trastuzumab deruxtecan: prescribing information – dosing, contraindications, interactions, side effects

Breast cancer

HER2-positive breast cancer
Enhertu in combination with pertuzumab is indicated for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer (for biomarker-based patient selection, see section 4.2).

Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens.

HER2-low and HER2-ultralow breast cancer
Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic
- hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer who have received at least one endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of treatment (see sections 4.2 and 5.1).

• HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy (see section 4.2).

Non-small cell lung cancer (NSCLC)

Enhertu as monotherapy is indicated for the treatment of adult patients with advanced NSCLC whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.

Gastric cancer

Enhertu as monotherapy is indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab- based regimen.

Other unresectable or metastatic solid tumours

Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumours who have received prior treatment and who have no satisfactory treatment options (see sections 4.4 and 5.1; for biomarker-based patient selection, see section 4.2).

Enhertu should be prescribed by a physician and administered under the supervision of a healthcare professional experienced in the use of anticancer medicinal products. In order to prevent medicinal product errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and not trastuzumab or trastuzumab emtansine.

Enhertu should not be substituted with trastuzumab or trastuzumab emtansine.

Patient selection

HER2-positive breast cancer
Patients treated with trastuzumab deruxtecan or trastuzumab deruxtecan in combination with pertuzumab for breast cancer should have documented HER2-positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a CE-marked in vitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 status should be assessed by an alternate validated test.

HER2-low or HER2-ultralow breast cancer
Patients treated with trastuzumab deruxtecan should have documented HER2-low tumour status, defined as a score of IHC 1+ or IHC 2+/ISH-, or HER2-ultralow tumour status, described as IHC 0 with membrane staining (IHC >0<1+), as assessed by a CE-marked IVD medical device. If a CE- marked IVD is not available, the HER2 status should be assessed by an alternate validated test (see section 5.1).

NSCLC
Patients treated with trastuzumab deruxtecan for advanced NSCLC should have an activating HER2 (ERBB2) mutation detected by a CE-marked in vitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 mutation status should be assessed by an alternate validated test.

Gastric cancer
Patients treated with trastuzumab deruxtecan for gastric or gastroesophageal junction cancer should have documented HER2-positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH), assessed by a CE-marked in vitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 status should be assessed by an alternate validated test.

Other unresectable or metastatic solid tumours
Patients treated with trastuzumab deruxtecan for solid tumours should have documented HER2- positive (IHC 3+) tumour status, assessed by a CE-marked in vitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 status should be assessed by an alternate validated test.

Posology

Breast cancer, NSCLC, and other unresectable or metastatic solid tumours
The recommended dose of Enhertu is 5.4 mg/kg body weight given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Enhertu in combination with pertuzumab (HER2-positive breast cancer)
The recommended dose of Enhertu, in combination with pertuzumab, is 5.4 mg/kg body weight given as an intravenous infusion once every 3 weeks (21-day cycle), with approximately 30 minutes between infusions, until disease progression or unacceptable toxicity.
- Cycle 1, Day 1: Administer 5.4 mg/kg of Enhertu followed by a separate intravenous infusion of pertuzumab at 840 mg.
- Subsequent cycles, Day 1: Administer 5.4 mg/kg of Enhertu followed by a separate intravenous infusion of pertuzumab at 420 mg.

Gastric cancer
The recommended dose of Enhertu is 6.4 mg/kg body weight given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

The initial dose should be administered as a 90-minute intravenous infusion. If the prior infusion was well tolerated, subsequent doses of Enhertu may be administered as 30-minute infusions.

The infusion rate of Enhertu should be slowed or interrupted if the patient develops infusion-related symptoms (see section 4.8). Enhertu should be permanently discontinued in case of severe infusion reactions.

Premedication

Enhertu is emetogenic (see section 4.8), which includes delayed nausea and/or vomiting. Prior to each dose of Enhertu, patients should be premedicated with a combination regimen of two or three medicinal products (e.g., dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1 receptor antagonist, as well as other medicinal products as indicated) for prevention of chemotherapy- induced nausea and vomiting.

Dose modifications

Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of Enhertu per guidelines provided in Tables 1 and 2.

Enhertu dose should not be re-escalated after a dose reduction is made.

Enhertu in combination with pertuzumab
When withholding, modifying, or discontinuing Enhertu, refer to Table 2. Pertuzumab dose modifications should be managed according to the pertuzumab SmPC. Pertuzumab is not to be administered as a single agent.

Table 1: Dose reduction schedule
Dose reduction schedule
Breast cancer, NSCLC, and
Other Solid Tumours
Gastric cancer
Recommended starting dose
5.4 mg/kg
6.4 mg/kg
First dose reduction
4.4 mg/kg
5.4 mg/kg
Second dose reduction
3.2 mg/kg
4.4 mg/kg
Requirement for further dose reduction
Discontinue treatment
Discontinue treatment

Table 2: Dose modifications for adverse reactions
Adverse reaction
Severity
Treatment modification
Interstitial lung disease
(ILD)/pneumonitis
Asymptomatic ILD/pneumonitis
(Grade 1)
Interrupt Enhertu until resolved to
Grade 0, then:
- if resolved in 28 days or less from date of onset, maintain dose.
- if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 1).
- consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (see section 4.4).
Symptomatic ILD/pneumonitis
(Grade 2 or greater)
- Permanently discontinue Enhertu.
- Promptly initiate corticosteroid treatment as soon as
ILD/pneumonitis is suspected (see section 4.4).
Neutropenia
Grade 3 (less than 1.0-0.5 × 109/L)
- Interrupt Enhertu until resolved to
Grade 2 or less, then maintain dose.
Grade 4 (less than 0.5 × 109/L)
- Interrupt Enhertu until resolved to
Grade 2 or less.
- Reduce dose by one level (see
Table 1).
Febrile neutropenia
Absolute neutrophil count of less than 1.0 × 109/L and temperature greater than 38.3 °C or a sustained temperature of 38 °C or greater for more than one hour.
- Interrupt Enhertu until resolved.
- Reduce dose by one level (see
Table 1).
Left ventricular dysfunction (LVD)
Left ventricular ejection fraction
(LVEF) greater than 45% and absolute decrease from baseline is
10% to 20%
- Continue treatment with Enhertu.
LVEF
40% to 45%
And absolute decrease from baseline is less than
10%
- Continue treatment with Enhertu.
- Repeat LVEF assessment within
3 weeks.
And absolute decrease from baseline is
10% to 20%
- Interrupt Enhertu.
- Repeat LVEF assessment within
3 weeks.
- If LVEF has not recovered to within
10% from baseline, permanently discontinue Enhertu.
- If LVEF recovers to within 10% from baseline, resume treatment with Enhertu at the same dose.

Adverse reaction
Severity
Treatment modification
LVEF less than 40% or absolute decrease from baseline is greater than 20%
- Interrupt Enhertu.
- Repeat LVEF assessment within
3 weeks.
- If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue Enhertu.
Symptomatic congestive heart failure (CHF)
- Permanently discontinue Enhertu.
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0).

Delayed or missed dose

If a planned dose is delayed or missed, it should be administered as soon as possible without waiting until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The infusion should be administered at the dose and rate the patient tolerated in the most recent infusion.

Special populations

Elderly
No dose adjustment of Enhertu is required in patients aged 65 years or older. Limited data are available in patients ≥ 75 years of age.

Renal impairment
No dose adjustment is required in patients with mild (creatinine clearance [CLcr] ≥ 60 and < 90 mL/min) or moderate (CLcr ≥ 30 and < 60 mL/min) renal impairment (see section 5.2). The potential need for dose adjustment in patients with severe renal impairment or end-stage renal disease cannot be determined as severe renal impairment was an exclusion criterion in clinical studies. A higher incidence of Grade 1 and 2 ILD/pneumonitis leading to an increase in discontinuation of therapy has been observed in patients with moderate renal impairment. In patients with moderate renal impairment at baseline who received Enhertu 6.4 mg/kg, a higher incidence of serious adverse reactions was observed compared to those with normal renal function. Patients with moderate or severe renal impairment should be monitored carefully for adverse reactions including ILD/pneumonitis (see section 4.4).

Hepatic impairment
No dose adjustment is required in patients with total bilirubin ≤ 1.5 times upper limit of normal (ULN), irrespective of aspartate transaminase (AST) value. The potential need for dose adjustment in patients with total bilirubin > 1.5 times ULN, irrespective of AST value, cannot be determined due to limited data; therefore, these patients should be monitored carefully (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of Enhertu in children and adolescents below the age of 18 years have not been established. No data are available.

Method of administration

Enhertu is for intravenous use. It must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. Enhertu must not be administered as an intravenous push or bolus.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

Enhertu as monotherapy

Enhertu 5.4 mg/kg
The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 5.4 mg/kg (n = 3057) across multiple tumour types in clinical studies. The median duration of treatment in this pool was 9.9 months (range: 0.2 to 76.0 months).

The most common adverse reactions were nausea (70.3%), fatigue (56.9%), vomiting (36.5%), neutropenia (35.9%), anaemia (35.4%), alopecia (34.4%), constipation (33.0%), diarrhoea (30.3%), decreased appetite (29.3%), transaminases increased (27.2%), musculoskeletal pain (24.0%), thrombocytopenia (23.4%) and leukopenia (20.8%).

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (18.5%), anaemia (9.9%), fatigue (8.2%), leukopenia (5.8%), thrombocytopenia (5.2%), nausea (4.8%), lymphopenia (4.2%), transaminases increased (3.7%), hypokalaemia (3.6%), diarrhoea (2.5%), vomiting (2.4%), decreased appetite (1.6%), pneumonia (1.4%) and ejection fraction decreased (1.0%). Grade 5 adverse reactions occurred in 1.1% of patients, including ILD/pneumonitis (1.0%).

Dose interruptions due to adverse reactions occurred in 34.3% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (12.7%), fatigue (4.4%), anaemia (4.3%), upper respiratory tract infection (3.8%), leukopenia (3.1%), ILD/pneumonitis (3.0%), thrombocytopenia (2.8%) and pneumonia (2.5%). Dose reductions occurred in 21.1% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were

fatigue (5.9%), nausea (4.9%), neutropenia (3.3%) and thrombocytopenia (2.2%). Discontinuation of therapy due to an adverse reaction occurred in 10.8% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD/pneumonitis (8.7%).

Enhertu 6.4 mg/kg
The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 6.4 mg/kg (n = 1133), across multiple tumour types in clinical studies. The median duration of treatment in this pool was 5.1 months (range: 0.4 to 41.0 months).

The most common adverse reactions were nausea (64.3%), fatigue (57.3%), anaemia (47.9%), decreased appetite (46.8%), neutropenia (45.9%), vomiting (34.7%), diarrhoea (33.0%), thrombocytopenia (32.9%), leukopenia (31.2%), alopecia (29.0%), constipation (28.2%) and transaminases increased (26.4%).

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events Grade 3 or 4 adverse reactions were neutropenia (28.4%), anaemia (22.8%), leukopenia (12.3%), thrombocytopenia (10.8%), fatigue (8.6%), hypokalaemia (5.8%), pancytopenia (5.6%), nausea (5.6%), lymphopenia (5.5%), decreased appetite (5.3%), transaminases increased (3.6%), pneumonia (3.0%), febrile neutropenia (2.6%), vomiting (2.6%), diarrhoea (1.9%), weight decreased (1.7%), abdominal pain (1.5%), blood alkaline phosphatase increased (1.2%), blood bilirubin increased (1.2%), interstitial lung disease (ILD, 1.1%) and ejection fraction decreased (1.1%). Grade 5 adverse reactions occurred in 2.2% of patients, including ILD (1.6%).

Dose interruptions due to adverse reactions occurred in 40.7% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (14.7%), anaemia (8.5%), fatigue (6.0%), ILD (4.7%), leukopenia (3.9%), pneumonia (3.3%), thrombocytopenia (3.2%), decreased appetite (2.7%) and upper respiratory tract infection (2.6%). Dose reductions occurred in 29.1% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were fatigue (8.4%), neutropenia (6.4%), nausea (5.6%), decreased appetite (4.1%) and thrombocytopenia (3.8%). Discontinuation of therapy due to an adverse reaction occurred in 13.8 % of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (10.1%).

In patients with gastric cancer treated with Enhertu 6.4 mg/kg (n = 546), 19.2% received a transfusion within 28 days after onset of anaemia or thrombocytopenia. Transfusions were primarily for anaemia.

Enhertu 5.4 mg/kg in combination with pertuzumab

The pooled safety population described has been evaluated for patients who received at least one dose of Enhertu 5.4 mg/kg in combination with pertuzumab in a pooled analysis of 431 patients with unresectable or metastatic breast cancer in DESTINY-Breast07 (n = 50) and DESTINY- Breast09 (n = 381). The median duration of treatment was 22 months (range 0.3 to 44.5).

The most common adverse reactions were nausea (74.2%), diarrhoea (64.0%), fatigue (53.4%), neutropenia (49.0%), alopecia (47.8%), vomiting (45.7%), anaemia (40.4%), transaminases increased (38.7%), upper respiratory tract infection (32.0%), constipation (31.3%), decreased appetite (31.3%), leukopenia (29.7%), decreased weight (28.1%), hypokalaemia (26.7%), thrombocytopenia (25.8%), ejection fraction decrease (25.3%), musculoskeletal pain (23.0%) and abdominal pain (22.3%).

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (24.8%), hypokalaemia (13.2%), anaemia (10.7%), diarrhoea (7.4%), fatigue (7.2%), thrombocytopenia (7.0%), transaminases increased (5.3%), leukopenia (5.1%), nausea (4.9%), lymphopenia (3.9%), ejection fraction decreased (3.2%), decreased weight (2.8%), febrile neutropenia (2.3%), decreased appetite (2.1%), vomiting (2.1%), upper respiratory tract infection (1.6%), pneumonia (1.2%) and stomatitis (1.2%).

Grade 5 adverse reactions occurred in 1.6% of patients, including pneumonia (0.9%), ILD/pneumonitis (0.5%), dyspnoea (0.2%) and febrile neutropenia (0.2%).

Dose interruptions due to adverse reactions occurred in 54.1% of patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia (15.5%), upper respiratory tract infection (12.3%), anaemia (7.2%), fatigue (7.2%), ILD (7.0%), hypokalaemia (6.3%), diarrhoea (5.8%), thrombocytopenia (5.3%), pneumonia (4.6%), leukopenia (3.9%), increased transaminases (3.7%), cough (2.6%), increased blood bilirubin (2.3%), decreased appetite (2.1%), pyrexia (2.1%) and vomiting (2.1%). Dose reductions occurred in 38.5% of patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue (11.6%), neutropenia (7.4%), nausea (6.5%), diarrhoea (6.0%), ILD (3.2%), thrombocytopenia (3.2%), vomiting (3.0%), increased transaminases (2.8%), decreased weight (2.3%) and febrile neutropenia (2.1%). The permanent discontinuation of any drug due to an adverse reaction occurred in 15.5% of patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD (6.3%).

Tabulated list of adverse reactions

The adverse reactions in patients who received at least one dose of Enhertu or Enhertu in combination with pertuzumab in clinical studies are presented in Table 3. The adverse reactions are listed by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as:
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions in patients treated with trastuzumab deruxtecan
System organ class
Frequency category
5.4 mg/kg monotherapy
Adverse reaction
6.4 mg/kg monotherapy
Adverse reaction
5.4 mg/kg + pertuzumab
Adverse reaction
Infections and infestations
Very common upper respiratory tract infectiona upper respiratory tract infectiona upper respiratory tract infectiona Common pneumonia pneumonia pneumonia Blood and lymphatic system disorders Very common anaemiab, thrombocytopeniad, neutropeniac, leukopeniae anaemiab, neutropeniac, thrombocytopeniad, leukopeniae, lymphopeniaf neutropeniac, thrombocytopeniad, anaemiab, leukopeniae, lymphopeniaf Common lymphopeniaf, pancytopeniag febrile neutropenia, pancytopeniag febrile neutropenia, pancytopeniag Uncommon febrile neutropenia

Metabolism and nutrition disorders
Very common hypokalaemiah, decreased appetite hypokalaemiah, decreased appetite hypokalaemiah, decreased appetite Common dehydration dehydration dehydration

System organ class
Frequency category
5.4 mg/kg monotherapy
Adverse reaction
6.4 mg/kg monotherapy
Adverse reaction
5.4 mg/kg + pertuzumab
Adverse reaction
Nervous system disorders
Very common headachei

headachei, dizziness, dysgeusia
Common dizziness, dysgeusia dizziness, headachei, dysgeusia

Eye disorders
Very common

dry eye
Common dry eye, vision blurredj dry eye, vision blurredj vision blurredj
Respiratory, thoracic and mediastinal disorders
Very common interstitial lung diseasek, cough interstitial lung diseasek, cough interstitial lung diseasek, cough Common dyspnoea, epistaxis dyspnoea, epistaxis dyspnoea, epistaxis Gastrointestinal disorders Very common vomiting, nausea, diarrhoea, abdominal painl, constipation, stomatitism, dyspepsia nausea, vomiting, diarrhoea, constipation, abdominal painl, stomatitism diarrhoea, vomiting, nausea, stomatitism, abdominal painl, constipation, dyspepsia Common gastritis, abdominal distension, flatulence dyspepsia, abdominal distension, gastritis, flatulence gastritis, abdominal distension, flatulence Hepatobiliary disorders Very common transaminases increasedn transaminases increasedn transaminases increasedn Skin and subcutaneous tissue disorders Very common alopecia alopecia rasho, pruritus, alopecia Common rasho, skin hyperpigmentationp, pruritus rasho, pruritus, skin hyperpigmentationp dry skin, skin hyperpigmentationp Musculoskeletal and connective tissue disorders Very common musculoskeletal painq musculoskeletal painq musculoskeletal painq General disorders and administration site condition Very common fatiguer, pyrexia fatiguer, pyrexia, oedema peripheral fatiguer, pyrexia Common oedema peripheral

mucosal inflammation

System organ class
Frequency category
5.4 mg/kg monotherapy
Adverse reaction
6.4 mg/kg monotherapy
Adverse reaction
5.4 mg/kg + pertuzumab
Adverse reaction
Investigations
Very common ejection fraction decreaseds, weight decreased ejection fraction decreaseds, weight decreased ejection fraction decreaseds, weight decreased, blood alkaline phosphatase increased Common blood bilirubin increasedt, blood creatinine increased, blood alkaline phosphatase increased blood alkaline phosphatase increased, blood bilirubin increasedt, blood creatinine increased blood bilirubin increasedt, blood creatinine increased Injury, poisoning and procedural complications Common infusion-related reactionsu

infusion-related reactionsu
Uncommon

infusion-related reactionsu

a For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis and upper respiratory tract infection. For 5.4 mg/kg + pertuzumab, includes influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis and upper respiratory tract infection.
b For all tumour types at 5.4 mg/kg, includes anaemia, haemoglobin decreased, red blood cell count decreased and haematocrit decreased. For all tumour types at 6.4 mg/kg, includes anaemia, haemoglobin decreased, haematocrit decreased and red blood cell count decreased. For 5.4 mg/kg + pertuzumab, includes anaemia, haematocrit decreased, haemoglobin decreased and red blood cell count decreased.
c Includes neutropenia and neutrophil count decreased.
d For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes thrombocytopenia and platelet count decreased. For 5.4 mg/kg + pertuzumab, includes platelet count decreased and thrombocytopenia.
e Includes leukopenia and white blood cell count decreased.
f For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes lymphopenia and lymphocyte count decreased. For 5.4 mg/kg + pertuzumab, includes lymphocyte count decreased and lymphopenia.
g Pancytopenia was defined as a subject that met all 3 criteria of Haemoglobin level < 100 g/L, Neutrophils < 1.5x109/L and Platelets < 100x109/L based on the same lab sample collection date and/or the preferred term pancytopenia.
h For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes hypokalaemia and blood potassium decreased. For 5.4 mg/kg + pertuzumab, includes blood potassium decreased and hypokalaemia.
i For all tumour types at 5.4 mg/kg, includes headache, sinus headache and migraine. For all tumour types at 6.4 mg/kg and 5.4 mg/kg + pertuzumab, includes headache and migraine.
j Includes vision blurred and visual impairment.
k For all tumour types at 5.4 mg/kg, interstitial lung disease includes events that were adjudicated ILD: acute respiratory failure (n = 2), alveolitis (n = 2), atypical pneumonia (n = 1), bronchiectasis (n = 1), bronchitis (n = 1), disease progression (n = 1), hypersensitivity pneumonitis (n = 1), idiopathic interstitial pneumonia (n = 1), interstitial lung disease (n = 121), lower respiratory tract infection (n = 1), lung disorder (n = 1), lung infiltration (n = 1), lung opacity (n = 4), lymphangitis (n = 1), organising pneumonia (n = 13), pneumonia (n = 9), pneumonia bacterial (n = 2), pneumonia fungal (n = 1), pneumonitis (n = 160), pulmonary fibrosis (n = 2), pulmonary mass (n = 1), pulmonary toxicity (n = 4), radiation pneumonitis (n = 6) and respiratory failure (n = 5). For all tumour types at 6.4 mg/kg, interstitial lung disease includes events that were adjudicated ILD: alveolitis (n = 1), interstitial lung disease (n = 68), lung opacity (n = 2), organising pneumonia (n = 4), pneumonia (n = 1), pneumonitis (n = 98), pulmonary toxicity (n = 1), radiation pneumonitis (n = 1) and respiratory failure (n = 5). For 5.4 mg/kg + pertuzumab, interstitial lung disease includes events that were adjudicated ILD: chronic obstructive pulmonary disease (n = 1), interstitial lung disease (n = 25), organising pneumonia (n = 1), pneumonia (n = 4), pneumonitis (n = 27) and radiation pneumonitis (n = 2).

l For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower and abdominal pain upper. For 5.4 mg/kg + pertuzumab, includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain.
m For all tumour types at 5.4 mg/kg, includes stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion and oral mucosal eruption. For all tumour types at 6.4 mg/kg, includes stomatitis, aphthous ulcer and mouth ulceration. For 5.4 mg/kg + pertuzumab, includes aphthous ulcer, mouth ulceration, oral mucosal eruption and stomatitis.
n For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic function abnormal, liver function test abnormal, liver function test increased and hypertransaminasaemia. For 5.4 mg/kg + pertuzumab, includes alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hepatic function abnormal, hypertransaminasaemia, liver function test increased and transaminases increased.
o For all tumour types at 5.4 mg/kg, includes rash, rash pustular, rash maculo-papular, rash papular, rash macular and rash pruritic. For all tumour types at 6.4 mg/kg, includes rash, rash pustular, rash maculo-papular, rash papular and rash pruritic. For 5.4 mg/kg + pertuzumab, includes rash, rash macular, rash maculo-papular, rash pruritic and rash pustular.
p For all tumour types at 5.4 mg/kg, includes skin hyperpigmentation, skin discolouration and pigmentation disorder. For all tumour types at 6.4 mg/kg, includes skin hyperpigmentation and pigmentation disorder. For 5.4 mg/kg + pertuzumab, includes pigmentation disorder, skin discolouration and skin hyperpigmentation.
q For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain and limb discomfort. For 5.4 mg/kg + pertuzumab, includes back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain and pain in extremity.
r For all tumour types at 5.4 mg/kg and all tumour types at 6.4 mg/kg, includes asthenia, fatigue, malaise and lethargy. For 5.4 mg/kg + pertuzumab, includes asthenia, fatigue, lethargy and malaise.
s For all tumour types at 5.4 mg/kg, ejection fraction decreased includes laboratory parameters of LVEF decrease (n = 434) and/or preferred terms of ejection fraction decreased (n = 170), cardiac failure (n = 5), cardiac failure acute (n = 1), cardiac failure chronic (n = 2), cardiac failure congestive (n = 1) and left ventricular dysfunction (n = 4). For all tumour types at 6.4 mg/kg, ejection fraction decreased includes laboratory parameters of LVEF decrease (n = 125) and/or preferred terms of ejection fraction decreased (n = 20), left ventricular dysfunction (n = 1), cardiac failure (n = 2), cardiac failure acute (n = 1) and cardiac failure congestive (n = 1). For 5.4 mg/kg + pertuzumab, ejection fraction decreased includes laboratory parameters of LVEF decrease (n = 104) and/or preferred terms of ejection fraction decreased (n = 36), cardiac failure (n = 5), cardiac failure chronic (n = 1) and left ventricular dysfunction (n = 5).
t For all tumour types at 5.4 mg/kg, includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased and blood bilirubin unconjugated increased. For all tumour types at 6.4 mg/kg, includes blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased. For 5.4 mg/kg + pertuzumab, includes bilirubin conjugated increased, blood bilirubin increased, blood bilirubin unconjugated increased and hyperbilirubinaemia.
u For all tumour types at 5.4 mg/kg, cases of infusion-related reactions include infusion-related reaction (n = 28) and hypersensitivity (n = 3). For all tumour types at 6.4 mg/kg, cases of infusion-related reactions include infusion-related reaction (n = 6) and hypersensitivity (n = 1). The majority of the cases of infusion-related reactions were Grade 1 and Grade 2. For 5.4 mg/kg + pertuzumab, includes infusion-related reaction (n = 10).

Description of selected adverse reactions

Interstitial lung disease/pneumonitis

Enhertu as monotherapy
In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 2553), ILD, pneumonitis, organising pneumonia and acute interstitial pneumonitis were reported by the investigator in 13.8% of patients. ILD/pneumonitis was confirmed by adjudication in 12.9% of patients, leading to drug discontinuation in 8.7% of patients and drug interruption in 3.0% of patients.
Most ILD/pneumonitis cases were Grade 1 (3.0%) and Grade 2 (8.1%). Grade 3 cases occurred in 0.7% and one Grade 4 case occurred. Grade 5 (fatal) events occurred in 1.0% of patients. Median time to first onset was 5.5 months (range: -0.3 to 40.2), including two patients adjudicated as having pre- existing ILD. Recovery was not reported for 27.4% of patients with adjudicated ILD/pneumonitis at a median follow up of 286 days (see sections 4.2 and 4.4).

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 1133), ILD, pneumonitis, organising pneumonia, and acute interstitial pneumonitis were reported by the investigator in 16.9% of patients. ILD/pneumonitis was confirmed by adjudication in 15.4% of patients, leading to drug discontinuation in 10.1% of patients and drug interruption in 4.7% of patients.
Most ILD/pneumonitis cases were Grade 1 (4.1%) and Grade 2 (8.6%). Grade 3 cases occurred in 1.1% and one Grade 4 case occurred. Grade 5 (fatal) events occurred in 1.6% of patients. Median time to first onset was 4.1 months (range: -0.5 to 21.0), including two patients adjudicated as having pre- existing ILD. Recovery was not reported for 37.4% of patients with adjudicated ILD/pneumonitis at a median follow up of 251 days (see sections 4.2 and 4.4).

Enhertu 5.4 mg/kg in combination with pertuzumab
In patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab (n = 431), ILD, pneumonitis, organising pneumonia and acute interstitial pneumonitis were reported by the investigator in 16.7% of patients. ILD was confirmed by adjudication in 13.0% of patients, leading to drug discontinuation in 6.3% of patients and drug interruption in 7.0% of patients. Most ILD cases were Grade 1 (3.9%) and Grade 2 (8.4%). Grade 3 cases occurred in 0.2%. No Grade 4 case occurred.
Grade 5 (fatal) events occurred in 0.5% of patients. Median time to first onset was 8.1 months (range: 0.6 to 33.8). Recovery was not reported for 26.8% of patients with adjudicated ILD/pneumonitis at a median follow up of 336 days (see sections 4.2 and 4.4).

Neutropenia

Enhertu as monotherapy
In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 3057) across multiple tumour types, neutropenia was reported in 35.9% of patients and 18.5% had Grade 3 or 4 events. Median time to onset was 43 days (range: 0 days to 51.5 months), and median duration of the first event was 21 days (range: 1 day to 30.8 months). Febrile neutropenia was reported in 0.9% of patients and one event (<0.1%) was Grade 5 (see section 4.2).

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 1133), neutropenia was reported in 45.9% of patients and 28.4% had Grade 3 or 4 events. Median time to onset was 16 days (range: 1 day to 24.8 months), and median duration of the first event was 9 days (range: 1 day to 17.2 months). Febrile neutropenia was reported in 2.6% of patients and 0.1% were Grade 5 (see section 4.2).

Enhertu 5.4 mg/kg in combination with pertuzumab
In patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab in clinical studies (n = 431), neutropenia was reported in 49% of patients and 24.8% had Grade 3 or 4 events. Median time to first onset was 42 days (range: 1 day to 36.8 months) and median duration of the first event was 20 days (range: 1 day to 27.6 months). Febrile neutropenia was reported in 2.6% of patients and one event (0.2%) was Grade 5 (see section 4.2).

Left ventricular dysfunction

Enhertu as monotherapy
In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 3057), left ventricular dysfunction was reported in 181 patients (5.9%), of which 17 (0.6%) were Grade 1, 147 (4.8%) were Grade 2, 16 (0.5%) were Grade 3 and 1 (<0.1%) was Grade 4. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 411/2740 (15.0%) for Grade 2 and 22/2740 (0.8%) for Grade 3. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment (see section 4.2).

Left ventricular dysfunction led to treatment interruption in 31/3057 (1.0%) patients. The median time to worst grade LVEF was 6.9 months, and the median time to recovery (≥90% baseline) from worst grade LVEF was 2.8 months.

In patients treated with Enhertu 6.4 mg/kg in clinical studies across multiple tumour types (n = 1133), LVEF decrease was reported in 23 patients (2.0%), of which 1 (0.1%) was Grade 1, 16 (1.4%) were Grade 2, and 6 (0.5%) were Grade 3. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 114/953 (12.0%) for Grade 2, and 11/953 (1.2%) for Grade 3.

Left ventricular dysfunction led to treatment interruption in 6/1133 (0.5%) patients. The median time to worst grade LVEF was 5.5 months, and the median time to recovery (≥90% baseline) from worst grade LVEF was 2.8 months.

Enhertu 5.4 mg/kg in combination with pertuzumab
In patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab (n = 431), left ventricular dysfunction was reported in 46 patients (10.7%), of which 4 (0.9%) were Grade 1, 33 (7.7%) were Grade 2, 8 (1.9%) were Grade 3 and 1 (0.2%) Grade 4. The observed frequency of LVEF decreased based on laboratory parameters (echocardiogram or MUGA scanning) was 90/407 (22.1%) for Grade 2 and 14/407 (3.4%) for Grade 3. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment (see section 4.2).

Left ventricular dysfunction led to treatment discontinuation in 8/431 (1.9%) patients and treatment interruption in 6/431 (1.4%) patients. The median time to worst grade LVEF was 11.6 months and the median time to recovery (≥90% baseline) from worst grade LVEF was 3.0 months.

Infusion-related reactions

Enhertu as monotherapy
In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 3057) across multiple tumour types, infusion-related reactions were reported in 31 patients (1.0%), the majority of which were Grade 1 or Grade 2 severity. Six events (0.2%) of infusion-related reactions led to dose interruptions, and one event (<0.1%) led to discontinuation.

In patients treated with Enhertu 6.4 mg/kg in clinical studies (n = 1133) across multiple tumour types, infusion-related reactions were reported in 7 patients (0.6%), all of which were Grade 1 or Grade 2 severity. No Grade 3 events were reported. One event (0.1%) of infusion-related reaction led to dose interruption, and no events led to discontinuation.

Enhertu 5.4 mg/kg in combination with pertuzumab
In patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab in clinical studies (n = 431), infusion-related reactions were reported in 10 patients (2.3%), the majority of which were Grade 1 or Grade 2 severity. Seven events (1.6%) of infusion-related reactions led to dose interruptions and no events led to discontinuation.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Across 5.4 mg/kg and 6.4 mg/kg doses evaluated in clinical studies, 2.2% (70/3124) of evaluable patients developed antibodies against trastuzumab deruxtecan following treatment with Enhertu. The incidence of treatment-emergent neutralising antibodies against trastuzumab deruxtecan was 0.1% (3/3124). There was no apparent effect between development of antibodies on the pharmacokinetics, safety and/or effectiveness of Enhertu.

Paediatric population

Safety has not been established in this population.

Elderly

Enhertu as monotherapy
In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 3057), 27.1% were 65 years or older and 5.8% were 75 years or older. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (48.2%) as compared to patients younger than 65 years old (44.3%), leading to more discontinuations due to adverse reactions.
The incidence of fatal adverse reactions was 2.2% in patients aged 65 years or older and 0.8% in patients younger than 65 years of age.

Of the 1133 patients across multiple tumour types in clinical studies treated with Enhertu 6.4 mg/kg, 39.6% were 65 years or older and 7.9% were 75 years or older. The incidence of Grade 3-4 adverse reactions observed in patients 65 years or older was 60.8% and 61.1% in younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients 75 years of age or older (64.4%) compared to patients less than 75 years of age (60.7%). In patients 75 years or older, there was a higher incidence of serious adverse reactions (34.4%) and fatal events (4.4%) compared to patients less than 75 years (21.2% and 1.6%). Data are limited to establish the safety in patients 75 years or older.

Enhertu 5.4 mg/kg in combination with pertuzumab
In patients treated with Enhertu 5.4 mg/kg in combination with pertuzumab (n = 431), 17.4% were 65 years or older and 3% were 75 years or older. The incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older was 52% and in younger patients was 55.1%. The incidence of fatal adverse reactions was 4.0% in patients aged 65 years or older and 1.1% in patients younger than 65 years of age. The incidence of adjudicated ILD/pneumonitis was 20.0% in patients aged 65 years or older and 11.5% in patients younger than 65 years of age.

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. Asian patients receiving Enhertu 6.4 mg/kg had a higher incidence (≥ 10% difference) of neutropenia (58.3% vs. 29.4%), anaemia (55.2% vs. 38.3%), leukopenia (46.7% vs.
10.5%), and thrombocytopenia (43.1% vs. 19.3%) compared to non-Asian patients. In Asian patients, 3.4% experienced a bleeding event within 14 days after onset of thrombocytopenia compared to 0.8% of non-Asian patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In order to prevent medicinal product errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and not trastuzumab or trastuzumab emtansine.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Interstitial lung disease/pneumonitis

Cases of interstitial lung disease (ILD), and/or pneumonitis, have been reported with Enhertu or Enhertu in combination with pertuzumab (see section 4.8). Fatal outcomes have been observed.
Patients should be advised to immediately report cough, dyspnoea, fever and/or any new or worsening respiratory symptoms. Patients should be monitored for signs and symptoms of ILD/pneumonitis.
Evidence of ILD/pneumonitis should be promptly investigated. Patients with suspected ILD/pneumonitis should be evaluated by radiographic imaging, preferably a computed tomography (CT) scan. Consultation with a pulmonologist should be considered. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g., ≥ 0.5 mg/kg/day prednisolone or equivalent).
Enhertu should be withheld until recovery to Grade 0 and may be resumed according to instructions in Table 2 (see section 4.2). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate corticosteroid treatment (e.g., ≥ 1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Enhertu should be permanently discontinued in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD/pneumonitis (see section 4.2).
Patients with a history of ILD/pneumonitis or patients with moderate or severe renal impairment may be at increased risk of developing ILD/pneumonitis and should be monitored carefully (see section 4.2). Fatal cases of pneumonia, including two cases adjudicated as ILD, were observed.

Neutropenia

Cases of neutropenia, including febrile neutropenia with a fatal outcome, were reported in clinical studies of Enhertu or Enhertu in combination with pertuzumab. Complete blood counts should be monitored prior to initiation of Enhertu and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, Enhertu may require dose interruption or reduction (see section 4.2).

Left ventricular dysfunction

Left ventricular dysfunction (LVD) has been observed with anti-HER2 therapies.
Standard cardiac function testing (echocardiogram or MUGA [multigated acquisition] scanning) should be performed to assess LVEF prior to initiation of Enhertu or Enhertu in combination with pertuzumab and at regular intervals during treatment as clinically indicated. LVD should be managed through treatment interruption. Enhertu should be permanently discontinued if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Enhertu should be permanently discontinued in patients with symptomatic congestive heart failure (CHF) (see Table 2 in section 4.2).

Embryo-foetal toxicity

Enhertu can cause foetal harm when administered to a pregnant woman. In post-marketing reports, use of trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. Based on

findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu, DXd, can also cause embryo-foetal harm when administered to a pregnant woman (see section 4.6).

The pregnancy status of females of reproductive potential should be verified prior to the initiation of Enhertu. The patient should be informed of the potential risks to the foetus. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 7 months following the last dose of Enhertu. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Enhertu and for at least 4 months after the last dose of Enhertu (see section 4.6).

Patients with moderate or severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. As metabolism and biliary excretion are the primary routes of elimination of the topoisomerase I inhibitor, DXd, Enhertu should be administered with caution in patients with moderate and severe hepatic impairment (see sections 4.2 and 5.2).

Efficacy across other unresectable or metastatic solid tumours

The efficacy of Enhertu in other unresectable or metastatic HER2-positive (IHC3+) solid tumours has been established in studies encompassing adult patients (N = 192). Favourable effects of Enhertu in this indication have been shown on the basis of objective response rate and response duration across tumour types. The effect may be quantitatively different depending on tumour type (see section 5.1).
For these reasons, Enhertu should only be used if there are no treatment options for which clinical benefit has been established, or where such treatment options have been exhausted (i.e., no satisfactory treatment options).

Co-administration with ritonavir, an inhibitor of OATP1B, CYP3A and P-gp, or with itraconazole, a strong inhibitor of CYP3A and P-gp, resulted in no clinically meaningful (approximately 10-20%) increase in exposures of trastuzumab deruxtecan or the released topoisomerase I inhibitor, DXd. No dose adjustment is required during co-administration of trastuzumab deruxtecan with medicinal products that are inhibitors of CYP3A or OATP1B or P-gp transporters (see section 5.2).

Women of childbearing potential/Contraception in males and females

Pregnancy status of women of childbearing potential should be verified prior to initiation of Enhertu.

Women of childbearing potential should use effective contraception during treatment with Enhertu and for at least 7 months following the last dose.

Men with female partners of childbearing potential should use effective contraception during treatment with Enhertu and for at least 4 months following the last dose.

Pregnancy

There is no available data on the use of Enhertu in pregnant women. However, trastuzumab, a HER2 receptor antagonist, can cause foetal harm when administered to a pregnant woman. In post- marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios in some cases manifested as fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu, DXd, can be expected to cause embryo-foetal harm when administered to a pregnant woman (see section 5.3).

Administration of Enhertu to pregnant women is not recommended, and patients should be informed of the potential risks to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor. If a woman becomes pregnant during treatment with Enhertu or within 7 months following the last dose of Enhertu, close monitoring is recommended.

Breast-feeding

It is not known if trastuzumab deruxtecan is excreted in human milk. Human IgG is secreted in human milk, and the potential for absorption and serious adverse reactions to the infant is unknown.
Therefore, women should not breast-feed during treatment with Enhertu or for 7 months after the last dose. A decision should be made to discontinue breast-feeding or to discontinue treatment taking into account the benefit of breast-feeding for the child and/or benefit of treatment with Enhertu for the mother.

Fertility

No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Based on results from animal toxicity studies, Enhertu may impair male reproductive function and fertility. It is not known whether trastuzumab deruxtecan or its metabolites are found in seminal fluid. Before starting treatment, male patients should be advised to seek counselling on sperm storage. Male patients must not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of Enhertu.

Enhertu may have a minor influence on the ability to drive and use machines. Patients should be advised to use caution when driving or operating machinery in case they experience fatigue, headache or dizziness during treatment with Enhertu (see section 4.8).

The maximum tolerated dose of trastuzumab deruxtecan has not been determined. In clinical studies, single doses higher than 8.0 mg/kg have not been tested. In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment initiated.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors, ATC code: L01FD04

Mechanism of action

Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is a humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by a tetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function of the antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. After binding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linker cleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the membrane- permeable DXd causes DNA damage and apoptotic cell death. DXd, an exatecan derivative, is approximately 10 times more potent than SN-38, the active metabolite of irinotecan.

In vitro studies indicate that the antibody portion of trastuzumab deruxtecan, which has the same amino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibody mediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3- kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2.

Clinical efficacy

HER2-positive breast cancer

DESTINY-Breast09 (NCT04784715)
The efficacy and safety of Enhertu in combination with pertuzumab were evaluated in DESTINY- Breast09, a Phase 3, randomised, three-arm, multicentre, global study that enrolled 1157 adult patients with HER2-positive (IHC 3+ or ISH+) advanced, or metastatic breast cancer, as determined at a central laboratory using PATHWAY/VENTANA anti-HER2/neu (4B5) and VENTANA HER2 Dual ISH DNA Probe Cocktail.

The study included adult patients with unresectable or metastatic HER2-positive breast cancer who had not received prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer. Patients were eligible if they (a) had de novo metastatic breast cancer disease or (b) had received neoadjuvant or adjuvant chemotherapy and/or HER2-targeted therapy which was completed more than 6 months before the diagnosis of advanced or metastatic disease. A single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer. The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patients with symptomatic brain metastases, or ECOG performance status >1 and patients with a history of clinically significant cardiac disease.

At the recommended dosage of Enhertu for patients with metastatic breast cancer, NSCLC, and HER2-positive (IHC 3+) solid tumours (5.4 mg/kg), the geometric mean (coefficient of variation [CV]%) Cmax at steady state of trastuzumab deruxtecan and topoisomerase I inhibitor, DXd, were 131 μg/mL (22%) and 5.1 ng/mL (47%), respectively, and the AUC at steady state of trastuzumab deruxtecan and DXd were 739 μg day/mL (34%) and 30.7 ng day/mL (49%), respectively.

At the recommended dosage of Enhertu for patients with HER2-positive gastric cancer (6.4 mg/kg), the geometric mean Cmax at steady state of trastuzumab deruxtecan and DXd were 131 μg/mL (21%)

and 5.2 ng/mL (42.0%), respectively, and the AUC at steady state of trastuzumab deruxtecan and DXd were 762 μg day/mL (29%) and 32.1 ng day/mL (44.1%), respectively.

Absorption

Trastuzumab deruxtecan is administered intravenously. There have been no studies performed with other routes of administration.

Distribution

Based on population pharmacokinetic analysis, the volume of distribution of the central compartment (Vc) of trastuzumab deruxtecan and DXd, were estimated to be 2.8 L and 28.0 L, respectively. The volume of distribution of the peripheral compartment (Vp) of trastuzumab deruxtecan was estimated to be 6.0 L.

In vitro, the mean human plasma protein binding of DXd was approximately 97%.

In vitro, the blood to plasma concentration ratio of DXd was approximately 0.6.

Biotransformation

Trastuzumab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release the DXd.

The humanised HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

In vitro metabolism studies in human liver microsomes indicate that DXd is metabolised mainly by CYP3A4 via oxidative pathways and does not undergo significant metabolism by uridine diphosphate- glucuronosyltransferases (UGT) or other CYP enzymes.

Elimination