Safety Data

ENHERTU has serious Warnings and Precautions. Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

Safety data from DESTINY-Breast03 confirmed the benefit-risk profile of ENHERTU for HER2+ mBC (5.4 mg/kg) demonstrated in prior studies^1,a

The majority of adverse reactions were Grade 1 or 2

Median duration of treatment was 14 months (range: 0.7 to 30) with ENHERTU and 7 months (range: 0.7 to 25) with T-DM1¹
Prophylactic or supportive treatment of ENHERTU or T-DM1–induced adverse reactions was at the discretion of the treating physician and institutional guidelines²

Common adverse reactions (≥10% All Grades or ≥2% Grades 3-4) in patients treated with ENHERTU in DESTINY-Breast03¹

Adverse reactions		ENHERTU 5.4 mg/kg (n=257)		T-DM1 3.6 mg/kg (n=261)
Adverse reactions		All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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^b	21	0.8	8	0.4
	Stomatitis^c	20	0.8	5	0
	Dyspepsia	11	0	6	0
General disorders and administration site conditions	Fatigue^d	49	6	35	0.8
Blood and lymphatic system disorders	Anemia^e	33	7	17	6
Skin and subcutaneous tissue disorders	Alopecia^f	37	0.4	3.1	0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain^g	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^h	22	0.8	12	1.1
	Epistaxis	11	0	16	0.4
	Cough	11	0.4	10	0
	Interstitial lung diseaseⁱ	11	0.8	1.9	0
Nervous system disorders	Headache^j	22	0.4	16	0
	Peripheral neuropathy^k	13	0.4	14	0.4
	Dizziness	13	0.4	8	0

Adverse reactions	ENHERTU 5.4 mg/kg (n=257)		T-DM1 3.6 mg/kg (n=261)
Adverse reactions	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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^b	21	0.8	8	0.4
Stomatitis^c	20	0.8	5	0
Dyspepsia	11	0	6	0
General disorders and administration site conditions
Fatigue^d	49	6	35	0.8
Blood and lymphatic system disorders
Anemia^e	33	7	17	0.4
Skin and subcutaneous tissue disorders
Alopecia^f	37	0.4	3.1	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain^g	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^h	22	0.8	12	1.1
Epistaxis	11	0	16	0.4
Cough	11	0.4	10	0
Interstitial lung diseaseⁱ	11	0.8	1.9	0
Nervous system disorders
Headache^j	22	0.4	16	0
Peripheral neuropathy^k	13	0.4	14	0.4
Dizziness	13	0.4	8	0

Events were graded using NCI-CTCAE v.5.0.

^aPrior ENHERTU HER2+ mBC studies: Phase 2 DESTINY-Breast01 and Phase 1 DS8201-A-J101.

^bGrouped term of abdominal pain includes PTs of abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain.

^cGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption.

^dGrouped term of fatigue includes PTs of fatigue, asthenia, malaise, and lethargy.

^eGrouped term of anemia includes PTs of anemia, decreased hemoglobin, and decreased red blood cell count.

^fThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.5.0, the highest NCI-CTCAE grade for alopecia is Grade 2.

^gGrouped term of musculoskeletal pain includes PTs of back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort.

^hGrouped term of respiratory infection includes PTs of respiratory tract infection, lower and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection.

ⁱInterstitial lung disease includes events that were adjudicated as ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For T-DM1: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism.

^jGrouped term of headache includes PTs of headache and migraine.

^kGrouped term of peripheral neuropathy includes PTs of peripheral neuropathy, peripheral sensory neuropathy, and paresthesia.

Selected laboratory abnormalities in patients in DESTINY-Breast03¹

Laboratory parameter		ENHERTU 5.4 mg/kg (n=257)		T-DM1 3.6 mg/kg (n=261)
Laboratory parameter		All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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
Hypokalemia		35	4.7	39	1.5
Increased blood bilirubin		20	0	14	0
Increased blood creatinine		16	0.8	8	0.4

Laboratory parameter	ENHERTU 5.4 mg/kg (n=257)		T-DM1 3.6 mg/kg (n=261)
Laboratory parameter	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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
Hypokalemia	35	4.7	39	1.5
Increased blood bilirubin	20	0	14	0
Increased blood creatinine	16	0.8	8	0.4

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.

	ENHERTU 5.4 mg/kg (n=257)	T-DM1 3.6 mg/kg (n=261)
Serious adverse reactions^l	19.1%	18.0%	For ENHERTU, serious ARs in >1% of patients were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to sudden death) For T-DM1, serious ARs in >1% of patients were pneumonia, anemia, and thrombocytopenia. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to acute kidney injury)
Discontinuations due to adverse reactions	14%	7%	For ENHERTU, most frequent (>2%) was ILD/pneumonitis^m (8%). Permanently discontinue ENHERTU in patients who are diagnosed with any symptomatic ILD (Grade ≥2) For T-DM1, most frequent (>2%) was thrombocytopenia
Dose interruptions due to adverse reactions	44%	23%	For ENHERTU, most frequent (>2%) were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis^m For T-DM1, most frequent (>2%) were anemiaⁿ and thrombocytopenia^o
Dose reductions due to adverse reactions	21%	13%	For ENHERTU, most frequent (>2%) were nausea, neutropenia, and fatigue For T-DM1, most frequent (>2%) were thrombocytopenia,^o ALT increased, and AST increased

ENHERTU 5.4 mg/kg (n=257)	T-DM1 3.6 mg/kg (n=261)
Serious adverse reactions^l
19.1%	18.0%
For ENHERTU, serious ARs in >1% of patients were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to sudden death) For T-DM1, serious ARs in >1% of patients were pneumonia, anemia, and thrombocytopenia. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to acute kidney injury)
Discontinuations due to adverse reactions
14%	7%
For ENHERTU, most frequent (>2%) was ILD/pneumonitis^m (8%). Permanently discontinue ENHERTU in patients who are diagnosed with any symptomatic ILD (Grade ≥2) For T-DM1, most frequent (>2%) was thrombocytopenia
Dose interruptions due to adverse reactions
44%	23%
For ENHERTU, most frequent (>2%) were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis^m For T-DM1, most frequent (>2%) were anemiaⁿ and thrombocytopenia^o
Dose reductions due to adverse reactions
21%	13%
For ENHERTU, most frequent (>2%) were nausea, neutropenia, and fatigue For T-DM1, most frequent (>2%) were thrombocytopenia,^o ALT increased, and AST increased

Other clinically relevant adverse reactions reported in <10% of patients receiving ENHERTU were dyspnea (8%), pruritus (8%), skin hyperpigmentation (6%),^p dysgeusia (6%), dehydration (4.3%), blurred vision (3.5%), asymptomatic left ventricular ejection fraction decrease (2.7%), infusion-related reactions (2.3%),^q and febrile neutropenia (0.8%)

^lAn adverse reaction was defined as either an AE that was absent before the first dose of study drug, an AE that worsened between the first dose and 47 days after the last dose, or an SAE that occurred ≥48 days after the last dose and was considered related to treatment.

^mILD includes events that were adjudicated as ILD and related to use of ENHERTU. Cases of potential ILD/pneumonitis were based on the current MedDRA v23.0 for the narrow ILD SMQ, selected terms from the broad ILD SMQ, and PTs of respiratory failure and acute respiratory failure.

ⁿGrouped term of anemia includes PTs of hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.

^oGrouped term of thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.

^pGrouped term includes PTs of skin hyperpigmentation, skin discoloration, and pigmentation disorder.

^qGrouped term includes PTs of hypersensitivity and infusion-related reactions.

Incidence of select common adverse reactions in DESTINY-Breast03

The majority of these adverse reactions were Grade 1 or 2^2,3

Adverse reactions	ENHERTU 5.4 mg/kg (n=257)
Adverse reactions	Grade 1 (%)	Grade 2 (%)	Grade 3 (%)	Grade 4 (%)
Nausea	41.6	27.6	6.6	0
Fatigue	29.2	14.0	5.8	0
Alopecia^r	26.5	9.3	0.4	0
Vomiting	31.1	16.3	1.2	0.4
Constipation	26.5	7.8	0	0
Decreased appetite	19.5	8.2	1.6	0
Diarrhea	19.8	8.2	1.2	0

^rThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.5.0, the highest NCI-CTCAE grade for alopecia is Grade 2.¹

Prophylactic or supportive treatment of ENHERTU or T-DM1–induced adverse reactions was at the discretion of the treating physician and institutional guidelines²
Premedication: ENHERTU is moderately emetogenic, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting¹
NCCN Guidelines^® for Antiemesis lists fam-trastuzumab deruxtecan-nxki (ENHERTU) as moderate emetic risk and recommends several prophylactic antiemetic regimens to help decrease potential vomiting⁴

Management of select common adverse reactions

Premedication: ENHERTU is moderately emetogenic, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting¹
NCCN Guidelines^® for Antiemesis lists fam-trastuzumab deruxtecan-nxki (ENHERTU) as moderate emetic risk and recommends several prophylactic antiemetic regimens to help decrease potential vomiting⁴

NCCN prophylactic and management strategies for acute and delayed emesis prevention: Moderate emetic risk parenteral anticancer agents^4,s-u

	Select treatment option D, E, or F	Days 2 and 3
	All treatment options are Category 1 and should be started before anticancer therapy^v
Day 1 before infusion of fam-trastuzumab deruxtecan-nxki (ENHERTU)	Treatment option D, use the following combination: 5-HT3 RA Dexamethasone^w,x	Treatment option D: Dexamethasone^w,x OR 5-HT3 RA monotherapy^cc: Granisetron Ondansetron Ondansetron
	Treatment option E, use the following combination^y: Olanzapine^z Palonosetron Dexamethasone^w,x	Treatment option E: Olanzapine^z
	Treatment option F, use the following combination^y: NK1 RA 5-HT3 RA^aa,bb Dexamethasone^w,x	Treatment option F: Aprepitant +/-Dexamethasone^w,x

	Select treatment option D, E, or F	Days 2 and 3
	All treatment options are Category 1 and should be started before anticancer therapy^v
Day 1 before infusion of fam-trastuzumab deruxtecan-nxki (ENHERTU)	Treatment option D, use the following combination: 5-HT3 RA Dexamethasone^w,x	Treatment option D: Dexamethasone^w,xOR 5-HT3 RA monotherapy^cc: Granisetron Ondansetron Ondansetron
	Treatment option E, use the following combination^y: Olanzapine^z Palonosetron Dexamethasone^w,x	Treatment option E: Olanzapine^z
	Treatment option F, use the following combination^y: NK1 RA 5-HT3 RA^aa,bb Dexamethasone^w,x	Treatment option F: Aprepitant +/-Dexamethasone^w,x

Adapted with permission from the NCCN Guidelines^® for Antiemesis V1.2022.

^sFor details regarding recommendations and specific dosing information, please refer to the NCCN Guidelines^® for Antiemesis.

^tAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors.

^uWith or without lorazepam 0.5–2 mg PO or IV or sublingual every 6 hours as needed days 1-4. With or without H2 blocker or proton pump inhibitor.

^vCategory 1 recommendations indicate uniform NCCN consensus that the intervention is appropriate based on high-level evidence.

^wEmerging data and clinical practice suggest dexamethasone doses may be individualized. Higher doses may be considered, especially when an NK1 RA is not given concomitantly. Lower doses, given for shorter durations, or even elimination of dexamethasone on subsequent days (for delayed nausea and emesis prevention) may be acceptable for non-cisplatin regimens based on patient characteristics. If dexamethasone eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative antiemetics (eg, olanzapine).

^xUse of corticosteroid premedications should be avoided with cellular therapies.

^yA 3-drug prophylactic regimen (E or F) is recommended for select patients with additional patient-related risk factors or previous treatment failure with a corticosteroid + 5-HT3 RA alone.

^zData suggest that a 5-mg dose of olanzapine is efficacious. Consider this dose especially for elderly or over sedated patients.

^aaIf netupitant/palonosetron or fosnetupitant/palonosetron fixed combination product used, no further 5-HT3 RA is required.

^bbWhen used in combination with an NK1 RA, there is no preferred 5-HT3 RA.

^ccNo further 5-HT3 therapy required if palonosetron or granisetron extended-release injection administered, or if granisetron transdermal patch applied, on day 1.

Drug interaction studies¹

Clinical studies: There were no clinically meaningful drug-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor), as well as ritonavir (OATP inhibitor)
In vitro studies: DXd did not inhibit common CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A) nor induce CYP1A2, CYP2B6, or CYP3A
In vitro studies: At clinically relevant concentrations, DXd has a low potential to inhibit the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP

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efficacy and safety data

5-HT3, 5-hydroxytryptamine 3; AE, adverse event; ALT, alanine aminotransferase; AR, adverse reaction; AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; H2, histamine type 2; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IV, intravenous; mBC, metastatic breast cancer; MATE, multidrug and toxic compound extrusion; MedDRA, Medical Dictionary for Regulatory Activities; NCCN, National Comprehensive Cancer Network; NCI-CTCAE, National Cancer Institute–Common Terminology Criteria for Adverse Events; NK1, neurokinin-1; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein; PO, by mouth; PT, preferred term; RA, receptor antagonist; SAE, serious adverse event; SMQ, Standardised MedDRA Query; T-DM1, ado-trastuzumab emtansine; TEAE, treatment-emergent adverse event.

Safety Data

Safety data from DESTINY-Breast03 confirmed the benefit-risk profile of ENHERTU for HER2+ mBC (5.4 mg/kg) demonstrated in prior studies1,a

The majority of adverse reactions were Grade 1 or 2

Common adverse reactions (≥10% All Grades or ≥2% Grades 3-4) in patients treated with ENHERTU in DESTINY-Breast031

Selected laboratory abnormalities in patients in DESTINY-Breast031