6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
Neutropenia [see Warnings and Precautions (5.2)]
Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]

6.1 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 Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

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 38% 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 (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%).

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 Metastatic Breast Cancer

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 [see Clinical Studies (14.1)]. 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 3 and 4 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03.

Table 3: 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
Adverse Reactions	All Grades %	Grades 3-4 %	All Grades %	Grades 3-4 %
Events were graded using NCI CTCAE version 5.0.
* Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain † Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption ‡ Including fatigue, asthenia, malaise, and lethargy § 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. ¶ Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort # 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 Þ 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. ß Including headache and migraine à Including peripheral neuropathy, peripheral sensory neuropathy, and paresthesia
Gastrointestinal Disorders
Nausea	76	7	30	0.4
Vomiting	49	1.6	10	0.8
Constipation	34	0	20	0
Diarrhea	29	1.2	7	0.4
Abdominal pain*	21	0.8	8	0.4
Stomatitis†	20	0.8	5	0
Dyspepsia	11	0	6	0
General Disorders and Administration Site Conditions
Fatigue‡	49	6	35	0.8
Skin and Subcutaneous Tissue Disorders
Alopecia§	37	0.4	3.1	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain¶	31	1.2	25	0.4
Metabolism and Nutrition Disorders
Decreased appetite	29	1.6	17	0.4
Investigations
Decreased weight	17	1.2	6	0.4
Respiratory, Thoracic, and Mediastinal Disorders
Respiratory infection#	22	0.8	12	1.1
Epistaxis	11	0	16	0.4
Cough	11	0.4	10	0
Interstitial lung diseaseÞ	11	0.8	1.9	0
Nervous System Disorders
Headacheß	22	0.4	16	0
Peripheral neuropathyà	13	0.4	14	0.4
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%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]
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%) [see Warnings and Precautions (5.3)]
Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.3%) [including hypersensitivity and infusion-related reactions]
Blood and Lymphatic System Disorders: febrile neutropenia (0.8%)

Table 4: 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
Laboratory Parameter	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	0.8
Decreased neutrophil count	70	18	30	2.3
Decreased hemoglobin	64	7	38	6
Decreased lymphocyte count	55	14	23	3.9
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	0.8
Decreased blood potassium	35	4.7	39	1.5
Increased blood bilirubin	20	0	14	0
Increased blood creatinine	16	0.8	8	0.4

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 [see Clinical Studies (14.1)]. 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 5 and 6 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02.

Table 5: 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
Adverse Reactions	All Grades %	Grades 3-4 %	All Grades %	Grades 3-4 %
Events were graded using NCI CTCAE version 5.0.
* Including abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain, and gastrointestinal pain † Including aphthous ulcer, mouth ulceration, and stomatitis ‡ Including asthenia, fatigue, lethargy, and malaise § Including back pain, bone pain, limb discomfort, musculoskeletal chest pain, musculoskeletal pain, muscle spasms, myalgia, neck pain, and pain in extremity ¶ Including headache and migraine # 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.
Gastrointestinal Disorders
Nausea	73	7	37	2.6
Vomiting	38	3.7	13	1
Constipation	35	0.3	11	0.5
Diarrhea	27	2.7	54	7
Abdominal pain*	22	1	20	2.1
Dyspepsia	12	0	9	0
Stomatitis†	12	1	21	1
General Disorders and Administration Site Conditions
Fatigue‡	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	0.5
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain§	25	0.7	18	0.5
Nervous System Disorders
Headache¶	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#	10	0.7	0.5	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%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritus (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder]
Nervous System Disorders: dizziness (8%) and dysgeusia (8%)
Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Warnings and Precautions (5.3)]
Eye Disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (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 6: Selected Laboratory Abnormalities in Patients in DESTINY-Breast02
Laboratory Parameter	ENHERTU 5.4 mg/kg N=404		Treatment of Physician's Choice N=195
Laboratory Parameter	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	3.2
Decreased hemoglobin	67	9	54	3.2
Decreased neutrophil count	64	16	34	4.7
Decreased lymphocyte count	58	17	38	4.7
Decreased platelet count	48	2.7	31	1.6
Chemistry
Increased alanine aminotransferase	43	1	32	1.6
Increased aspartate aminotransferase	37	0.7	29	2.1
Increased blood alkaline phosphatase	37	0	17	0
Decreased blood potassium	30	3.7	29	8
Increased blood bilirubin	23	0.3	44	2.1
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) [see Clinical Studies (14.1)]. 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 7 and 8 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients in DESTINY-Breast01 and Study DS8201-A-J101.

Table 7: 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
Adverse Reactions	All Grades %	Grades 3 or 4 %
Events were graded using NCI CTCAE version 4.03.
* Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain † 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). ‡ Including fatigue and asthenia § 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. ¶ Including rash, pustular rash, and maculo-papular rash # 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. Þ All events had fatal outcomes (n=6). ß Including headache, sinus headache, and migraine à Including influenza, influenza-like illness, and upper respiratory tract infection è 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.
Gastrointestinal Disorders
Nausea	79	7
Vomiting	47	3.8
Constipation	35	0.9
Diarrhea	29	1.7
Abdominal pain*	19	1.3
Stomatitis†	14	0.9
Dyspepsia	12	0
General Disorders and Administration Site Conditions
Fatigue‡	59	6
Skin and Subcutaneous Tissue Disorders
Alopecia	46	0.4§
Rash¶	10	0
Metabolism and Nutrition Disorders
Decreased appetite	32	1.3
Respiratory, Thoracic, and Mediastinal Disorders
Cough	20	0
Dyspnea	13	1.3
Epistaxis	13	0
Interstitial lung disease#	9	2.6Þ
Nervous System Disorders
Headacheß	19	0
Dizziness	10	0
Infections and Infestations
Upper respiratory tract infectionà	15	0
Eye Disorders
Dry eye	11	0.4è

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 8: 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
Laboratory Parameter	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	3.4
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 [see Clinical Studies (14.2)]. 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 9 and 10 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast06.

Table 9: 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.
* Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain † Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption ‡ Including fatigue, asthenia, malaise, and lethargy § Including dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular ¶ Including COVID-19, COVID-19 pneumonia # Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis Þ Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort ß Including migraine, headache, and sinus headache à Including bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity
Gastrointestinal Disorders
Nausea	70	2.1	30	0.5
Diarrhea	34	2.3	27	2.6
Vomiting	34	1.4	12	0.2
Constipation	32	0.7	15	0.5
Abdominal pain*	20	0.5	14	0.2
Stomatitis†	15	0	11	0.5
Dyspepsia	12	0	4.8	0
General Disorders and Administration Site Conditions
Fatigue‡	53	4.4	40	2.4
Pyrexia	12	0.2	7	0
Skin and Subcutaneous Tissue Disorders
Alopecia	48	0	21	0.5
Rash§	12	0.2	43	8
Metabolism and Nutrition Disorders
Decreased appetite	26	1.4	12	0.5
Infections and Infestations
COVID-19¶	26	0.9	13	1
Upper respiratory tract infection#	19	0	9	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painÞ	24	0.5	23	1.9
Nervous System Disorders
Headacheß	18	0.5	10	0
Dysgeusia	12	0.2	6	0
Respiratory, Thoracic, and Mediastinal Disorders
Cough	16	0	9	0
Interstitial lung diseaseà	11	0.7	0.2	0
Epistaxis	10	0	3.6	0.2

Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:

Nervous System Disorders: dizziness (9%)
General Disorders and Administration Site Conditions: peripheral edema (8%)
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%)
Infections and Infestations: pneumonia (4.6%)
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 10: 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	0.7
Increased blood alkaline phosphatase	43	0.2	22	0.2
Increased aspartate aminotransferase	41	2.6	27	1.2
Decreased blood potassium	35	8	15	2.9
Increased blood bilirubin	16	1.9	23	1.5
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 [see Clinical Studies (14.2)]. 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 11 and 12 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast04.

Table 11: 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.
* Including abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain † Including stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation ‡ Including fatigue, asthenia, and malaise § 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 ¶ 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 # 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 Þ Including headache and migraine ß Including peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia à Including dizziness, postural dizziness, and vertigo è Including upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis ð Interstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis.
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	1.7
Abdominal pain*	18	0.5	13	0
Stomatitis†	13	0.3	12	0.6
General Disorders and Administration Site Conditions
Fatigue‡	54	9	48	4.7
Pyrexia	12	0.3	13	0
Skin and Subcutaneous Tissue Disorders
Alopecia	40	0	33	0
Rash§	13	0	23	4.7
Metabolism and Nutrition Disorders
Decreased appetite	32	2.4	19	1.2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain¶	32	1.3	31	0.6
Investigations
Decreased weight	16	0.3	8	0
Vascular Disorders
Hemorrhage#	16	0	3.5	0
Nervous System Disorders
HeadacheÞ	15	0.3	6	0
Peripheral neuropathyß	13	0	29	5
Dizzinessà	11	0.5	6	0
Infections and Infestations
Upper respiratory tract infectionè	14	0.3	5	0
Respiratory, Thoracic and Mediastinal Disorders
Interstitial lung diseaseð	12	1.3	0.6	0
Dyspnea	10	1.3	9	1.2

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%) [including blurred vision and visual impairment]
Skin and Subcutaneous Tissue Disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) [including skin hyperpigmentation, skin discoloration, and pigmentation disorder]
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%) [including injection-site reaction and chills]

Table 12: 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	0.6
Chemistry
Increased aspartate aminotransferase	38	2.2	38	4.1
Increased alanine aminotransferase	36	0.8	38	4.1
Increased blood alkaline phosphatase	34	0.3	24	0
Decreased blood potassium	25	3.3	17	1.2
Increased blood bilirubin	16	2.7	15	0.6
Increased blood creatinine	15	1.1	9	0.6

HER2-Mutant Unresectable or Metastatic NSCLC

DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); 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 [see Clinical Studies (14.3)]. Patients received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. Nineteen percent of patients were exposed for greater than 6 months. The median age was 59 years (range 30 to 83); 64% were female; 23% were White, 64% were Asian, and 14% were other races.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued due to an adverse reaction in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting.

Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis.

Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.

Tables 13 and 14 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Lung02.

Table 13: 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
Adverse Reactions	All Grades %	Grades 3 or 4 %
Events were graded using NCI CTCAE version 5.0.
* Including vomiting and retching † Including mucosal inflammation and stomatitis ‡ Including asthenia, fatigue, and malaise § Including back pain, musculoskeletal stiffness, musculoskeletal chest pain, arthralgia, musculoskeletal pain, myalgia, and pain in extremity
Gastrointestinal Disorders
Nausea	61	3
Constipation	31	1
Vomiting*	26	2
Diarrhea	19	1
Stomatitis†	12	0
General Disorders and Administration Site Conditions
Fatigue‡	32	4
Metabolism and Nutrition Disorders
Decreased appetite	30	1
Skin and Subcutaneous Tissue Disorders
Alopecia	21	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain§	15	1

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

Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease (6%) [including interstitial lung disease that was adjudicated as drug-induced ILD including pneumonitis, interstitial lung disease, pulmonary toxicity, and respiratory failure], dyspnea (5%), and epistaxis (3%)
Gastrointestinal Disorders: abdominal pain (9%) [including abdominal discomfort, abdominal pain, and upper abdominal pain]
Skin and Subcutaneous Disorders: rash (3%) [including rash and maculo-papular rash]
Infections and Infestations: upper respiratory tract infection (4%) [including upper respiratory tract infection, pharyngitis, and laryngitis]
Nervous System Disorders: headache (4%) [including headache and migraine]

Table 14: Select Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-Mutant NSCLC in DESTINY-Lung02
Laboratory Parameter	ENHERTU 5.4 mg/kg N=101*
Laboratory Parameter	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. ‡ The denominator used to calculate the rate varied from 98 to 99 based on the number of patients with a baseline value and at least one post-treatment value.
Hematology‡
Decreased white blood cell count	60	4
Decreased hemoglobin	58	10
Decreased neutrophil count	52	12
Decreased lymphocyte count	43	16
Decreased platelet count	40	4
Chemistry
Decreased albumin	39	0
Increased aspartate aminotransferase	35	1
Increased alanine aminotransferase	34	2
Increased alkaline phosphatase	22	0
Decreased blood potassium	17	2

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 [see Clinical Studies (14.4)]. 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/m2 biweekly or paclitaxel (N=7) 80 mg/m2 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 15 and 16 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.

Table 15: 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.
	* Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain † Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering ‡ Including fatigue, asthenia, and malaise § 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.
Gastrointestinal Disorders
Nausea	63	4.8	47	1.6
Diarrhea	32	2.4	32	1.6
Vomiting	26	0	8	0
Constipation	24	0	23	0
Abdominal pain*	14	0.8	15	3.2
Stomatitis†	11	1.6	4.8	0
Metabolism and Nutrition Disorders
Decreased appetite	60	17	45	13
Dehydration	6	2.4	3.2	1.6
Blood and Lymphatic System Disorders
Febrile neutropenia	4.8	4.8	3.2	3.2
General Disorders and Administration Site Conditions
Fatigue‡	55	9	44	4.8
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§	10	2.4	0	0
Hepatobiliary Disorders
Abnormal hepatic function	8	3.2	1.6	1.6

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

Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)]
Infections and Infestations: pneumonia (6%)
Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%)

Table 16: 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
Laboratory Parameter	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	1.7
Decreased blood potassium	30	4.8	18	8
Increased blood bilirubin	24	7	5	3.4

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 [see Clinical Studies (14.1 and 14.5)]. 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 40% had an ECOG performance status 0 and 41% 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 17 and 18 summarize the common adverse reactions and laboratory abnormalities in DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-Breast01, and DESTINY-CRC02.

Table 17: 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
Adverse Reactions	All Grades %	Grade 3 or 4 %
* Including stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis. † Including abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain. ‡ Including fatigue, asthenia, malaise, lethargy. § Including peripheral edema, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema ¶ Including rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash dermatitis acneiform, dermatitis, eczema, palmar-plantar erythrodysesthesia syndrome. # Including influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis. Þ Including back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort. ß Including cough, productive cough, upper-airway cough syndrome à 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. è Including dyspnea, exertional dyspnea ð Including migraine, headache, sinus headache.
Gastrointestinal Disorders
Nausea	69	7
Vomiting	35	3.5
Diarrhea	31	4.3
Constipation	28	0.6
Stomatitis*	20	0.9
Abdominal pain†	18	2
Dyspepsia	12	0.3
General Disorders and Administration Site Conditions
Fatigue‡	59	10
Pyrexia	11	0
Edema§	11	0.6
Metabolism and Nutrition Disorders
Decreased appetite	34	2.6
Skin and Subcutaneous Tissue Disorders
Alopecia	34	0.3
Rash¶	13	0.6
Infections and Infestations
Upper respiratory tract infection#	20	0
Pneumonia	6	2.3
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painÞ	19	0.3
Respiratory, Thoracic and Mediastinal Disorders
Coughß	18	0
Interstitial lung diseaseà	16	0.6
Dyspneaè	12	1.7
Nervous System Disorders
Headacheð	15	0
Investigations
Decreased weight	10	0.3

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%) [including dizziness, postural dizziness, and vertigo] and dysgeusia (6%)
Skin and Subcutaneous Disorders: pruritus (5%) and skin hyperpigmentation (4.3%) [including skin hyperpigmentation, skin discoloration, pigmentation disorder]
Eye Disorders: blurred vision (4%) [including blurred vision, visual impairment]
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%) [including administration related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction]

Table 18: 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*
	All Grades %	Grades 3 or 4 %
* 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.
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	1.5
Increased alanine aminotransferase	44	1.5
Increased blood alkaline phosphatase	36	1.2
Decreased blood potassium	29	6
Decreased sodium	22	2.9
Increased blood bilirubin	15	0.6
Increased blood creatinine	14	0.6