ENHERTU 100mg powder for concentrate infusion solution medication leaflet

Enhertu 100 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumabderuxtecan. After reconstitution, one vial of 5 mL solution contains 20 mg/mL of trastuzumabderuxtecan (see section 6.6).

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) that contains a humanised anti-

HER2 IgG1 monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab,produced by mammalian (Chinese Hamster Ovary) cells, covalently linked to DXd, an exatecanderivative and a topoisomerase I inhibitor, via a tetrapeptide-based cleavable linker. Approximately8 molecules of deruxtecan are attached to each antibody molecule.

Each 100 mg vial contains 1.5 mg of polysorbate 80 (E433).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to yellowish-white lyophilised powder.

Breast cancer

HER2-positive breast cancer

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 havereceived at least one endocrine therapy in the metastatic setting and who are not consideredsuitable 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 ordeveloped disease recurrence during or within 6 months of completing adjuvantchemotherapy (see section 4.2).

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

Gastric cancer

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

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

Enhertu should not be substituted with trastuzumab or trastuzumab emtansine.

Patient selection

HER2-positive breast cancer

Patients treated with trastuzumab deruxtecan 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 byin situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a CE-marked invitro diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2 status shouldbe 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 0with 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 (seesection 5.1).

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 shouldhave 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 notavailable, the HER2 status should be assessed by an alternate validated test.

Breast cancer

The recommended dose of Enhertu is 5.4 mg/kg body weight given as an intravenous infusion onceevery 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

The recommended dose of Enhertu is 5.4 mg/kg body weight given as an intravenous infusion onceevery 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Gastric cancer

The recommended dose of Enhertu is 6.4 mg/kg body weight given as an intravenous infusion onceevery 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 waswell 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-relatedsymptoms (see section 4.8). Enhertu should be permanently discontinued in case of severe infusionreactions.

Premedication

Enhertu is emetogenic (see section 4.8), which includes delayed nausea and/or vomiting. Prior to eachdose of Enhertu, patients should be premedicated with a combination regimen of two or threemedicinal products (e.g., dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1receptor antagonist, as well as other medicinal products as indicated) for prevention of chemotherapy-induced nausea and vomiting.

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

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

Table 1: Dose reduction schedule

Dose reduction schedule Breast cancer and NSCLC 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 Discontinue treatment Discontinue treatmentreduction

Table 2: Dose modifications for adverse reactions

Adverse reaction Severity Treatment modification

Interstitial lung Asymptomatic ILD/pneumonitis Interrupt Enhertu until resolved todisease (Grade 1) Grade 0, then:(ILD)/pneumonitis * if resolved in 28 days or less fromdate of onset, maintain dose.

* if resolved in greater than 28 daysfrom date of onset, reduce dose onelevel (see Table 1).

* consider corticosteroid treatment assoon as ILD/pneumonitis issuspected (see section 4.4).

Symptomatic ILD/pneumonitis * Permanently discontinue Enhertu.(Grade 2 or greater) * Promptly initiate corticosteroidtreatment as soon as

ILD/pneumonitis is suspected (seesection 4.4).

Adverse reaction Severity Treatment modification

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 * Interrupt Enhertu until resolved.

than 1.0 × 109/L and temperature * Reduce dose by one level (seegreater than 38.3 °C or a sustained Table 1).temperature of 38 °C or greater formore than one hour.

Left ventricular LVEF greater than 45% and * Continue treatment with Enhertu.ejection fraction absolute decrease from baseline is(LVEF) decreased 10% to 20%

LVEF And absolute * Continue treatment with Enhertu.40% to 45% decrease from * Repeat LVEF assessment withinbaseline is less than 3 weeks.10%

And absolute * Interrupt Enhertu.decrease from * Repeat LVEF assessment withinbaseline is 3 weeks.10% to 20% * If LVEF has not recovered to within10% from baseline, permanentlydiscontinue Enhertu.

* If LVEF recovers to within 10%from baseline, resume treatmentwith Enhertu at the same dose.

LVEF less than 40% or absolute * Interrupt Enhertu.decrease from baseline is greater * Repeat LVEF assessment withinthan 20% 3 weeks.

* If LVEF of less than 40% orabsolute decrease from baseline ofgreater than 20% is confirmed,permanently discontinue Enhertu.

Symptomatic congestive heart * Permanently discontinue Enhertu.failure (CHF)

Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse

Events Version 5.0 (NCI-CTCAE v.5.0).

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

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

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). Thepotential need for dose adjustment in patients with severe renal impairment or end-stage renal diseasecannot be determined as severe renal impairment was an exclusion criterion in clinical studies. Ahigher incidence of Grade 1 and 2 ILD/pneumonitis leading to an increase in discontinuation oftherapy has been observed in patients with moderate renal impairment. In patients with moderate renalimpairment at baseline who received Enhertu 6.4 mg/kg, a higher incidence of serious adversereactions was observed compared to those with normal renal function. Patients with moderate orsevere renal impairment should be monitored carefully for adverse reactions including

ILD/pneumonitis (see section 4.4).

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 inpatients with total bilirubin > 1.5 times ULN, irrespective of AST value, cannot be determined due tolimited data; therefore, these patients should be monitored carefully (see sections 4.4 and 5.2).

The safety and efficacy of Enhertu in children and adolescents below the age of 18 years have notbeen established. No data are available.

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

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

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

In order to prevent medicinal product errors, it is important to check the vial labels to ensure that themedicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and nottrastuzumab or trastuzumab emtansine.

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 (seesection 4.8). Fatal outcomes have been observed. Patients should be advised to immediately reportcough, dyspnoea, fever and/or any new or worsening respiratory symptoms. Patients should bemonitored for signs and symptoms of ILD/pneumonitis. Evidence of ILD/pneumonitis should bepromptly investigated. Patients with suspected ILD/pneumonitis should be evaluated by radiographicimaging, preferably a computed tomography (CT) scan. Consultation with a pulmonologist should beconsidered. 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 0and 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/dayprednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least4 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 orpatients with moderate or severe renal impairment may be at increased risk of developing

ILD/pneumonitis and should be monitored carefully (see section 4.2).

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

Left ventricular ejection fraction (LVEF) decrease 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 and at regular intervals duringtreatment as clinically indicated. LVEF decrease should be managed through treatment interruption.

Enhertu should be permanently discontinued if LVEF of less than 40% or absolute decrease frombaseline of greater than 20% is confirmed. Enhertu should be permanently discontinued in patientswith 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, useof trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramniosmanifesting as fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. Based onfindings 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 reproductivepotential should be advised to use effective contraception during treatment and for at least 7 monthsfollowing the last dose of Enhertu. Male patients with female partners of reproductive potential shouldbe advised to use effective contraception during treatment with Enhertu and for at least 4 months afterthe 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 withsevere hepatic impairment. As metabolism and biliary excretion are the primary routes of eliminationof the topoisomerase I inhibitor, DXd, Enhertu should be administered with caution in patients withmoderate and severe hepatic impairment (see sections 4.2 and 5.2).

Co-administration with ritonavir, an inhibitor of OATP1B, CYP3A and P-gp, or with itraconazole, astrong 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. Nodose adjustment is required during co-administration of trastuzumab deruxtecan with medicinalproducts that are inhibitors of CYP3A or OATP1B or P-gp transporters (see section 5.2).

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 andfor at least 7 months following the last dose.

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

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 somecases manifested as fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. Based onfindings 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 (seesection 5.3).

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

It is not known if trastuzumab deruxtecan is excreted in human milk. Human IgG is secreted in humanmilk, 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 lastdose. A decision should be made to discontinue breast-feeding or to discontinue treatment taking intoaccount the benefit of breast-feeding for the child and/or benefit of treatment with Enhertu for themother.

No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Based on resultsfrom animal toxicity studies, Enhertu may impair male reproductive function and fertility. It is notknown whether trastuzumab deruxtecan or its metabolites are found in seminal fluid. Before startingtreatment, male patients should be advised to seek counselling on sperm storage. Male patients mustnot freeze or donate sperm throughout the treatment period, and for at least 4 months after the finaldose of Enhertu.

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

Enhertu 5.4 mg/kg

The pooled safety population has been evaluated for patients who received at least one dose of Enhertu5.4 mg/kg (n = 2335) across multiple tumour types in clinical studies. The median duration oftreatment in this pool was 9.0 months (range: 0.7 to 45.1 months).

The most common adverse reactions were nausea (71.1%), fatigue (55.3%), vomiting (37.3%),alopecia (36.1%), anaemia (35.9%), neutropenia (35.1%), constipation (31.7%), decreased appetite(30.6%), diarrhoea (30.1%), transaminases increased (26.6%), musculoskeletal pain (23.6%),thrombocytopenia (23.1%), and leukopenia (21.5%).

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 (18.0%), anaemia (10.5%),fatigue (7.8%), leukopenia (6.0%), thrombocytopenia (5.4%), nausea (4.9%), lymphopenia (3.9%),hypokalaemia (3.8%), transaminases increased (3.5%), diarrhoea (2.5%), vomiting (2.4%), decreasedappetite (1.8%), pneumonia (1.3%), and ejection fraction decreased (1.0%). Grade 5 adverse reactionsoccurred in 1.4% of patients, including ILD/pneumonitis (1.1%).

Dose interruptions due to adverse reactions occurred in 32.6% of patients treated with Enhertu. Themost frequent adverse reactions associated with dose interruption were neutropenia (12.4%), fatigue(4.7%), anaemia (4.6%), leukopenia (3.2%), upper respiratory tract infection (3.0%), ILD/pneumonitis(2.6%), thrombocytopenia (2.4%), and pneumonia (2.0%). Dose reductions occurred in 20.3% ofpatients treated with Enhertu. The most frequent adverse reactions associated with dose reduction werefatigue (5.1%), nausea (4.8%), neutropenia (3.5%), and thrombocytopenia (2.3%). Discontinuation oftherapy due to an adverse reaction occurred in 11.7% of patients treated with Enhertu. The mostfrequent adverse reaction associated with permanent discontinuation was ILD/pneumonitis (8.4%).

Enhertu 6.4 mg/kg

The pooled safety population has been evaluated for patients who received at least one dose of Enhertu6.4 mg/kg (n = 1133), across multiple tumour types in clinical studies. The median duration oftreatment 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%), andtransaminases 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 adversereactions 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. Themost 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%), 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 reductionwere fatigue (8.4%), neutropenia (6.4%), nausea (5.6%), decreased appetite (4.1%), andthrombocytopenia (3.8%). Discontinuation of therapy due to an adverse reaction occurred in 13.8 % ofpatients treated with Enhertu. The most frequent adverse reaction associated with permanentdiscontinuation was ILD (10.1%).

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

The adverse reactions in patients who received at least one dose of Enhertu in clinical studies arepresented in Table 3. The adverse reactions are listed by MedDRA system organ class (SOC) andcategories 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 frequencygrouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions in patients treated with trastuzumab deruxtecan 5.4 mg/kg and6.4 mg/kg in multiple tumour types

System organ class 5.4 mg/kg 6.4 mg/kg

Frequency category Adverse reaction Adverse reaction

Very common upper respiratory tract upper respiratory tractinfectiona infectiona

Common pneumonia pneumonia

Very common anaemiab, neutropeniac, anaemiab, neutropeniac,thrombocytopeniad, thrombocytopeniad,leukopeniae leukopeniae, lymphopeniaf

Common lymphopeniaf, febrile febrile neutropenia,neutropenia, pancytopeniag pancytopeniag

Very common hypokalaemiah, decreased hypokalaemiah, decreasedappetite appetite

Common dehydration dehydration

Very common headachei

Common dizziness, dysgeusia dizziness, headachei, dysgeusia

Common dry eye, vision blurredj dry eye, vision blurredj

Very common interstitial lung diseasek, cough interstitial lung diseasek, cough

Common dyspnoea, epistaxis dyspnoea, epistaxis

Very common nausea, vomiting, constipation, nausea, vomiting, diarrhoea,diarrhoea, abdominal painl, constipation, abdominal painl,stomatitism, dyspepsia stomatitism

Common abdominal distension, gastritis, dyspepsia, abdominalflatulence distension, gastritis, flatulence

Very common transaminases increasedn transaminases increasedn

Very common alopecia alopecia

Common rasho, pruritus, skin rasho, pruritus, skinhyperpigmentationp hyperpigmentationp

System organ class 5.4 mg/kg 6.4 mg/kg

Frequency category Adverse reaction Adverse reaction

Very common musculoskeletal painq musculoskeletal painq

General disorders and administration site condition

Very common fatiguer, pyrexia fatiguer, pyrexia, oedemaperipheral

Common oedema peripheral

Very common ejection fraction decreaseds, ejection fraction decreaseds,weight decreased weight decreased

Common blood alkaline phosphatase blood alkaline phosphataseincreased, blood bilirubin increased, blood bilirubinincreasedt, blood creatinine increasedt, blood creatinineincreased increased

Common infusion-related reactionsu

Uncommon infusion-related reactionsua Includes influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis and upperrespiratory tract infection.b For all tumour types at 5.4 mg/kg, includes anaemia, haemoglobin decreased, red blood cell count decreasedand haematocrit decreased. For all tumour types at 6.4 mg/kg, includes anaemia, haemoglobin decreased,haematocrit decreased and red blood cell count decreased.

c Includes neutropenia and neutrophil count decreased.d Includes thrombocytopenia and platelet count decreased.e Includes leukopenia and white blood cell count decreased.f Includes lymphopenia and lymphocyte count decreased.g Pancytopenia was defined as a subject that met all 3 criteria of Haemoglobin level < 100 g/L & CTCAEgrade 2 or above, Neutrophils < 1.5x109/L & CTCAE grade 1 or above, and Platelets < 100x109/L & non-missing CTCAE grade based on the same lab sample collection date and/or the preferred term pancytopenia.

h Includes hypokalaemia and blood potassium decreased.i For all tumour types at 5.4 mg/kg, includes headache, sinus headache and migraine. For all tumour types at6.4 mg/kg, 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: acuterespiratory failure (n = 2), alveolitis (n = 2), bronchiectasis (n = 1), disease progression (n = 1),hypersensitivity pneumonitis (n = 1), idiopathic interstitial pneumonia (n = 1), interstitial lung disease(n = 109), lower respiratory tract infection (n = 1), lung disorder (n = 1), lung infiltration (n = 1), lung opacity(n = 4), lymphangitis (n = 1), organising pneumonia (n = 9), pneumonia (n = 9), pneumonia bacterial (n = 2),pneumonia fungal (n = 1), pneumonitis (n = 136), pulmonary fibrosis (n = 2), pulmonary mass (n = 1),pulmonary toxicity (n = 3), radiation pneumonitis (n = 4), respiratory failure (n = 5). For all tumour types at6.4 mg/kg, interstitial lung disease includes events that were adjudicated ILD: alveolitis (n = 1), interstitiallung disease (n = 68), lung opacity (n = 2), organising pneumonia (n = 4), pneumonia (n = 1), pneumonitis(n = 98), pulmonary toxicitiy (n = 1), radiation pneumonitis (n = 1), and respiratory failure (n = 5).

l Includes abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower and abdominalpain upper.

m For all tumour types at 5.4 mg/kg, includes stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosionand oral mucosal eruption. For all tumour types at 6.4 mg/kg, includes stomatitis, aphthous ulcer, and mouthulceration.

n Includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased, hepatic function abnormal, liver function test abnormal, liver functiontest increased and hypertransaminasaemia.

o For all tumour types at 5.4 mg/kg, includes rash, rash pustular, rash maculo-papular, rash papular, rashmacular and rash pruritic. For all tumour types at 6.4 mg/kg, includes rash, rash pustular, rash maculo-papular,rash papular, and rash pruritic.

p For all tumour types at 5.4 mg/kg, includes skin hyperpigmentation, skin discolouration and pigmentationdisorder. For all tumour types at 6.4 mg/kg, includes skin hyperpigmentation and pigmentation disorder.

q Includes back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain,musculoskeletal chest pain and limb discomfort.

r Includes asthenia, fatigue, malaise and lethargy.s For all tumour types at 5.4 mg/kg, ejection fraction decreased includes laboratory parameters of LVEFdecrease (n = 312) and/or preferred terms of ejection fraction decreased (n = 99), cardiac failure (n = 5),cardiac failure acute (n = 1), cardiac failure chronic (n = 1), cardiac failure congestive (n = 1) and leftventricular dysfunction (n = 3). For all tumour types at 6.4 mg/kg, ejection fraction decreased includeslaboratory 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 cardiacfailure congestive (n = 1).

t For all tumour types at 5.4 mg/kg, includes blood bilirubin increased, hyperbilirubinaemia, bilirubinconjugated increased and blood bilirubin unconjugated increased. For all tumour types at 6.4 mg/kg, includesblood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased.

u For all tumour types at 5.4 mg/kg, cases of infusion-related reactions include infusion-related reaction (n = 23)and hypersensitivity (n = 2). For all tumour types at 6.4 mg/kg, cases of infusion-related reactions includeinfusion-related reaction (n = 6) and hypersensitivity (n = 1). All cases of infusion-related reactions were

Grade 1 and Grade 2.

Interstitial lung disease/pneumonitis

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 2335),

ILD, pneumonitis, organising pneumonia, and acute interstitial pneumonitis were reported by theinvestigator in 13.3% of patients. ILD/pneumonitis was confirmed by adjudication in 12.2% ofpatients, leading to drug discontinuation in 8.4% of patients and drug interruption in 2.6% of patients.

Most ILD/pneumonitis cases were Grade 1 (2.9%) and Grade 2 (7.5%). Grade 3 cases occurred in0.7% and one Grade 4 case occurred. Grade 5 (fatal) events occurred in 1.1% of patients. Median timeto first onset was 5.5 months (range: -0.3 to 31.5 ), including two patients adjudicated as having pre-existing ILD. Recovery was not reported for 30.8% of patients with adjudicated ILD/pneumonitis at amedian follow up of 280 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 theinvestigator in 16.9% of patients. ILD/pneumonitis was confirmed by adjudication in 15.4% ofpatients, 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 in1.1% and one Grade 4 case occurred. Grade 5 (fatal) events occurred in 1.6% of patients. Median timeto 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 amedian follow up of 251 days (see sections 4.2 and 4.4).

In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 2335) across multiple tumour types,neutropenia was reported in 35.1% of patients and 18.0% had Grade 3 or 4 events. Median time toonset was 42 days (range: 1 day to 31.9 months), and median duration of the first event was 21 days(range: 1 day to 17.1 months). Febrile neutropenia was reported in 1.0% of patients and <0.1% were

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 toonset 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).

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 2335),

LVEF decrease was reported in 108 patients (4.6%), of which 14 (0.6%) were Grade 1, 80 (3.4%)were Grade 2, 13 (0.6%) were Grade 3 and 1 (<0.1%) were Grade 4. The observed frequency of LVEFdecreased based on laboratory parameters (echocardiogram or MUGA scanning) was296/2075 (14.3%) for Grade 2 and 15/2075 (0.7%) for Grade 3. Treatment with Enhertu has not beenstudied in patients with LVEF less than 50% prior to initiation of treatment (see section 4.2).

Left ventricular dysfunction led to treatment interruption in 27/2335 (1.2%) patients. The median timeto worst grade LVEF was 4.8 months, and the median time to recovery (≥90% baseline) from worstgrade LVEF was 6.3 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 laboratoryparameters (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 timeto worst grade LVEF was 5.5 months, and the median time to recovery (≥90% baseline) from worstgrade LVEF was 2.8 months.

In patients treated with Enhertu 5.4 mg/kg in clinical studies (n = 2335) across multiple tumour types,infusion-related reactions were reported in 25 patients (1.1%), the majority of which were Grade 1 or

Grade 2 severity. Five events (0.2%) of infusion-related reactions led to dose interruptions, and1 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 2severity. No Grade 3 events were reported. One event (0.1%) of infusion-related reaction led to doseinterruption, and no events led to discontinuation.

As with all therapeutic proteins, there is a potential for immunogenicity. Across 5.4 mg/kg and6.4 mg/kg doses evaluated in clinical studies, 2.2% (70/3124) of evaluable patients developedantibodies against trastuzumab deruxtecan following treatment with Enhertu. The incidence oftreatment-emergent neutralising antibodies against trastuzumab deruxtecan was 0.1% (3/3124). Therewas no apparent effect between development of antibodies on the pharmacokinetics, safety and/oreffectiveness of Enhertu.

Safety has not been established in this population.

In patients treated with Enhertu 5.4 mg/kg in clinical studies across multiple tumour types (n = 2335),28.9% were 65 years or older and 6.3% were 75 years or older. There was a higher incidence of

Grade 3-4 adverse reactions observed in patients aged 65 years or older (48.4%) as compared topatients younger than 65 years old (43.2%), leading to more discontinuations due to adverse reactions.

The incidence of fatal adverse reactions was 2.4% in patients aged 65 years or older and 1% inpatients 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 adversereactions observed in patients 65 years or older was 60.8% and 61.1% in younger patients. There wasa 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, therewas a higher incidence of serious adverse reactions (34.4%) and fatal events (4.4%) compared topatients less than 75 years (21.2% and 1.6%). Data are limited to establish the safety in patients75 years or older.

Ethnic differences

In clinical studies, no relevant differences in exposure or efficacy were observed between patients ofdifferent 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 closelymonitored for signs or symptoms of adverse reactions and appropriate symptomatic treatmentinitiated.

Pharmacotherapeutic group: Antineoplastic agents, HER2 (Human Epidermal Growth Factor

Receptor 2) inhibitors, ATC code: L01FD04

Enhertu, trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate. The antibody is ahumanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor (DXd) bound by atetrapeptide-based cleavable linker. The antibody-drug conjugate is stable in plasma. The function ofthe antibody portion is to bind to HER2 expressed on the surface of certain tumour cells. Afterbinding, the trastuzumab deruxtecan complex then undergoes internalisation and intracellular linkercleavage 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, isapproximately 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 sameamino acid sequence as trastuzumab, also binds to FcγRIIIa and complement C1q. The antibodymediates antibody-dependent cellular cytotoxicity (ADCC) in human breast cancer cells thatoverexpress HER2. In addition, the antibody inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway in human breast cancer cells that overexpress HER2.

HER2-positive breast cancer

DESTINY-Breast03 (NCT03529110)

The efficacy and safety of Enhertu were studied in DESTINY-Breast03, a multicentre, open-label,active-controlled, randomised, two-arm phase 3 study that enrolled patients with HER2-positive,unresectable or metastatic breast cancer who received prior trastuzumab and taxane therapy formetastatic disease or developed disease recurrence during or within 6 months of completing adjuvanttherapy.

Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or

ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring treatment withsteroids or ILD/pneumonitis at screening, patients with untreated and symptomatic brain metastases,patients with a history of clinically significant cardiac disease and patients with prior treatment with ananti-HER2 antibody-drug conjugate in the metastatic setting. Patients were randomised 1:1 to receiveeither Enhertu 5.4 mg/kg (N = 261) or trastuzumab emtansine 3.6 mg/kg (N = 263) administered byintravenous infusion once every three weeks. Randomisation was stratified by hormone receptorstatus, prior treatment with pertuzumab, and history of visceral disease. Treatment was administereduntil disease progression, death, withdrawal of consent, or unacceptable toxicity.

The primary efficacy outcome measure was progression-free survival (PFS) as evaluated by blindedindependent central review (BICR) according to Response Evaluation Criteria in Solid Tumours(RECIST v1.1). Overall survival (OS) was a key secondary efficacy outcome measure. PFS based oninvestigator assessment, confirmed objective response rate (ORR), and duration of response (DOR)were secondary endpoints.

Patient demographics and baseline disease characteristics were balanced between treatment arms. Ofthe 524 patients randomised, the baseline demographic and disease characteristics were: median age54 years (range: 20 to 83); 65 years or older (20.2%); female (99.6%); Asian (59.9%), White (27.3%),

Black or African American (3.6%); Eastern Cooperative Oncology Group (ECOG) performancestatus 0 (62.8%) or 1 (36.8%); hormone receptor status (positive: 51.9%); presence of visceral disease(73.3%); presence of brain metastases at baseline (15.6%); and 48.3% of patients received one line ofprior systemic therapy in the metastatic setting. The percentage of patients who had not received priortreatment for metastatic disease was 9.5%. The percentage of patients who were previously treatedwith pertuzumab was 61.1%.

At the prespecified interim analysis for PFS based on 245 events (73% of total events planned for finalanalysis), the study showed a statistically significant improvement in PFS per BICR in patientsrandomised to Enhertu compared to trastuzumab emtansine. PFS by BICR data from the primaryanalysis (data cutoff 21 May 2021) and updated OS, ORR and DOR results from data cutoff 25 July2022 are presented in Table 4.

Table 4: Efficacy results in DESTINY-Breast03

Efficacy parameter Enhertu trastuzumab emtansine

N = 261 N = 263

Progression-free survival (PFS) per BICRa

Number of events (%) 87 (33.3) 158 (60.1)

Median, months (95% CI) NR (18.5, NE) 6.8 (5.6, 8.2)

Hazard ratio (95% CI) 0.28 (0.22, 0.37)p-value p < 0.000001†

Overall survival (OS)b

Number of events (%) 72 (27.6) 97 (36.9)

Median, months (95% CI) NR (40.5, NE) NR (34.0, NE)

Hazard ratio (95% CI) 0.64 (0.47, 0.87)p-valuec p = 0.0037

PFS per BICR (updated)b

Number of events (%) 117 (44.8) 171 (65.0)

Median, months (95% CI) 28.8 (22.4, 37.9) 6.8 (5.6, 8.2)

Hazard ratio (95% CI) 0.33 (0.26, 0.43)

Confirmed objective response rate (ORR) per BICRbn (%) 205 (78.5) 92 (35.0)95% CI (73.1, 83.4) (29.2, 41.1)

Complete response n (%) 55 (21.1) 25 (9.5)

Partial response n (%) 150 (57.5) 67 (25.5)

Duration of response per BICRb

Median, months (95% CI) 36.6 (22.4, NE) 23.8 (12.6, 34.7)

CI = confidence interval; NE = not estimable; NR = not reached†Presented as 6 decimal placesa Data cutoff 21 May 2021b Data cutoff 25 July 2022 for a pre-planned OS interim analysisc The p-value is based on a stratified log-rank test; crossed the efficacy boundary of 0.013.

Figure 1: Kaplan-Meier plot of overall survival (Data cutoff 25 July 2022)

Figure 2: Kaplan-Meier plot of progression-free survival per BICR (Data cutoff 25 July 2022)

Similar PFS results were observed across prespecified subgroups including prior pertuzumab therapy,hormone receptor status, and presence of visceral disease.

DESTINY-Breast02 (NCT03523585)

The efficacy and safety of Enhertu were evaluated in study DESTINY-Breast02, a Phase 3,randomised, multicentre, open-label, active-controlled study that enrolled patients with unresectable ormetastatic HER2-positive breast cancer, who were resistant or refractory to prior T-DM1 therapy.

Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or

ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring treatment withsteroids or ILD/pneumonitis at screening, patients with untreated and symptomatic brain metastasesand patients with a history of clinically significant cardiac disease. Patients were randomised 2:1 toreceive either Enhertu 5.4 mg/kg (n = 406) by intravenous infusion every three weeks, or treatment ofphysician’s choice (n = 202, trastuzumab plus capecitabine or lapatinib plus capecitabine).

Randomisation was stratified by hormone receptor status, prior treatment with pertuzumab and historyof visceral disease. Treatment was administered until disease progression, death, withdrawal ofconsent or unacceptable toxicity.

The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blindedindependent central review (BICR) based on RECIST v1.1. Overall survival (OS) was a key secondaryefficacy outcome measure. PFS based on investigator assessment, confirmed objective response rate(ORR) and duration of response (DOR) were secondary objectives.

Demographic and baseline disease characteristics were similar between treatment arms. Of the 608patients randomised, the median age was 54 years (range 22 to 88); female (99.2%); White (63.2%),

Asian (29.3%), Black or African American (2.8%); Eastern Cooperative Oncology Group (ECOG)performance status 0 (57.4%) or 1 (42.4%); hormone receptor status (positive: 58.6%); presence ofvisceral disease (78.3%); presence of brain metastases at baseline (18.1%) and 4.9% of patientsreceived one line of prior systemic therapy in the metastatic setting.

Efficacy results are summarised in Table 5 and Figures 3 and 4.

Table 5: Efficacy results in DESTINY-Breast02

Efficacy parameter Enhertu Treatment of physician’s

N = 406 choice

N = 202

PFS per BICR

Number of events (%) 200 (49.3) 125 (61.9)

Median, months (95% CI) 17.8 (14.3, 20.8) 6.9 (5.5, 8.4)

Hazard ratio (95% CI) 0.36 (0.28, 0.45)p-value p < 0.000001†

Overall survival (OS)

Number of events (%) 143 (35.2) 86 (42.6)

Median, months (95% CI) 39.2 (32.7, NE) 26.5 (21.0, NE)

Hazard ratio (95% CI) 0.66 (0.50, 0.86)p-valuea p = 0.0021

PFS per investigator assessment

Number of events (%) 206 (50.7) 152 (75.2)

Median, months (95% CI) 16.7 (14.3, 19.6) 5.5 (4.4, 7.0)

Hazard ratio (95% CI) 0.28 (0.23, 0.35)

Confirmed objective response rate (ORR) per BICRn (%) 283 (69.7) 59 (29.2)95% CI (65.0, 74.1) (23.0, 36.0)

Complete response n (%) 57 (14.0) 10 (5.0)

Partial response n (%) 226 (55.7) 49 (24.3)

Duration of response per BICR

Median, months (95% CI) 19.6 (15.9, NE) 8.3 (5.8, 9.5)

CI = confidence interval; NE = not estimable† Presented as 6 decimal placesa The p-value is based on a stratified log-rank test; crossed the efficacy boundary of 0.004.

Figure 3: Kaplan-Meier plot of progression-free survival per BICR

Figure 4: Kaplan-Meier plot of overall survival

DESTINY-Breast01 (NCT03248492)

The efficacy and safety of Enhertu were studied in DESTINY-Breast01, a multicentre, open-label,single-arm Phase 2 study that enrolled patients with HER2-positive, unresectable and/or metastaticbreast cancer who had received two or more prior anti-HER2-based regimens, including trastuzumabemtansine (100%), trastuzumab (100%) and pertuzumab (65.8%). Archival breast tumour sampleswere required to show HER2 positivity defined as HER2 IHC 3+ or ISH-positive. The study excludedpatients with a history of treated ILD or ILD at screening, patients with untreated or symptomaticbrain metastases, and patients with a history of clinically significant cardiac disease. Patients enrolledhad at least 1 measurable lesion per RECIST v1.1. Enhertu was administered by intravenous infusionat 5.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent, orunacceptable toxicity. The primary efficacy outcome measure was confirmed objective response rate(ORR) according to RECIST v1.1 in the intent-to-treat (ITT) population as evaluated by independentcentral review (ICR). The secondary efficacy outcome measure was duration of response (DOR).

Of the 184 patients enrolled in DESTINY-Breast01, baseline demographic and disease characteristicswere: median age 55 years (range: 28 to 96); 65 years or older (23.9%); female (100%); White(54.9%), Asian (38.0%), Black or African American (2.2%); Eastern Cooperative Oncology Group(ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%);presence of visceral disease (91.8%); previously treated and stable brain metastases (13.0%); mediannumber of prior therapies in the metastatic setting: 5 (range: 2 to 17); sum of diameters of targetlesions (< 5 cm: 42.4%, ≥ 5 cm: 50.0%).

An earlier analysis (median duration of follow-up 11.1 months [range: 0.7 to 19.9 months]) showed aconfirmed objective response rate of 60.9% (95% CI: 53.4, 68.0) with 6.0% being completeresponders and 54.9% being partial responders; 36.4% had stable disease, 1.6% had progressivedisease and 1.1% were not evaluable. Median duration of response at that time was 14.8 months(95% CI: 13.8, 16.9) with 81.3% of responders having a response of ≥ 6 months (95% CI: 71.9, 87.8).

Efficacy results from an updated data cutoff with median duration of follow-up of 20.5 months (range:0.7 to 31.4 months) are shown in Table 6.

Table 6: Efficacy results in DESTINY-Breast01 (intent-to-treat analysis set)

DESTINY-Breast01

N = 184

Confirmed objective response rate (95% CI)*† 61.4% (54.0, 68.5)

Complete response (CR) 6.5%

Partial response (PR) 54.9%

Duration of response‡

Median, months (95% CI) 20.8 (15.0, NR)% with duration of response ≥ 6 months (95%

CI)§ 81.5% (72.2, 88.0)

ORR 95% CI calculated using Clopper-Pearson method

CI = confidence interval95% CIs calculated using Brookmeyer-Crowley method

*Confirmed responses (by blinded independent central review) were defined as a recorded response of either

CR/PR, confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed.†Of the 184 patients, 35.9% had stable disease, 1.6% had progressive disease and 1.1% were not evaluable.‡Includes 73 patients with censored data§Based on Kaplan-Meier estimation

NR = not reached

Consistent anti-tumour activity was observed across prespecified subgroups based on priorpertuzumab therapy and hormone receptor status.

HER2-low and HER2-ultralow breast cancer

DESTINY-Breast06 (NCT04494425)

The efficacy and safety of Enhertu were evaluated in study DESTINY-Breast06, a randomised,multicentre, open-label Phase 3 study that randomised 866 adult patients with advanced or metastatic

HR+ breast cancer with HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow expression asdetermined by the PATHWAY/VENTANA anti-HER2/neu (4B5) evaluated at a central laboratory.

HER2-ultralow (IHC 0 with membrane staining, described as IHC >0<1+ in the study) is defined asfaint and incomplete membrane HER2 staining that is seen in 10% or fewer tumour cells. Patientswere eligible if they had disease progression on (a) at least 2 lines of endocrine therapy in themetastatic setting or (b) one line of endocrine therapy in the metastatic setting and demonstratedprogression within 24 months of the start of adjuvant endocrine therapy, or within 6 monthsof starting first line endocrine therapy in combination with a CDK 4/6 inhibitor in the metastaticsetting. Patients with prior chemotherapy in the neo-adjuvant or adjuvant setting were eligible if theyhad a disease-free interval greater than 12 months. The study excluded patients with priorchemotherapy for advanced or metastatic disease, patients with a history of ILD/pneumonitis requiringtreatment with steroids or ILD/pneumonitis at screening, uncontrolled or significant cardiovasculardisease, untreated and symptomatic brain metastases, or ECOG performance status >1.

Patients were randomised 1:1 to receive either Enhertu 5.4 mg/kg (N = 436) by intravenous infusionevery three weeks or physician’s choice of single agent chemotherapy (N = 430, capecitabine 60%,nab-paclitaxel 24%, or paclitaxel 16%). Randomisation was stratified by prior CDK4/6 inhibitor use(yes or no), prior taxane use in the non-metastatic setting (yes or no), and HER2 IHC status of tumoursamples (IHC 2+/ISH-, IHC 1+, IHC >0 <1+). Treatment with Enhertu was administered until diseaseprogression, death, withdrawal of consent, or unacceptable toxicity.

The primary efficacy outcome measure was PFS in patients with HER2-low breast cancer assessed by

BICR based on RECIST v1.1. Key secondary efficacy outcome measures were PFS assessed by BICRbased on RECIST v1.1 in the overall population (HER2-low and HER2-ultralow), OS in HER2-lowpatients, and OS in the overall population. ORR and DOR were secondary endpoints.

In the overall population, demographics and baseline tumour characteristics were similar betweentreatment arms. Of the 866 patients randomised, the median age was 57 years (range: 28 to 87); 31%were age 65 or older; 99.9% were female; 53% were White, 35% were Asian, and 1% were Black or

African American. Patients had an ECOG performance status of 0 (59%) or 1 (39%) at baseline; 18%were IHC >0<1+, 55% were IHC 1+, 27% were IHC 2+/ISH-; 67% had liver metastases, 32% hadlung metastases, 8% had brain metastases, and 3% had bone-only metastases. Patients had a median of2 prior lines of endocrine therapy in the metastatic setting (range: 1 to 5) with 17% having 1 and 68%having 2. Eighty-nine percent of patients had prior endocrine therapy in combination with CDK4/6itreatment in the metastatic setting, 47% had prior anthracycline use, and 41% had prior taxane use inthe non-metastatic setting.

Efficacy results are summarised in Table 7 and Figures 5 and 6.

Table 7: Efficacy Results in DESTINY-Breast06

HER2 -low Overall Population

Efficacy (HER2-low and HER2-ultralow)

Parameter Enhertu Chemotherapy Enhertu Chemotherapy(N = 359) (N = 354) (N = 436) (N = 430)

Progression Free Survival per BICR

Number of events(%) 225 (62.7) 232 (65.5) 269 (61.7) 271 (63.0)

Median, months(95% CI) 13.2 (11.4, 15.2) 8.1 (7.0, 9.0) 13.2 (12.0, 15.2) 8.1 (7.0, 9.0)

Hazard ratio(95% CI) 0.62 (0.52, 0.75) 0.64 (0.54, 0.76)p-value <0.0001 <0.0001

Overall Survival*

Number of events(%) 136 (37.9) 146 (41.2) 161 (36.9) 174 (40.5)

Median, months(95% CI) 28.9 (25.7, 33.7) 27.1 (23.5, 29.9) 28.9 (26.4, 32.7) 27.4 (23.9, 29.9)

Hazard ratio(95% CI) 0.83 (0.66, 1.05) 0.81 (0.66, 1.01)

Confirmed Objective Response Rate per BICR†n (%) 203 (56.5) 114 (32.2) 250 (57.3) 134 (31.2)95% CI 51.2, 61.7 27.4, 37.3 52.5, 62.0 26.8, 35.8

Duration of Response per BICR†

Median, months(95% CI) 14.1 (11.8, 15.9) 8.6 (6.7, 11.3) 14.3 (12.5, 15.9) 8.6 (6.9, 11.5)

Data cutoff: 18 March 2024

CI = confidence interval

*First planned interim analysis†Results were not controlled for type 1 error and should be interpreted descriptively

Consistent PFS benefit was observed across multiple prespecified subgroups, including HER2expression (IHC >0 <1+, IHC 1+, IHC 2+/ISH-), prior CDK4/6 inhibitor use (yes or no), prior taxaneuse in the non-metastatic setting (yes or no), and number of prior lines of endocrine therapy in themetastatic setting.

In the HER2-ultralow subgroup (n = 152), median PFS was 13.2 months (95% CI: 9.8, 17.3) inpatients randomised to Enhertu (N = 76) and 8.3 months (95% CI: 5.8, 15.2) in patients randomised tochemotherapy with a hazard ratio of 0.78 (95% CI: 0.50, 1.21). Median OS was 29.5 months (95% CI:27.9, NE) in patients randomised to Enhertu and 27.4 months (95% CI: 19.4, NE) in patientsrandomised to chemotherapy with a hazard ratio of 0.75 (95% CI: 0.43, 1.29). Confirmed objectiveresponse rate was 61.8% (95% CI: 50.0, 72.8) and 26.3% (95% CI: 16.9, 37.7) in patients randomisedto Enhertu and chemotherapy, respectively. Median duration of response was 14.3 months (95% CI:9.2, 20.7) and 14.1 months (95% CI: 5.9, not estimable) in patients randomised to Enhertu andchemotherapy, respectively.

Figure 5: Kaplan-Meier Plot of Progression Free Survival (Overall Population)

Figure 6: Kaplan-Meier Plot of Overall Survival (Overall Population)

DESTINY-Breast04 (NCT03734029)

The efficacy and safety of Enhertu were studied in DESTINY-Breast04, a phase 3, randomised,multicentre, open-label study that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The study included 2 cohorts: 494 hormone receptor positive (HR+) patients and63 hormone receptor negative (HR-) patients. HER2-low expression was defined as IHC 1+ (definedas faint, partial staining of the membrane in greater than 10% of the cancer cells) or IHC 2+/ISH-, asdetermined by the PATHWAY/VENTANA anti-HER2/neu (4B5) evaluated at a central laboratory.

Patients must have received chemotherapy in the metastatic setting or have developed diseaserecurrence during or within 6 months of completing adjuvant chemotherapy. According to theinclusion criteria, patients who were HR+ must have received at least one endocrine therapy and beineligible for further endocrine therapy at the time of randomisation. Patients were randomised 2:1 toreceive either Enhertu 5.4 mg/kg (N = 373) by intravenous infusion every three weeks or physician’schoice of chemotherapy (N = 184, eribulin 51.1%, capecitabine 20.1%, gemcitabine 10.3%, nabpaclitaxel 10.3%, or paclitaxel 8.2%). Randomisation was stratified by HER2 IHC status of tumoursamples (IHC 1+ or IHC 2+/ISH-), number of prior lines of chemotherapy in the metastatic setting (1or 2) and HR status/prior CDK4/6i treatment (HR+ with prior CDK4/6 inhibitor treatment, HR+without prior CDK4/6 inhibitor treatment, or HR-). Treatment was administered until diseaseprogression, death, withdrawal of consent, or unacceptable toxicity. The study excluded patients witha history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening andclinically significant cardiac disease. Patients were also excluded for untreated or symptomatic brainmetastases or ECOG performance status > 1.

The primary efficacy endpoint was progression-free survival (PFS) in patients with HR+ breast cancerassessed by BICR based on RECIST v1.1. Key secondary efficacy endpoints were PFS assessed by

BICR based on RECIST v1.1 in the overall population (all randomised HR+ and HR- patients), overallsurvival (OS) in HR+ patients and OS in the overall population. ORR, DOR and patient-reportedoutcomes (PROs) were secondary endpoints.

Demographics and baseline tumour characteristics were similar between treatment arms. Of the557 patients randomised, the median age was 57 years (range: 28 to 81); 23.5% were age 65 or older;99.6% were female and 0.4% were male; 47.9% were White, 40.0% were Asian and 1.8% were Blackor African American. Patients had an ECOG performance status of 0 (54.8%) or 1 (45.2%) at baseline;57.6% were IHC 1+, 42.4% were IHC 2+/ISH-; 88.7% were HR+ and 11.3% HR-; 69.8% had livermetastases, 32.9% had lung metastases, and 5.7% had brain metastases. The percentage of patientswho had prior anthracycline use in the (neo)adjuvant setting was 46.3% and 19.4% in the locallyadvanced and/or metastatic setting. In the metastatic setting, patients had a median of 3 prior lines ofsystemic therapy (range: 1 to 9) with 57.6% having 1 and 40.9% having 2 prior chemotherapyregimens; 3.9% were early progressors (progression in the neo/adjuvant setting). In HR+ patients, themedian number of prior lines of endocrine therapy was 2 (range: 0 to 9) and 70% had prior CDK4/6inhibitor treatment.

Efficacy results are summarised in Table 8 and Figures 7 and 8.

Table 8: Efficacy results in DESTINY-Breast04

HR+ cohort Overall population

Efficacy (HR+ and HR- cohort)parameter Enhertu Chemotherapy Enhertu Chemotherapy(N = 331) (N = 163) (N = 373) (N = 184)

Overall survival

Number ofevents (%) 126 (38.1) 73 (44.8) 149 (39.9) 90 (48.9)

Median,months (95% 23.9 (20.8, 24.8) 17.5 (15.2, 22.4) 23.4 (20.0, 24.8) 16.8 (14.5, 20.0)

CI)

HR+ cohort Overall population

Efficacy (HR+ and HR- cohort)parameter Enhertu Chemotherapy Enhertu Chemotherapy(N = 331) (N = 163) (N = 373) (N = 184)

Hazard ratio(95% CI) 0.64 (0.48, 0.86) 0.64 (0.49, 0.84)p-value 0.0028 0.001

Progression-free survival per BICR

Number ofevents (%) 211 (63.7) 110 (67.5) 243 (65.1) 127 (69.0)

Median,months (95% 10.1 (9.5, 11.5) 5.4 (4.4, 7.1) 9.9 (9.0, 11.3) 5.1 (4.2, 6.8)

CI)

Hazard ratio(95% CI) 0.51 (0.40, 0.64) 0.50 (0.40, 0.63)p-value < 0.0001 < 0.0001

Confirmed objective response rate per BICR*n (%) 175 (52.6) 27 (16.3) 195 (52.3) 30 (16.3)95% CI 47.0, 58.0 11.0, 22.8 47.1, 57.4 11.3, 22.5

Complete

Response n 12 (3.6) 1 (0.6) 13 (3.5) 2 (1.1)(%)

Partial

Response n 164 (49.2) 26 (15.7) 183 (49.1) 28 (15.2)(%)

Duration of response per BICR*

Median,months (95% 10.7 (8.5, 13.7) 6.8 (6.5, 9.9) 10.7 (8.5, 13.2) 6.8 (6.0, 9.9)

CI)

CI = confidence interval

*Based on data from electronic case report form for the HR+ cohort: N = 333 for Enhertu arm and N = 166chemotherapy arm.

Consistent OS and PFS benefit were observed across prespecified subgroups, including HR status,prior CDK4/6i treatment, number of prior chemotherapies and IHC 1+ and IHC 2+/ISH- status. In the

HR- subgroup, median OS was 18.2 months (95% CI: 13.6, not estimable) in patients randomised to

Enhertu compared to 8.3 months (95% CI: 5.6, 20.6) in patients randomised to chemotherapy with ahazard ratio of 0.48 (95% CI: 0.24, 0.95). Median PFS was 8.5 months (95% CI: pct. 4.3, 11.7) in patientsrandomised to Enhertu and 2.9 months (95% CI: 1.4, 5.1) in patients randomised to chemotherapywith a hazard ratio of 0.46 (95% CI: 0.24, 0.89).

At an updated descriptive analysis with a median follow-up of 32 months, OS improvements wereconsistent with the primary analysis. The HR in the overall population was 0.69 (95% CI: 0.55, 0.86)with a median OS of 22.9 months (95% CI: 21.2, 24.5) in the Enhertu arm versus 16.8 months(95% CI: 14.1, 19.5) in the chemotherapy arm. The Kaplan-Meier curve for the updated OS analysis isshown in Figure 7.

Figure 7: Kaplan-Meier plot of overall survival (overall population) (updated analysis)

Figure 8: Kaplan-Meier plot of progression-free survival per BICR (overall population)

DESTINY-Lung02 (NCT04644237)

The efficacy and safety of Enhertu were studied in DESTINY-Lung02, a phase 2, randomised studyevaluating two dose levels. The treatment dosage assignment was blinded to patients and investigators.

The study included adult patients with metastatic HER2-mutant NSCLC who had received at least oneregimen containing platinum-based chemotherapy. Identification of an activating HER2 (ERBB2)mutation was prospectively determined in tumour tissue by local laboratories using a validated testsuch as next generation sequencing, polymerase chain reaction or mass spectrometry. Patients wererandomised 2:1 to receive Enhertu 5.4 mg/kg or 6.4 mg/kg every 3 weeks, respectively.

Randomisation was stratified by prior anti-programmed cell death receptor-1 (PD-1) and/or anti-programmed cell death ligand 1 (PD-L1) treatment (yes versus no). Treatment was administered untildisease progression, death, withdrawal of consent, or unacceptable toxicity. The study excludedpatients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis atscreening and clinically significant cardiac disease. Patients were also excluded for untreated andsymptomatic brain metastases or ECOG performance status >1.

The primary efficacy outcome measure was confirmed ORR as assessed by BICR using RECIST v1.1.

The secondary efficacy outcome measure was DOR.

Demographic and baseline disease characteristics from the 102 patients enrolled in the 5.4 mg/kg armwere: median age 59.4 years (range 31 to 84); female (63.7%); Asian (63.7%), White (22.5%), or

Other (13.7%); ECOG performance status 0 (28.4%) or 1 (71.6%); 97.1% had a mutation in the

ERBB2 kinase domain, 2.9% in the extracellular domain; 96.1% had a HER2 mutation in exon 19 orexon 20; 34.3% had stable brain metastases; 46.1% were former smokers, none were current smokers;21.6% had a prior lung resection. In the metastatic setting, 32.4% had greater than 2 prior systemictherapies, 100% received platinum-based therapy, 73.5% received anti-PD-1/PD-L1 therapy, and50.0% had prior treatment with platinum therapy and anti-PD-1/PD-L1 therapy in combination.

Efficacy results are summarised in Table 9. The median duration of follow-up was 11.5 months (datacutoff: 23 December 2022).

Table 9: Efficacy results in DESTINY-Lung02

DESTINY-Lung02

Efficacy parameter 5.4 mg/kg

N = 102

Confirmed objective response rate (ORR) per BICRn (%) 50 (49.0)(95% CI)* (39.0, 59.1)

Complete response (CR) n (%) 1 (1.0)

Partial response (PR) n (%) 49 (48.0)

Duration of response

Median, months (95% CI) † 16.8 (6.4, NE)

*95% CI calculated using Clopper-Pearson method

CI = confidence interval, NE = not estimable†95% CI calculated using Brookmeyer-Crowley method

Gastric cancer

DESTINY-Gastric04 (NCT04704934)

The efficacy and safety of Enhertu were evaluated in DESTINY-Gastric04, a Phase 3, randomised,multicentre, open-label, active-controlled study. The study included adult patients with HER2-positivelocally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma who had progressed onor after a trastuzumab-containing regimen. Patients were randomised 1:1 to receive either Enhertu(N=246) or ramucirumab plus paclitaxel (N=248). Randomisation was stratified by HER2 status(IHC 3+ or IHC 2+/ISH-positive), geographical region (Asia [excluding mainland China] versus

Western Europe versus mainland China/rest of the world), and time to progression on first-line therapy(<6 months or ≥6 months). Tumour samples were required to have locally or centrally confirmed

HER2 positivity defined as IHC 3+ or IHC 2+/ISH-positive. The study excluded patients with ahistory of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patientswith a history of clinically significant cardiac disease, and patients with active brain metastases.

Treatment was administered until disease progression, death, or unacceptable toxicity. The primaryefficacy outcome measure was overall survival (OS). PFS, confirmed ORR, and DOR were secondaryoutcome measures.

Demographic and baseline disease characteristics were similar between treatment arms. Of the 494patients enrolled in DESTINY-Gastric04, the median age was 63.7 years (range 21.1 to 87.0); 79.4%were male; 49.8% were White, 40.1% were Asian, and 0.4% were Black or African American.

Patients had an ECOG performance status of either 0 (37.4%) or 1 (61.9%); 61.1% had gastricadenocarcinoma and 38.9% had GEJ adenocarcinoma; 84% were IHC 3+ and 16% were

IHC 2+/ISH-positive; 70% of patients had two or more metastatic sites, 61.7% had liver metastases,6.9% had brain metastases; 15.6% of patients previously received immunotherapy.

Efficacy results are summarised in Table 10 and Figure 9.

Table 10: Efficacy results in DESTINY-Gastric04

Ramucirumab plus

Efficacy Parameter Enhertu

N=246 paclitaxel

N=248

Overall Survival (OS)

Number of events (%) 124 (50.4) 142 (57.3)

Median, months (95% CI) 14.7 (12.1, 16.6) 11.4 (9.9, 15.5)

Hazard ratio (95% CI)* 0.70 (0.55, 0.90)p-value† P=0.0044

Progression-free Survival (PFS) per Investigator Assessment

Number of events (%) 166 (67.5) 156 (62.9)

Median, months (95% CI) 6.7 (5.6, 7.1) 5.6 (4.9, 5.8)

Hazard ratio (95% CI)* 0.74 (0.59, 0.92)p-value† p=0.0074

Confirmed Objective Response Rate (ORR) per Investigator Assessment††n (%) 104 (44.3) 69 (29.1)95% CI (37.8, 50.9) (23.4, 35.3)p-value§ p=0.0006

Complete Response n (%) 7 (3.0) 3 (1.3)

Partial Response n (%) 97 (41.3) 66 (27.8)

Duration of Response (DOR) per Investigator Assessment

Median, months (95% CI) 7.4 (5.7, 10.1) 5.3 (4.1, 5.7)

CI=confidence interval

*Two-sided p-value from stratified log-rank test and stratified Cox proportional hazards model adjusted for IRTstratification factors: HER2 status (IHC 3+ or IHC 2+/ISH+).†Based on log rank test stratified by HER2 status (IHC3+ or IHC2+/ISH+)††ORR-eligible subjects are those who were randomised at least 77 days (i.e., 2 × 6 weeks - 1 week) before DCOdate of interim analysis. Confirmed ORR is calculated using the eligible subjects as the denominator:

Enhertu = 235, ramucirumab plus paclitaxel = 237§p-value for the difference in ORR uses the Cochran-Mantel-Haenszel test adjusted for stratification factor:

HER2 status (IHC 3+ or IHC 2+/ISH+).

Figure 9: Kaplan-Meier plot of overall survival (full analysis set)

DESTINY-Gastric02 (NCT04014075)

The efficacy and safety of Enhertu were studied in DESTINY-Gastric02, a Phase 2, multicentre, open-label, single-arm study conducted at sites in Europe and the United States. The study enrolled patientswith locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who hadprogressed on a prior trastuzumab-based regimen. Patients were required to have centrally confirmed

HER2 positivity defined as IHC 3+ or IHC 2+/ISH-positive. The study excluded patients with ahistory of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patientswith a history of clinically significant cardiac disease, and patients with active brain metastases.

Enhertu was administered by intravenous infusion at 6.4 mg/kg every three weeks until diseaseprogression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy outcomemeasure was confirmed ORR assessed by ICR based on RECIST v1.1. DOR and OS were secondaryendpoints.

Of the 79 patients enrolled in DESTINY-Gastric02, demographic and baseline disease characteristicswere: median age 61 years (range 20 to 78); 72% were male; 87% were White, 5.0% were Asian and1.0% were Black or African American. Patients had an ECOG performance status of either 0 (37%) or1 (63%); 34% had gastric adenocarcinoma and 66% had GEJ adenocarcinoma; 86% were IHC 3+ and13% were IHC 2+/ISH-positive, and 63% had liver metastases.

Efficacy results for ORR and DOR are summarised in Table 11.

Table 11: Efficacy results in DESTINY-Gastric02 (full analysis set*)

Efficacy parameter DESTINY-Gastric02

N = 79

Data cutoff date 08 November 2021

Confirmed objective response rate†% (95% CI)‡ 41.8 (30.8, 53.4)

Efficacy parameter DESTINY-Gastric02

N = 79

Data cutoff date 08 November 2021

Complete response n (%) 4 (5.1)

Partial response n (%) 29 (36.7)

Duration of response

Median§, months (95% CI)¶ 8.1 (5.9, NE)

NE = Not estimable

*Includes all patients who received at least one dose of Enhertu†Assessed by independent central review‡Calculated using Clopper-Pearson method§Based on Kaplan-Meier estimate¶Calculated using the Brookmeyer and Crowley method

DESTINY-Gastric01 (NCT03329690)

The efficacy and safety of Enhertu were studied in DESTINY-Gastric01, a Phase 2, multicentre, open-label, randomised study conducted at sites in Japan and South Korea. This supportive study includedadult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma whohad progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine agent, and aplatinum agent. Patients were randomised 2:1 to receive either Enhertu (N = 126) or physician’schoice of chemotherapy: either irinotecan (N = 55) or paclitaxel (N = 7). Tumour samples wererequired to have centrally confirmed HER2 positivity defined as IHC 3+ or IHC 2+/ISH-positive. Thestudy excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or

ILD/pneumonitis at screening, patients with a history of clinically significant cardiac disease, andpatients with active brain metastases. Treatment was administered until disease progression, death,withdrawal of consent, or unacceptable toxicity. The primary efficacy outcome measure wasunconfirmed ORR assessed by ICR based on RECIST v1.1. Overall survival (OS), progression-freesurvival (PFS), DOR, and confirmed ORR were secondary outcome measures.

Demographic and baseline disease characteristics were similar between treatment arms. Of the 188patients, the median age was 66 years (range 28 to 82); 76% were male; 100% were Asian. Patientshad an ECOG performance status of either 0 (49%) or 1 (51%); 87% had gastric adenocarcinoma and13% had GEJ adenocarcinoma; 76% were IHC 3+ and 23% were IHC 2+/ISH-positive; 54% had livermetastases; 29% had lung metastases; the sum of diameters of target lesions was < 5 cm in 47%, ≥ 5 to< 10 cm in 30%, and ≥ 10 cm in 17%; 55% had two and 45% had three or more prior regimens in thelocally advanced or metastatic setting.

Efficacy results (data cutoff date: 03 June 2020) for Enhertu (n = 126) vs. physician’s choice ofchemotherapy (n = 62) were confirmed ORR 39.7% (95% CI: 31.1, 48.8) vs. 11.3% (95% CI: 4.7,21.9). Complete response rate was 7.9% vs. 0% and partial response rate was 31.7% vs. 11.3%.

Additional efficacy results for Enhertu vs. physician’s choice of chemotherapy were median DOR of12.5 months (95% CI: 5.6, NE) vs. 3.9 months (95% CI: 3.0, 4.9). Median PFS was 5.6 months(95% CI: pct. 4.3, 6.9) vs. 3.5 months (95% CI: 2.0, pct. 4.3; hazard ratio = 0.47 [95% CI: 0.31, 0.71]). An OSanalysis, prespecified at 133 deaths, showed survival benefit with Enhertu treatment compared to thephysician’s choice group (hazard ratio = 0.60). The median OS was 12.5 months (95% CI: 10.3, 15.2)in the Enhertu group and 8.9 months (95% CI: 6.4, 10.4) in the physician’s choice group.

The European Medicines Agency has waived the obligation to submit the results of studies in allsubsets of the paediatric population in breast cancer, NSCLC and gastric cancer (see section 4.2 forinformation on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

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

Based on population pharmacokinetic analysis, the volume of distribution of the central compartment(Vc) of trastuzumab deruxtecan and topoisomerase I inhibitor, DXd, were estimated to be 2.68 L and28.0 L, respectively.

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.

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 andamino 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.

Following intravenous administration of trastuzumab deruxtecan in patients with metastatic HER2-positive, HER2-low breast cancer or HER2-mutant NSCLC, the clearance of trastuzumab deruxtecanin population pharmacokinetic analysis was calculated to be 0.4 L/day and the clearance of DXd was18.4 L/h. In patients with locally advanced or metastatic gastric or GEJ adenocarcinoma, trastuzumabderuxtecan clearance was approximately 20% higher than in patients with metastatic HER2-positivebreast cancer. In cycle 3, the apparent elimination half-life (t1/2) of trastuzumab deruxtecan andreleased DXd was approximately 7 days. Moderate accumulation (approximately 35% in cycle 3compared to cycle 1) of trastuzumab deruxtecan was observed.

Following intravenous administration of DXd to rats, the major excretion pathway was faeces via thebiliary route. DXd was the most abundant component in urine, faeces, and bile. Following singleintravenous administration of trastuzumab deruxtecan (6.4 mg/kg) to monkeys, unchanged released

DXd was the most abundant component in urine and faeces. DXd excretion was not studied inhumans.

In vitro interactions

Effects of Enhertu on the pharmacokinetics of other medicinal products

In vitro studies indicate DXd does not inhibit major CYP450 enzymes including CYP1A2, 2B6, 2C8,2C9, 2C19, 2D6 and 3A. In vitro studies indicate that DXd does not inhibit OAT1, OAT3, OCT1,

OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.

Effects of other medicinal products on the pharmacokinetics of Enhertu

In vitro, DXd was a substrate of P-gp, OATP1B1, OATP1B3, MATE2-K, MRP1, and BCRP.

No clinically meaningful interaction is expected with medicinal products that are inhibitors of

MATE2-K, MRP1, P-gp, OATP1B, or BCRP transporters (see section 4.5).

The exposure of trastuzumab deruxtecan and released DXd when administered intravenouslyincreased in proportion to dose in the 3.2 mg/kg to 8.0 mg/kg dose range (approximately0.6 to 1.5 times the recommended dose) with low to moderate inter-subject variability. Based onpopulation pharmacokinetic analysis, inter-subject variability in trastuzumab deruxtecan and DXdelimination clearances were 24% and 28%, respectively, and for central volume of distribution were16% and 55%, respectively. The intra-subject variability in trastuzumab deruxtecan and DXd AUCvalues (area under the serum concentration versus time curve) was approximately 8% and 14%,respectively.

Based on population pharmacokinetic analysis, age (20-96 years), race, ethnicity, sex and body weightdid not have a clinically meaningful effect on exposure of trastuzumab deruxtecan or released DXd.

The population PK analysis showed that age (range: 20-96 years) did not affect the PK of trastuzumabderuxtecan.

No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysisincluding patients with mild (creatinine clearance [CLcr] ≥ 60 and < 90 mL/min) or moderate(CLcr ≥ 30 and < 60 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokineticsof the released DXd was not affected by mild or moderate renal impairment as compared to normalrenal function (CLcr ≥ 90 mL/min).

No dedicated hepatic impairment study was conducted. Based on population pharmacokineticanalysis, the impact of changes on pharmacokinetics of trastuzumab deruxtecan in patients with totalbilirubin ≤ 1.5 times ULN, irrespective of AST level, is not clinically meaningful. There is limiteddata for patients with total bilirubin > 1.5 to 3 times ULN, irrespective of AST level, to drawconclusions, and no data is available for patients with total bilirubin > 3 times ULN, irrespective of

AST level (see sections 4.2 and 4.4).

No studies have been conducted to investigate the pharmacokinetics of trastuzumab deruxtecan inchildren or adolescents.

In animals, toxicities were observed in lymphatic and haematopoietic organs, intestines, kidneys,lungs, testes and skin following the administration of trastuzumab deruxtecan at exposure levels of thetopoisomerase I inhibitor (DXd) below clinical plasma exposure. In these animals, antibody-drugconjugate (ADC) exposure levels were similar or above clinical plasma exposure.

DXd was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinesehamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reversemutation assay.

Carcinogenicity studies have not been conducted with trastuzumab deruxtecan.

Dedicated fertility studies have not been conducted with trastuzumab deruxtecan. Based on resultsfrom general animal toxicity studies, trastuzumab deruxtecan may impair male reproductive functionand fertility.

There were no animal reproductive or developmental toxicity studies conducted with trastuzumabderuxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan and DXdwere toxic to rapidly dividing cells (lymphatic/haematopoietic organs, intestine, or testes), and DXdwas genotoxic, suggesting the potential for embryotoxicity and teratogenicity.

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80 (E433)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Sodium chloride solution for infusion must not be used for reconstitution or dilution since it may causeparticulate formation.

Unopened vial4 years.

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 2 ºC to 8 ºC.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 ºC to 8 ºC, unless reconstitution has taken place incontrolled and validated aseptic conditions.

It is recommended that the diluted solution be used immediately. If not used immediately, thereconstituted solution diluted in infusion bags containing 5% glucose solution may be stored at roomtemperature (≤ 30 ºC) for up to 4 hours including preparation and infusion or in a refrigerator at 2 ºCto 8 ºC for up to 24 hours, protected from light.

Store in a refrigerator (2 ºC - 8 ºC).

Do not freeze.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Enhertu is provided in 10 mL Type 1 amber borosilicate glass vial sealed with a fluoro-resin laminatedbutyl rubber stopper, and a polypropylene/aluminium yellow flip-off crimp cap.

Each carton contains 1 vial.

In order to prevent medicinal product errors, it is important to check the vial labels to ensure that themedicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and nottrastuzumab or trastuzumab emtansine.

Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used.

Appropriate aseptic technique should be used for the following reconstitution and dilution procedures.

* Reconstitute immediately before dilution.

* More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume ofreconstituted Enhertu solution required, and the number of vial(s) of Enhertu needed (seesection 4.2).

* Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of water for injectioninto each vial to obtain a final concentration of 20 mg/mL.

* Swirl the vial gently until completely dissolved. Do not shake.

* From a microbiological point of view, the product should be used immediately. If not usedimmediately, chemical and physical in-use stability has been demonstrated for up to 48 hours at2 ºC to 8 ºC. Store the reconstituted Enhertu vials in a refrigerator at 2 ºC to 8 ºC, protectedfrom light. Do not freeze.

* The reconstituted product contains no preservative and is intended for single use only.

* Withdraw the calculated amount from the vial(s) using a sterile syringe. Inspect thereconstituted solution for particulates and discolouration. The solution should be clear andcolourless to light yellow. Do not use if visible particles are observed or if the solution is cloudyor discoloured.

* Dilute the calculated volume of reconstituted Enhertu in an infusion bag containing 100 mL of5% glucose solution for infusion. Do not use sodium chloride solution (see section 6.2). Aninfusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene andpolypropylene) is recommended.

* Gently invert the infusion bag to thoroughly mix the solution. Do not shake.

* Cover the infusion bag to protect from light.

* If not used immediately, store at room temperature (≤ 30 ºC) for up to 4 hours includingpreparation and infusion or in a refrigerator at 2 ºC to 8 ºC for up to 24 hours, protected fromlight. Do not freeze.

* Discard any unused portion left in the vial.

* If the prepared infusion solution was stored refrigerated (2 ºC to 8 ºC), it is recommended thatthe solution be allowed to equilibrate to room temperature prior to administration, protectedfrom light.

* Administer Enhertu as an intravenous infusion only with a 0.20 or 0.22 micron in-linepolyethersulfone (PES) or polysulfone (PS) filter.

* The initial dose should be administered as a 90-minute intravenous infusion. If the priorinfusion was well tolerated, subsequent doses of Enhertu may be administered as 30-minuteinfusions. Do not administer as an intravenous push or bolus (see section 4.2).

* Cover the infusion bag to protect from light.

* Do not mix Enhertu with other medicinal products or administer other medicinal productsthrough the same intravenous line.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Daiichi Sankyo Europe GmbH

Zielstattstrasse 4881379 Munich

Germany

EU/1/20/1508/001

Date of first authorisation: 18 January 2021

Date of latest renewal: 28 October 2024

{DD month YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu