Enhertu Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. HER2-Positive, HER2-Low, and HER2-Ultralow Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) ENHERTU as Monotherapy The pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for greater than 6 months and 39% were exposed for greater than 12 months. In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (43%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%). ENHERTU in Combination with Pertuzumab The pooled safety population described in WARNINGS and PRECAUTIONS reflects exposure to ENHERTU 5.4 mg/kg in combination with pertuzumab intravenously every 3 weeks in 431 patients in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). Among these patients, 86% were exposed for greater than 6 months and 73% were exposed for greater than 12 months.

In this pooled safety population, the most common (≥20%) adverse reactions (including laboratory abnormalities) were decreased white blood cell count (86%), decreased hemoglobin (80%), decreased neutrophil count (79%), nausea (74%), increased alanine aminotransferase (65%), diarrhea (64%), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase (54%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (32%), constipation (31%), decreased appetite (31%), decreased weight (28%), musculoskeletal pain (23%), increased blood bilirubin (23%), and abdominal pain (22%). ENHERTU followed by THP The data described in the WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks for four cycles followed by THP for four cycles in 320 patients in Study DESTINY-Breast11. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The data described in WARNINGS and PRECAUTIONS reflect exposure to ENHERTU 6.4 mg/kg intravenously every 3 weeks in 125 patients in DESTINY-Gastric01. HER2-Positive Early Breast Cancer DESTINY-Breast11 The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least one dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11 . ENHERTU was administered by intravenous infusion once every three weeks for four cycles followed by THP for four cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP. Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (one patient each). In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%. Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU. The most common (≥20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased white blood cell count, nausea, peripheral neuropathy, diarrhea, decreased neutrophil count, alopecia, fatigue, decreased lymphocyte count, rash, musculoskeletal pain, decreased blood potassium, constipation, vomiting, stomatitis, and decreased appetite.

Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast11. Table 4: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) Patients in DESTINY-Breast11 Adverse Reactions ENHERTU 5.4 mg/kg followed by THP N = 320 ddAC followed by THP N = 312 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % THP= paclitaxel, trastuzumab, and pertuzumab; ddAC=dose dense doxorubicin and cyclophosphamide; Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 65 1.9 52

Diarrhea 59 6 54 3.2 Constipation 29 0.3 24 0 Vomiting 29

0.9 21

Stomatitis Including aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, and stomatitis.

23 0.3 36

Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain

upper, and gastrointestinal pain. 16 0 12 0 Nervous System Disorders Peripheral neuropathy Including dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. 59 2.5 47

Headache Including headache, migraine, and sinus headache. 18 0 16 0 Skin

and Subcutaneous Tissue Disorders Alopecia 48 0 49 0 Rash Including dermatitis, dermatitis acneiform, dermatitis bullous, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and urticarial dermatitis. 31 0.9 25

General Disorders and

Administration Site Conditions Fatigue Including asthenia, fatigue, and malaise. 41 0.6 55

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including arthralgia, back pain, bone

pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 30 0 28

Metabolism and Nutrition Disorders Decreased appetite 20 0 18 0.3 Respiratory, Thoracic

and Mediastinal Disorders Epistaxis 15 0 10 0 Cough 10 0 14 0 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 13 0.6 20

COVID-19 10 0.9 11 0.3 Other clinically relevant adverse reactions reported in

less than 10% of patients in the ENHERTU followed by THP treated group were: General disorders and administration site conditions: peripheral edema (9%), pyrexia (8%), mucosal inflammation (1.9%) Nervous System Disorders: dysgeusia (9%), dizziness (4.7%) Eye Disorders: dry eye (8%), blurred vision (6%) Gastrointestinal disorders: dyspepsia (8%), gastritis (3.4%), abdominal distension (2.5%), flatulence (0.9%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), ILD (4.4%). Skin and Subcutaneous Tissue Disorders: pruritus (6%) and skin hyperpigmentation (1.6%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (4.7%) Investigations : decreased weight (3.4%) Blood and Lymphatic System Disorders: febrile neutropenia (0.9%) Metabolism and Nutrition Disorders: dehydration (0.3%) Table 5: Selected Laboratory Abnormalities in Patients in DESTINY-Breast11 Laboratory Parameter ENHERTU 5.4 mg/kg followed by THP N=320 ddAC followed by THP N = 312 All Grades % Grades 3-4 % All Grades % Grades 3-4 % THP= paclitaxel, trastuzumab, and pertuzumab; ddAC= dose dense doxorubicin and cyclophosphamide Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased hemoglobin 83 2.2 97 10 Decreased white blood cell count 67 8 87 31 Decreased neutrophil count 58 17 66 38 Decreased lymphocyte count 40 3.1 93 39 Decreased platelet count 8 0.9 28

Chemistry Increased alanine aminotransferase 79 5 77 4.2 Increased aspartate aminotransferase 74

2.5 68 1 Decreased blood potassium 29 4.1 25

Increased blood alkaline phosphatase 19 0 24 0 Decreased sodium 19 1.9

23

Increased blood creatinine 8 0.6 8 1.3 Increased blood bilirubin 7 0

4.2

DESTINY-Breast05

The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU. Serious adverse reactions occurred in 17% of patients receiving ENHERTU. Serious adverse reactions in ≥1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased.

Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (one patient). Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients. The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients.

Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia. Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased lymphocyte count, decreased neutrophil count, nausea, decreased hemoglobin, increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, decreased platelet count, increased blood alkaline phosphatase, constipation, vomiting, decreased blood potassium, diarrhea, musculoskeletal pain, and decreased appetite. Tables 6 and 7 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast05. Table 6: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast05 Adverse Reactions ENHERTU 5.4 mg/kg N= 806 Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kg N=801 All Grades % Grade 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 71 4.5 29

Constipation 32 0 16 0.1 Vomiting 31 1.1 9 0.1 Diarrhea 23

1.2 9

Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain

upper, and gastrointestinal pain. 15 0.2 9

Stomatitis Including aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, and

stomatitis. 10 0.2 6

General Disorders and

Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise. 54 6 37

Pyrexia 10 0.1 12 0.2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain

Including arthralgia, back pain, bone pain, limb discomfort, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 23 0.7 32

Metabolism and Nutrition Disorders Decreased appetite 20 0.9 10 0 Infections and

Infestations Upper respiratory tract infection Including influenza, influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 18 0.1 17

COVID-19 17 0.5 20 0.4 Respiratory, Thoracic and Mediastinal Disorders Interstitial lung

disease Including COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades 3 or 4 and for T-DM1, 1.6% for all Grades and 0% for Grades 3 or 4. 17 1.1 3.7

Cough 13 0 11 0 Nervous System Disorders Headache Including headache, migraine

and sinus headache. 16 0.2 21

Peripheral neuropathy Including dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral motor

neuropathy, peripheral sensory neuropathy, and polyneuropathy. 13 0.4 20

Skin and Subcutaneous Tissue Disorders Alopecia 16 0 1.2 0 Rash Including

dermatitis, dermatitis acneiform, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, and Stevens-Johnson syndrome. 10 0.4 14

Investigations Decreased weight 12 0.2 7 0.1 Other clinically relevant adverse reactions

reported in less than 10% of patients in the ENHERTU-treated group were: Gastrointestinal disorders: dyspepsia (8%), gastritis (2.5%), abdominal distension (1.7%), flatulence (1.5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (4.5%), epistaxis (3.8%) Skin and Subcutaneous Tissue Disorders: pruritus (4.2%), skin hyperpigmentation (3.5%) Nervous System Disorders: dysgeusia (3.7%) Eye Disorders: dry eye (2.7%), vision blurred (2.7%) Metabolism and Nutrition Disorders: dehydration (1%) Injury, Poisoning, and Procedural Complications: infusion related reaction (0.7%) Blood and Lymphatic System Disorders: febrile neutropenia (0.5%) Table 7: Selected Laboratory Abnormalities in Patients in DESTINY-Breast05 Laboratory Parameter ENHERTU 5.4 mg/kg N=806 Ado-Trastuzumab Emtansine (T-DM1) 3.6mg/kg N = 801 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 80 17 46

Decreased lymphocyte count 72 35 54 17 Decreased neutrophil count 72 23

38

Decreased hemoglobin 61 2.9 36 2 Decreased platelet count 46 8 93

33 Chemistry Increased aspartate aminotransferase 60 1 91

Increased alanine aminotransferase 53 1 80 4.2 Increased blood alkaline phosphatase 39

0 53

Decreased blood potassium 27 1.7 44 2.1 Increased blood creatinine 13 0.2

9

Increased blood bilirubin 9 0 20 0 Radiotherapy-Related Pneumonitis and Skin Injury

in the Post Neoadjuvant Early Breast Cancer Setting Among patients receiving sequential or concurrent adjuvant radiotherapy in DESTINY-Breast05, radiation pneumonitis occurred in 31% of patients receiving ENHERTU 5.4 mg/kg (N=757) and 31% of patients receiving ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg (N=750), as reported by the investigator. All cases of patients receiving ENHERTU and adjuvant radiotherapy (ART) were either Grade 1 (27%) or Grade 2 (4.9%). Similarly, all cases of patients receiving T-DM1 and ART were either Grade 1 (24%) or Grade 2 (7%). A higher incidence of radiation pneumonitis was reported for patients who received sequential vs. concurrent ART, irrespective of treatment arm: 34% for ENHERTU vs. 37% for T-DM1, respectively, with sequential ART and 29% vs. 27%, respectively, with concurrent ART. For patients treated with ENHERTU, median time to onset of first event of radiation pneumonitis was 4.1 months (range: 1.3 – 11.6 months). Among patients receiving ART and ENHERTU, radiation skin injury occurred in 20% of all patients, of which 1.6% were Grade 3 and none were Grade 4. Among patients receiving ART and T-DM1, radiation skin injury occurred in 18% of all patients, of which 0.4% were Grade 3 and none were Grade 4. HER2-Positive Metastatic Breast Cancer DESTINY-Breast09 The safety of ENHERTU 5.4 mg/kg in combination with pertuzumab was evaluated in DESTINY-Breast09, a randomized, three-arm, multicenter study including 763 patients with HER2-positive (IHC 3+ or ISH+) unresectable or metastatic breast cancer . Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane, trastuzumab, and pertuzumab). Among patients who received ENHERTU in combination with pertuzumab, the median duration of treatment was 22 months (range: 0.3 months to 44.5 months). Serious adverse reactions occurred in 27% of patients receiving ENHERTU in combination with pertuzumab. Serious adverse reactions in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis.

Fatalities due to adverse reactions occurred in 3.4% of patients including pneumonia (n=3), ILD (n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (one patient each). ENHERTU was discontinued for adverse reactions in 21% of patients. The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis (6%). Dose interruptions due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, neutropenia, upper respiratory tract infection, fatigue, anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia, diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased appetite, and blood bilirubin increased.

Dose reductions occurred in 46% of patients treated with ENHERTU in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase decreased lymphocyte count, decreased platelet count, increased blood alkaline phosphatase, decreased blood potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased blood bilirubin, and abdominal pain.

Tables 8 and 9 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast09. Table 8: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in Combination with Pertuzumab in DESTINY-Breast09 Adverse Reactions ENHERTU 5.4 mg/kg + Pertuzumab N= 381 THP THP=taxane, trastuzumab, and pertuzumab N=382 All Grades % Grade 3-4 % All Grades % Grades 3-4 % Gastrointestinal Disorders Nausea 75 5 34

Diarrhea 64 8 62 6 Vomiting 46 2.4 18 0.5 Constipation 33

0.3 12 0 Abdominal pain Including abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain. 23 0.3 13 0 Stomatitis Including aphthous ulcer, mouth ulceration, oral mucosal eruption, and stomatitis. 16 1.3 17

Dyspepsia 12 0 6 0 General Disorders and

Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise. 53 8 42

Pyrexia 16 0 18 1.0 Skin and Subcutaneous Tissue Disorders Alopecia 48

0 53

Rash Including rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular.

17 0.3 22

Pruritus 11 0 11 0.3 Infections and Infestations Upper respiratory tract infection

Including Influenza, Influenza like illness, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection. 33 1.6 30

COVID-19 28 0.3 22 0.3 Metabolism and Nutrition Disorders Decreased appetite 32

2.4 18

Hypoalbuminemia 11 0.3 8 0.3 Investigations Decreased weight 30 3.1 11 0.8

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity. 24 1 33

Nervous System Disorders Headache Including headache and migraine. 19 0.3 14 0

Dysgeusia 13 0 9 0 Dizziness 12 0.3 10 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 17 0.3 13 0 Interstitial lung disease Interstitial lung disease includes chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), and pneumonitis (n=22). These events were adjudicated as ILD and related to use of ENHERTU 12 0 1 0 Eye Disorders Dry eye 11 0 6 0 Other clinically relevant adverse reactions reported in less than 10% of patients treated with ENHERTU in combination with pertuzumab were: Blood and Lymphatic System Disorders: febrile neutropenia (2.9%) Eye Disorders: blurred vision (4.2%) Gastrointestinal Disorders: abdominal distension (6%), gastritis (3.9%), flatulence (2.4%) General Disorders and Administration Site Conditions: mucosal inflammation (9%) Injury, poisoning, and procedural complications: infusion related reactions (2.6%) Metabolism and Nutrition Disorders: dehydration (2.9%) Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (8%), dyspnea (6%) Skin and Subcutaneous Tissue Disorders: dry skin (7%), skin hyperpigmentation (6%) Table 9: Selected Laboratory Abnormalities in Patients in DESTINY-Breast09 Laboratory Parameter ENHERTU 5.4 mg/kg + Pertuzumab N= 381 THP THP=taxane, trastuzumab, and pertuzumab] N=382 All Grades % Grade 3-4 % All Grades % Grades 3-4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 87 11 82 31 Decreased hemoglobin 80 12 86 6 Decreased neutrophil count 78 29 66 40 Decreased lymphocyte count 62 14 58 11 Decreased platelet count 56 8 20

Chemistry Increased alanine aminotransferase 66 3.2 45 1.9 Increased aspartate aminotransferase 62

2.1 41

Increased blood alkaline phosphatase 55 0.3 36 0.3 Decreased blood potassium 54

20 29 6 Increased blood bilirubin 23 0.3 10

Increased blood creatinine 9 1.8 7 0.3

DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03 . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU and 7 months (range: 0.7 to 25) for patients who received ado-trastuzumab emtansine. Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection.

Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, decreased blood potassium, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis.

Tables 10 and 11 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03. Table 10: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03 Adverse Reactions ENHERTU 5.4 mg/kg N=257 Ado-trastuzumab emtansine 3.6 mg/kg N=261 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 76 7 30

Vomiting 49 1.6 10 0.8 Constipation 34 0 20 0 Diarrhea 29

1.2 7

Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper

abdominal pain. 21 0.8 8

Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral

mucosal eruption. 20 0.8 5 0 Dyspepsia 11 0 6 0 General Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, and lethargy. 49 6 35

Skin and Subcutaneous Tissue Disorders Alopecia

This Grade 3 event was reported by the investigator. Per NCI CTCAE v.5.0, the highest NCI CTCAE grade for alopecia is Grade 2. 37 0.4 3.1 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 31 1.2 25

Metabolism and Nutrition Disorders Decreased appetite 29 1.6 17 0.4 Investigations Decreased

weight 17 1.2 6

Respiratory, Thoracic, and Mediastinal Disorders Respiratory infection Including respiratory tract infection, lower

and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection. 22 0.8 12

Epistaxis 11 0 16 0.4 Cough 11 0.4 10 0 Interstitial lung

disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For ado-trastuzumab emtansine: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism. 11 0.8 1.9 0 Nervous System Disorders Headache Including headache and migraine. 22 0.4 16 0 Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, and paresthesia. 13 0.4 14

Dizziness 13 0.4 8 0 Other clinically relevant adverse reactions reported in

less than 10% of patients in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) Nervous System Disorders: dysgeusia (6%) Metabolism and Nutrition Disorders: dehydration (4.3%) Eye Disorders: blurred vision (3.5%) Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) Blood and Lymphatic System Disorders: febrile neutropenia (0.8%) Table 11: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03 Laboratory Parameter ENHERTU 5.4 mg/kg N=257 Ado-trastuzumab emtansine 3.6 mg/kg N=261 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 74 8 24

Decreased neutrophil count 70 18 30 2.3 Decreased hemoglobin 64 7 38

6 Decreased lymphocyte count 55 14 23

Decreased platelet count 52 7 79 24 Chemistry Increased aspartate aminotransferase 67

0.8 83 5 Increased alanine aminotransferase 53 1.6 67 6 Increased blood alkaline phosphatase 49 0.8 46

Decreased blood potassium 35 4.7 39 1.5 Increased blood bilirubin 20 0

14 0 Increased blood creatinine 16 0.8 8

DESTINY-Breast02

The safety of ENHERTU was evaluated in 404 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast02 . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received ENHERTU. Serious adverse reactions occurred in 26% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were COVID-19, ILD, pneumonia, vomiting, fatigue, and nausea. Fatalities due to adverse reactions occurred in 2.5% of patients including pneumonitis (2 patients), acute myeloid leukemia, brain edema, COVID-19, hemorrhage, hepatitis B, malignant pleural effusion, pneumonia, and vasogenic cerebral edema (one patient each). ENHERTU was permanently discontinued in 20% of patients, of which ILD accounted for 9%. Dose interruptions due to adverse reactions occurred in 45% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, COVID-19, anemia, fatigue, leukopenia, upper respiratory tract infection, and thrombocytopenia.

Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, neutropenia, and vomiting. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, decreased appetite, decreased blood potassium, diarrhea, musculoskeletal pain, increased blood bilirubin, abdominal pain, and headache. Tables 12 and 13 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02. Table 12: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast02 Adverse Reactions ENHERTU 5.4 mg/kg N=404 Treatment of Physician's Choice N=195 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 73 7 37

Vomiting 38 3.7 13 1 Constipation 35 0.3 11 0.5 Diarrhea 27

2.7 54 7 Abdominal pain Including abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain 22 1 20

Dyspepsia 12 0 9 0 Stomatitis Including aphthous ulcer, mouth ulceration, and

stomatitis 12 1 21 1 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, lethargy, and malaise 62 9 37 1 Skin and Subcutaneous Tissue Disorders Alopecia 37 0.3 4.1 0 Metabolism and Nutrition Disorders Decreased appetite 31 1.7 18

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, bone pain

limb discomfort, musculoskeletal chest pain, musculoskeletal pain, muscle spasms, myalgia, neck pain, and pain in extremity 25 0.7 18

Nervous System Disorders Headache Including headache and migraine 20 0.3 6 0

Investigations Decreased weight 18 0.3 3.6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 10 0 Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, idiopathic interstitial pneumonia, lung disorder, pulmonary toxicity, and pneumonia. 10 0.7 0.5

Other clinically relevant adverse reactions reported in less than 10% of patients

in the ENHERTU-treated group were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (8%) and epistaxis (8%) Skin and Subcutaneous Tissue Disorders: rash (8%), pruritus (5%), skin hyperpigmentation (5%) Nervous System Disorders: dizziness (8%) and dysgeusia (8%) Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) Eye Disorders: dry eye (6%) and blurred vision (3%) Metabolism and Nutrition Disorders: dehydration (2.7%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.2%) Blood and Lymphatic System Disorders: febrile neutropenia (0.3%) Table 13: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02 Laboratory Parameter ENHERTU 5.4 mg/kg N=404 Treatment of Physician's Choice N=195 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 70 12 42

Decreased lymphocyte count 58 17 38 4.7 Decreased platelet count 48 2.7

31

Chemistry Increased alanine aminotransferase 43 1 32 1.6 Increased aspartate aminotransferase 37

0.7 29

Increased blood alkaline phosphatase 37 0 17 0 Decreased blood potassium 30

3.7 29 8 Increased blood bilirubin 23 0.3 44

Increased blood creatinine 7 0.3 13 0

DESTINY-Breast01 and Study DS8201-A-J101 The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31). In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%) or 1 (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, decreased blood potassium, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelet count, constipation, decreased appetite, diarrhea, decreased blood potassium, and cough. Tables 14 and 15 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101. Table 14: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101 Adverse Reactions ENHERTU 5.4 mg/kg N=234 All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea 79 7 Vomiting 47

Constipation 35 0.9 Diarrhea 29 1.7 Abdominal pain Including abdominal discomfort, gastrointestinal

pain, abdominal pain, lower abdominal pain, and upper abdominal pain 19

Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral

mucosa blistering. One Grade 1 event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). 14

Dyspepsia 12 0 General Disorders and

Administration Site Conditions Fatigue Including fatigue and asthenia 59 6 Skin and Subcutaneous Tissue Disorders Alopecia 46

This Grade 3 event was reported by the investigator. Per

NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2. Rash Including rash, pustular rash, and maculo-papular rash 10 0 Metabolism and Nutrition Disorders Decreased appetite 32

Respiratory, Thoracic, and Mediastinal Disorders Cough 20 0 Dyspnea 13 1.3 Epistaxis

13 0 Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 9

All events had fatal outcomes (n=6). Nervous System Disorders Headache Including headache

sinus headache, and migraine 19 0 Dizziness 10 0 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, and upper respiratory tract infection 15 0 Eye Disorders Dry eye 11

This Grade 4 event was reported by the investigator. Per

NCI CTCAE v.4.03, the highest NCI CTCAE grade for dry eye is Grade 3. Other clinically relevant adverse reactions reported in less than 10% of patients were: Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%) Blood and Lymphatic System Disorders: febrile neutropenia (1.7%) Table 15: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101 Laboratory Parameter ENHERTU 5.4 mg/kg N=234 All Grades % Grades 3 or 4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 70 7 Decreased hemoglobin 70 7 Decreased neutrophil count 62 16 Decreased platelet count 37

Chemistry Increased aspartate aminotransferase 41 0.9 Increased alanine aminotransferase 38 0.4 Decreased

blood potassium 26 3 HER2-Low and HER2-Ultralow Metastatic Breast Cancer DESTINY-Breast06 The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast06 . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease (ILD)/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients.

The most frequent adverse reactions (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19, and musculoskeletal pain.

Tables 16 and 17 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06. Table 16: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast06 Adverse Reactions ENHERTU 5.4 mg/kg Chemotherapy N=434 N=417 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 70 2.1 30

Diarrhea 34 2.3 27 2.6 Vomiting 34 1.4 12 0.2 Constipation 32

0.7 15

Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal

pain, and gastrointestinal pain. 20 0.5 14

Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal

blistering, and oral mucosal eruption. 15 0 11

Dyspepsia 12 0 4.8 0 General Disorders and

Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, and lethargy. 53 4.4 40

Pyrexia 12 0.2 7 0 Skin and Subcutaneous Tissue Disorders Alopecia 48

0 21

Rash Including dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash

rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 12 0.2 43 8 Metabolism and Nutrition Disorders Decreased appetite 26 1.4 12

Infections and Infestations

COVID-19 Including COVID-19, COVID-19 pneumonia. 26 0.9 13 1 Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis. 19 0 9 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort. 24 0.5 23

Nervous System Disorders Headache Including migraine, headache, and sinus headache. 18 0.5

10 0 Dysgeusia 12 0.2 6 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 16 0 9 0 Interstitial lung disease Including bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity. 11 0.7 0.2 0 Epistaxis 10 0 3.6

Other clinically relevant adverse reactions reported in less than 10% of patients

in the ENHERTU-treated group were: Nervous System Disorders: dizziness (9%) Investigations: decreased weight (7%) Eye Disorders: dry eye (7%), and blurred vision (5%) Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (6%) Gastrointestinal Disorders: abdominal distension (4.8%), flatulence (2.3%), and gastritis (0.7%) Skin and Subcutaneous Tissue Disorders: pruritus (3.9%), and skin hyperpigmentation (0.9%) Metabolism and Nutrition Disorders: dehydration (1.6%) Blood and lymphatic system disorders: febrile neutropenia (1.2%) Injury, Poisoning, and Procedural Complications: infusion related reaction (1.2%) Table 17: Selected Laboratory Abnormalities in Patients in DESTINY-Breast06 Laboratory Parameter ENHERTU 5.4 mg/kg Chemotherapy N=434 N=417 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 86 13 71 11 Decreased neutrophil count 75 27 53 20 Decreased hemoglobin 69 9 58 5 Decreased lymphocyte count 66 19 46 8 Decreased platelet count 48 6 25 1 Chemistry Increased alanine aminotransferase 44 3.2 30

Increased blood alkaline phosphatase 43 0.2 22 0.2 Increased aspartate aminotransferase 41

2.6 27

Decreased blood potassium 35 8 15 2.9 Increased blood bilirubin 16 1.9

23

Increased blood creatinine 10 1.9 8 1

DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg in DESTINY-Breast04 . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia.

Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea, and decreased blood potassium. Tables 18 and 19 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04. Table 18: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients Treated with ENHERTU in DESTINY-Breast04 Adverse Reactions ENHERTU 5.4 mg/kg Chemotherapy N=371 N=172 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 76 4.6 30 0 Vomiting 40 1.6 13 0 Constipation 34 0.8 22 0 Diarrhea 27 1.3 22

Abdominal pain Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper

abdominal pain 18 0.5 13 0 Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation 13 0.3 12

General Disorders and

Administration Site Conditions Fatigue Including fatigue, asthenia, and malaise 54 9 48

Pyrexia 12 0.3 13 0 Skin and Subcutaneous Tissue Disorders Alopecia 40

0 33 0 Rash Including rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous 13 0 23

Metabolism and Nutrition Disorders Decreased appetite 32 2.4 19 1.2 Musculoskeletal and

Connective Tissue Disorders Musculoskeletal pain Including back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain 32 1.3 31

Investigations Decreased weight 16 0.3 8 0 Vascular Disorders Hemorrhage Including esophageal

varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage 16 0 3.5 0 Nervous System Disorders Headache Including headache and migraine 15 0.3 6 0 Peripheral neuropathy Including peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia 13 0 29 5 Dizziness Including dizziness, postural dizziness, and vertigo 11 0.5 6 0 Infections and Infestations Upper respiratory tract infection Including upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis 14 0.3 5 0 Respiratory, Thoracic and Mediastinal Disorders Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis. 12 1.3 0.6 0 Dyspnea 10 1.3 9

Other clinically relevant adverse reactions reported in less than 10% of patients

treated with ENHERTU: Nervous System Disorders: dysgeusia (10%) Respiratory, Thoracic and Mediastinal Disorders: cough (10%) Gastrointestinal Disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%) Eye Disorders: blurred vision (4.9%) Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) Metabolism and Nutrition Disorders: dehydration (1.9%) Blood and Lymphatic System Disorders: febrile neutropenia (1.1%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (0.5%) Table 19: Selected Laboratory Abnormalities in Patients in DESTINY-Breast04 Laboratory Parameter ENHERTU 5.4 mg/kg Chemotherapy N=371 N=172 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. Hematology Decreased white blood cell count 70 9 78 25 Decreased hemoglobin 64 8 53 6 Decreased neutrophil count 64 14 73 38 Decreased lymphocyte count 55 18 40 11 Decreased platelet count 44 6 21

Chemistry Increased aspartate aminotransferase 38 2.2 38 4.1 Increased alanine aminotransferase 36

0.8 38

Increased blood alkaline phosphatase 34 0.3 24 0 Decreased blood potassium 25

3.3 17

Increased blood bilirubin 16 2.7 15 0.6 Increased blood creatinine 15 1.1

9

HER2-Mutant Unresectable or Metastatic

NSCLC DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg and 6.4 mg/kg ); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients in DESTINY-Lung02 . Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. The median duration of treatment was 8 months (range: 0.7 to 28) for patients who received ENHERTU. The median age was 59 years (range 31 to 84); 64% were female; 23% were White, 64% were Asian, and 14% were other races.

Serious adverse reactions occurred in 40% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pleural effusion, thrombocytopenia, dyspnea, nausea, pneumonia, vomiting, myocarditis, pulmonary embolism, and increased troponin I. Fatalities due to adverse reactions occurred in 3% of patients including ILD/pneumonitis, cerebrovascular accident, and pneumococcal sepsis (one patient each). ENHERTU was permanently discontinued due to an adverse reaction in 17% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, pneumonia, blood bilirubin increased, hypokalemia, metastases to meninges, and myocarditis. Dose interruptions of ENHERTU due to adverse reactions occurred in 50% of patients.

Adverse reactions which required dose interruption (>2%) included neutropenia, COVID-19, ILD/pneumonitis, fatigue, anemia, and pneumonia. Dose reductions due to an adverse reaction occurred in 20% of patients. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, fatigue, and decreased appetite.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, nausea, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, increased aspartate aminotransferase, decreased albumin, decreased platelet count, fatigue, increased alanine aminotransferase, decreased appetite, constipation, increased alkaline phosphatase, vomiting, decreased blood potassium, diarrhea, alopecia, and musculoskeletal pain. Tables 20 and 21 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02. Table 20: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02 Adverse Reactions ENHERTU 5.4 mg/kg N=101 All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 5.0. Gastrointestinal Disorders Nausea 67 4 Constipation 38 1 Vomiting Including vomiting and retching 32 3 Diarrhea 24 1 Stomatitis Including mucosal inflammation, stomatitis, and mouth ulceration 17 0 Abdominal pain Including abdominal discomfort, abdominal pain, and upper abdominal pain 10 0 General Disorders and Administration Site Conditions Fatigue Including asthenia, fatigue, and malaise 48 8 Metabolism and Nutrition Disorders Decreased appetite 41 2 Skin and Subcutaneous Tissue Disorders Alopecia 22 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, bone pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity 21 1 Respiratory, Thoracic, and Mediastinal Disorders Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure 15 1 Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, and laryngitis 12 0 Other clinically relevant adverse reactions reported in less than 10% of patients were: Respiratory, Thoracic, and Mediastinal Disorders: dyspnea (7%), and epistaxis (5%) Nervous System Disorders: headache (7%) Skin and Subcutaneous Disorders: rash (6%) Table 21: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02 Laboratory Parameter ENHERTU 5.4 mg/kg N=101 Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All Grades Frequencies were based on NCI CTCAE v.5.0 grade-derived laboratory abnormalities. % Grades 3 or 4 % Hematology The denominator used to calculate the rate varied from 100 to 101 based on the number of patients with a baseline value and at least one post-treatment value.

Decreased hemoglobin 68 12 Decreased white blood cell count 66 7 Decreased neutrophil count 59 19 Decreased lymphocyte count 56 26 Decreased platelet count 49 5 Chemistry Increased aspartate aminotransferase 51 1 Decreased albumin 50 0 Increased alanine aminotransferase 41 2 Increased alkaline phosphatase 37 0 Decreased blood potassium 29 5 HER2-Positive Locally Advanced or Metastatic Gastric Cancer The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 . Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m 2 biweekly or paclitaxel (N=7) 80 mg/m 2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg.

Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%). ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased blood potassium, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01. Table 22: Adverse Reactions in ≥10% All Grades or ≥2% Grades 3 or 4 of Patients Receiving ENHERTU in DESTINY-Gastric01 ENHERTU 6.4 mg/kg N=125 Irinotecan or Paclitaxel N=62 Adverse Reactions All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Events were graded using NCI CTCAE version 4.03. Gastrointestinal Disorders Nausea 63 4.8 47

Diarrhea 32 2.4 32 1.6 Vomiting 26 0 8 0 Constipation 24

0 23 0 Abdominal pain Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain 14 0.8 15

Stomatitis Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral

mucosal blistering 11 1.6 4.8 0 Metabolism and Nutrition Disorders Decreased appetite 60 17 45 13 Dehydration 6 2.4 3.2

Blood and Lymphatic System Disorders Febrile neutropenia 4.8 4.8 3.2 3.2 General

Disorders and Administration Site Conditions Fatigue Including fatigue, asthenia, and malaise 55 9 44

Pyrexia 24 0 16 0 Peripheral edema 10 0 0 0 Skin

and Subcutaneous Tissue Disorders Alopecia 22 0 15 0 Respiratory, Thoracic and Mediastinal Disorders Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. 10 2.4 0 0 Hepatobiliary Disorders Abnormal hepatic function 8 3.2 1.6

Other clinically relevant adverse reactions reported in less than 10% of patients

were: Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) Infections and Infestations: pneumonia (6%) Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%) Table 23: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01 Laboratory Parameter ENHERTU 6.4 mg/kg N=125 Irinotecan or Paclitaxel N=62 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI CTCAE v.4.03 grade-derived laboratory abnormalities. Hematology Decreased hemoglobin 75 38 55 23 Decreased white blood cell count 74 29 53 13 Decreased neutrophil count 72 51 45 23 Decreased lymphocyte count 70 28 53 12 Decreased platelet count 68 12 12 5 Chemistry Increased aspartate aminotransferase 58 9 32 8 Increased blood alkaline phosphatase 54 8 34 10 Increased alanine aminotransferase 47 9 17

Decreased blood potassium 30 4.8 18 8 Increased blood bilirubin 24 7

5

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 . ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 8.3 months (range 0.7 to 30.2). The median age was 60 years (range 23 to 96); 74% were female; 51% were White, 42% were Asian, 2.9% were Black or African American, 3.5% were of Hispanic or Latino ethnicity; and 51% had an ECOG performance status 0 and 48% had an ECOG performance status of 1. Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. Tables 24 and 25 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02. Table 24: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 Adverse Reactions ENHERTU 5.4 mg/kg N= 347 All Grades % Grade 3 or 4 % Gastrointestinal Disorders Nausea 69 7 Vomiting 35

Diarrhea 31 4.3 Constipation 28 0.6 Stomatitis Including stomatitis, mucosal inflammation, aphthous

ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis. 20

Abdominal pain Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal

pain, gastrointestinal pain. 18 2 Dyspepsia 12

General Disorders and

Administration Site Conditions Fatigue Including fatigue, asthenia, malaise, lethargy. 59 10 Pyrexia 11 0 Edema Including peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema 11

Metabolism and Nutrition Disorders Decreased appetite 34 2.6 Skin and Subcutaneous Tissue

Disorders Alopecia 34

Rash Including rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic

rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome. 13

Infections and Infestations Upper respiratory tract infection Including influenza, influenza-like illness, upper

respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis. 20 0 Pneumonia 6

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Including back pain, myalgia, pain

in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort. 19

Respiratory, Thoracic and Mediastinal Disorders Cough Including cough, productive cough, upper-airway cough

syndrome 18 0 Interstitial lung disease Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, ILD, organizing pneumonia, respiratory failure, acute respiratory failure, alveolitis, lung opacity, lymphangitis, pneumonia, bacterial pneumonia, pulmonary fibrosis, and radiation pneumonitis. Grade 5 adjudicated drug-induced ILD events were pneumonitis, respiratory failure, acute respiratory failure, lymphangitis, pulmonary fibrosis. 16

Dyspnea Including dyspnea, exertional dyspnea 12 1.7 Nervous System Disorders Headache Including

migraine, headache, sinus headache. 15 0 Investigations Decreased weight 10

Other clinically relevant adverse reactions reported in less than 10% of patients

were: Respiratory, Thoracic, and Mediastinal Disorders: epistaxis (9%) Nervous System Disorders: dizziness (9%) and dysgeusia (6%) Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) Eye Disorders : blurred vision (4%) Metabolism and Nutrition Disorders : dehydration (3.2%) Gastrointestinal Disorders: abdominal distension (2.6%), flatulence (1.7%) and gastritis (0.9%) Blood and Lymphatic System Disorders: febrile neutropenia (1.7%) Injury, Poisoning, and Procedural Complications : infusion-related reactions (1.4%) Table 25: Selected Laboratory Abnormalities in HER2-positive (IHC 3+) Patients Treated with ENHERTU in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 Laboratory Parameter ENHERTU 5.4 mg/kg N= 347 Percentages were calculated using the number of patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. All Grades % Grades 3 or 4 % Hematology Decreased white blood cell count 75 11 Decreased hemoglobin 67 10 Decreased neutrophil count 66 21 Decreased lymphocyte count 58 21 Decreased platelet count 51 7 Chemistry Increased aspartate aminotransferase 45

Increased alanine aminotransferase 44 1.5 Increased blood alkaline phosphatase 36 1.2 Decreased

blood potassium 29 6 Decreased sodium 22

Pregnancy Risk Summary Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death ( see Data ). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells . Advise patients of the potential risks to a fetus.

There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU ( see Clinical Considerations ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ENHERTU during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data There are no available data on the use of ENHERTU in pregnant women.

In postmarketing reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received a HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped.

Animal Data There were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.

Pediatric Use Safety and effectiveness of ENHERTU have not been established in pediatric patients. Animal Data Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki. In a six-week repeat-dose toxicity study in rats, intravenous administration of fam-trastuzumab deruxtecan-nxki resulted in incisor tooth toxicity including single cell necrosis in the base area (e.g., ameloblasts, odontoblasts) and degeneration of the enamel at ≥60 mg/kg (approximately ≥9 times the human recommended dose of 5.4 mg/kg based on AUC), abnormal formation or hypoplasia of the dentin, hemorrhage in the sub-enamel organ tissue, and focal lack of the cementum at 197 mg/kg (approximately 19 times the human recommended dose of 5.4 mg/kg based on AUC). Degeneration of the enamel organ, abnormal dentin formation, hemorrhage in the sub-enamel organ tissue, focal lack of the cementum, and root fracture were observed at 197 mg/kg following a 9-week recovery period.