a taxane, or within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or a taxane, were randomised 1:1 to trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1).

Between July 2018 and June 2020, 261 patients were assigned to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks and 263 patients were assigned to receive trastuzumab emtansine 3.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity. 

The primary endpoint was progression free survival (PFS) as determined by independent central review. The key secondary endpoint was overall survival (OS) and other secondary endpoints included overall response, PFS (as determined by investigator review) and safety.

Efficacy

The median duration of follow-up was 16.2 months in the trastuzumab deruxtecan group and 15.3 months in the trastuzumab emtansine group in the interim analysis. The analysis demonstrated improved PFS with trastuzumab deruxtecan compared to trastuzumab emtansine [not reached (95% CI, 18.5 to could not be estimated) vs 6.8 months (95% CI, 5.6 to 8.2) respectively]. At 12 months the hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22 to 0.37, p<0.001). There was a trend towards OS despite the early analysis however the p value did not meet the pre-specified boundary for benefit.1

Kaplan-Meier curve of PFS1

© N Engl J Med 2022

Kaplan-Meier curve of OS1

© N Engl J Med 2022

Toxicity

Rates of treatment-related grade 3 or 4 toxicity were similar at 45% in the trastuzumab deruxtecan arm vs 39% in the trastuzumab emtansine arm. Of note pneumonitis occurred in 10.5% of trastuzumab deruxtecan patients compared to 1.9% of trastuzumab emtansine patients, with a median onset time of 5.5 months (range 1.1 to 20.8). 8.3% of patients in the trastuzumab deruxtecan group had to discontinue treatment due to pneumonitis compared to 1.1% in the trastuzumab emtansine group. Nausea was also more common in the trastuzumab deruxtecan group at 72.8% vs 27.6%, as was alopecia at 36.2% vs 2.3% respectively.1

Adverse events1

© N Engl J Med 2022

1
Cortés, J., S. B. Kim, W. P. Chung, et al. 2022. "Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer." N Engl J Med 386(12):1143-1154.
2
Rugo, H. S., G. Bianchini, J. Cortes, et al. 2022. "Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer." ESMO Open 7(4):100553.

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Version 4

Date Summary of changes
17/01/2025
  • Indications second subpoint updated to include "(neo)adjuvant" therapy
  • Cautions:
    • Left ventricular ejection fraction (LVEF) updated to "50% or less"
    • Added "History of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids."
    • Added "Current or suspected ILD/pneumonitis."

Version increased to V.4. 

Version 3

Date Summary of changes
19/07/2023

Protocol updated with ADDIKD guideline recommendations. 

PDF of previous protocol.

Version number changed to V.3.
01/11/2023 Drug status updated to PBS authority.
02/11/2023 Approximate treatment time in administration section updated to 2.5 hours (initial); 90 minutes (subsequent). "How long it will take" in patient information section updated to align with this change.
15/11/2023 "Non-PBS" footnote for netupitant and palonosetron removed from detailed treatment schedule.
05/12/2023 "Allow refrigerated solution to warm to room temperature prior to administration" removed from administration section.

Version 2

Date Summary of changes
29/05/2023 Protocol updated to reflect change in emetogenicity status from 'moderate' to 'high' risk as per NCCN Guidelines Antiemesis Version 2.2023. Treatment schedule and clinical information sections updated.

Version 1

Date Summary of changes
05/08/2022 New protocol approved at Medical Oncology reference committee meeting.
12/09/2022 Protocol published on eviQ. Next review in 1 year.
15/09/2022 Drug status updated from TGA provisionally approved to TGA approved.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/4150

14 Mar 2025