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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
- 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 or 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) |
|||
---|---|---|---|---|---|
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 painb | 21 | 0.8 | 8 | 0.4 | |
Stomatitisc | 20 | 0.8 | 5 | 0 | |
Dyspepsia | 11 | 0 | 6 | 0 | |
General disorders and administration site conditions |
Fatigued | 49 | 6 | 35 | 0.8 |
Blood and lymphatic system disorders |
Anemiae | 33 | 7 | 17 | 6 |
Skin and subcutaneous tissue disorders |
Alopeciaf | 37 | 0.4 | 3.1 | 0 |
Musculoskeletal and connective tissue disorders |
Musculoskeletal paing | 31 | 1.2 | 25 | 0.4 |
Metabolism and nutritional disorders |
Decreased appetite | 29 | 1.6 | 17 | 0.4 |
Investigations | Decreased weight | 17 | 1.2 | 6 | 0.4 |
Respiratory, thoracic, and mediastinal disorders |
Respiratory infectionh | 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 |
Headachej | 22 | 0.4 | 16 | 0 |
Peripheral neuropathyk | 13 | 0.4 | 14 | 0.4 | |
Dizziness | 13 | 0.4 | 8 | 0 |
Adverse reactions |
ENHERTU 5.4
mg/kg (n=257) |
|
---|---|---|
All Grades (%) |
Grades 3-4 (%) |
|
Gastrointestinal disorders | ||
Nausea | 76 | 7 |
Vomiting | 49 | 1.6 |
Constipation | 34 | 0 |
Diarrhea | 29 | 1.2 |
Abdominal painb | 21 | 0.8 |
Stomatitisc | 20 | 0.8 |
Dyspepsia | 11 | 0 |
General disorders and administration site conditions | ||
Fatigued | 49 | 6 |
Blood and lymphatic system disorders | ||
Anemiae | 33 | 7 |
Skin and subcutaneous tissue disorders | ||
Alopeciaf | 37 | 0.4 |
Musculoskeletal and connective tissue disorders | ||
Musculoskeletal paing | 31 | 1.2 |
Metabolism and nutrition disorders | ||
Decreased appetite | 29 | 1.6 |
Investigations | ||
Decreased weight | 17 | 1.2 |
Respiratory, thoracic, and mediastinal disorders | ||
Respiratory infectionh | 22 | 0.8 |
Epistaxis | 11 | 0 |
Cough | 11 | 0.4 |
Interstitial lung diseasei | 11 | 0.8 |
Nervous system disorders | ||
Headachej | 22 | 0.4 |
Peripheral neuropathyk | 13 | 0.4 |
Dizziness | 13 | 0.4 |
Adverse reactions |
T-DM1 3.6 mg/kg (n=261) |
|
---|---|---|
All Grades (%) |
Grades 3-4 (%) |
|
Gastrointestinal disorders | ||
Nausea | 30 | 0.4 |
Vomiting | 10 | 0.8 |
Constipation | 20 | 0 |
Diarrhea | 7 | 0.4 |
Abdominal painb | 8 | 0.4 |
Stomatitisc | 5 | 0 |
Dyspepsia | 6 | 0 |
General disorders and administration site conditions | ||
Fatigued | 35 | 0.8 |
Blood and lymphatic system disorders | ||
Anemiae | 17 | 6 |
Skin and subcutaneous tissue disorders | ||
Alopeciaf | 3.1 | 0 |
Musculoskeletal and connective tissue disorders | ||
Musculoskeletal paing | 25 | 0.4 |
Metabolism and nutrition disorders | ||
Decreased appetite | 17 | 0.4 |
Investigations | ||
Decreased weight | 6 | 0.4 |
Respiratory, thoracic, and mediastinal disorders | ||
Respiratory infectionh | 12 | 1.1 |
Epistaxis | 16 | 0.4 |
Cough | 10 | 0 |
Interstitial lung diseasei | 1.9 | 0 |
Nervous system disorders | ||
Headachej | 16 | 0 |
Peripheral neuropathyk | 14 | 0.4 |
Dizziness | 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
Selected laboratory abnormalities in patients in DESTINY-Breast032
Laboratory parameter | ENHERTU 5.4
mg/kg (n=257) |
T-DM1 3.6
mg/kg (n=261) |
|||
---|---|---|---|---|---|
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 alkaline phosphatase | 49 | 0.8 | 46 | 0.8 | |
Hypokalemia | 35 | 4.7 | 39 | 15 | |
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) |
|
---|---|---|
All Grades (%) |
Grades 3-4 (%) |
|
Hematology | ||
Decreased white blood cell count | 74 | 8 |
Decreased neutrophil count | 70 | 18 |
Decreased hemoglobin | 64 | 7 |
Decreased lymphocyte count | 55 | 14 |
Decreased platelet count | 52 | 7 |
Chemistry | ||
Increased aspartate aminotransferase | 67 | 0.8 |
Increased alanine aminotransferase | 53 | 1.6 |
Increased alkaline phosphatase | 49 | 0.8 |
Hypokalemia | 35 | 4.7 |
Increased blood bilirubin | 20 | 0 |
Increased blood creatinine | 16 | 0.8 |
Laboratory parameter |
T-DM1 3.6 mg/kg
(n=261) |
|
---|---|---|
All Grades (%) |
Grades 3-4 (%) |
|
Hematology | ||
Decreased white blood cell count | 24 | 0.8 |
Decreased neutrophil count | 30 | 2.3 |
Decreased hemoglobin | 38 | 6 |
Decreased lymphocyte count | 23 | 3.9 |
Decreased platelet count | 79 | 2.4 |
Chemistry | ||
Increased aspartate aminotransferase | 83 | 5 |
Increased alanine aminotransferase | 67 | 6 |
Increased alkaline phosphatase | 46 | 0.8 |
Hypokalemia | 39 | 1.5 |
Increased blood bilirubin | 14 | 0 |
Increased blood creatinine | 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.
Updated safety analysis from DESTINY-Breast03 further confirmed the benefit-risk profile of ENHERTU for HER2+ mBC (5.4 mg/kg) demonstrated in prior studies1-4,l
- Initial analysis (May 2021 data cutoff): Median duration of treatment was 14 months (range: 0.7 to 30) with ENHERTU and 7 months (range: 0.7 to 25) with T-DM1
ENHERTU 5.4 mg/kg (n=257) |
T-DM1 3.6 mg/kg (n=261) |
||
---|---|---|---|
Serious adverse reactions | 19.1% | 18% |
|
Discontinuations due to adverse reactions | 14% | 7% |
|
Dose interruptions due to adverse reactions | 44% | 23% |
|
Dose reductions due to adverse reactions | 21% | 13% |
|
ENHERTU 5.4 mg/kg (n=257) |
T-DM1 3.6 mg/kg (n=261) |
---|---|
Serious adverse reactions | |
19.1% | 18% |
|
|
Discontinuations due to adverse reactions | |
14% | 7% |
|
|
Dose interruptions due to adverse reactions | |
44% | 23% |
|
|
Dose reductions due to adverse reactions | |
21% | 13% |
|
- Other clinically relevant adverse reactions reported in <10% of patients receiving ENHERTU were dyspnea (8%), pruritus (8%), skin hyperpigmentation (6%), dysgeusia (6%), dehydration (4.3%), blurred vision (3.5%), asymptomatic left ventricular ejection fraction decrease (2.7%), infusion-related reactions (2.3%), and febrile neutropenia (0.8%)
Updated analysis (July 2022)4
- The median duration of treatment increased to 18 months for ENHERTU (IQR: 9.0 to 29.4) and remained 7 months for T-DM1 (IQR: 2.8 to 12.3)
- Discontinuations, dose interruptions, and dose reductions due to ARs were 20%, 42%, and 25%, respectively, for ENHERTU
- No new safety signals were observed for ENHERTU
lPrior ENHERTU HER2+ mBC studies: Phase 2 DESTINY-Breast01 and Phase 1 DS8201-A-J101.
m Grouped term of anemia includes PTs of hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.2
nGrouped term of thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.2
ILD and pneumonitis were reported in DESTINY-Breast03; the majority of events were Grade 1 or 2 in the ENHERTU arm (n=25/27)1,2
No Grade 4 or 5 adjudicated drug-related ILD/pneumonitis events were observedo
Adjudicated as drug-related ILD, n (%) |
ENHERTU 5.4 mg/kg (n=257) |
T-DM1 3.6 mg/kg (n=261) |
|
---|---|---|---|
Grade 1 | 7 (2.7) | 4 (1.5) | |
Grade 2 | 18 (7.0) | 1 (0.4) | |
Grade 3 | 2 (0.8) | 0 | |
Grade 4 | 0 | 0 | |
Grade 5 | 0 | 0 | |
All Grades | 27 (10.5) | 5 (1.9) |
Adjudicated as drug-related ILD, n (%) |
ENHERTU 5.4 mg/kg (n=257) |
---|---|
Grade 1 | 7 (2.7) |
Grade 2 | 18 (7.0) |
Grade 3 | 2 (0.8) |
Grade 4 | 0 |
Grade 5 | 0 |
All Grades | 27 (10.5) |
Adjudicated as drug-related ILD, n (%) |
T-DM1 3.6 mg/kg (n=261) |
---|---|
Grade 1 | 4 (1.5) |
Grade 2 | 1 (0.4) |
Grade 3 | 0 |
Grade 4 | 0 |
Grade 5 | 0 |
All Grades | 5 (1.9) |
Updated analysis (July 2022)4
- Overall incidence of ILD was 15% in the ENHERTU arm and 3% in the T-DM1 arm
- No Grade 4 or 5 adjudicated drug-related ILD/pneumonitis events were observed
oGrade 5=fatal cases.4
Incidence of select common adverse reactions in DESTINY-Breast032,3
The majority of these adverse reactions were Grade 1 or 2
Adverse Reactions | ENHERTU
5.4
mg/kg
(n=257) |
|||
---|---|---|---|---|
Grade 1
(%) |
Grade 2 (%) |
Grade 3 (%) |
Grade
4 (%) |
|
Nausea | 41.6 | 27.6 | 6.6 | 0 |
Fatigue | 29.2 | 14.0 | 5.8 | 0 |
Alopeciap | 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 |
Adverse Reactions |
ENHERTU 5.4 mg/kg (n=257) |
|
---|---|---|
Grade 1
(%) |
Grade 2 (%) |
|
Nausea | 41.6 | 27.6 |
Fatigue | 29.2 | 14.0 |
Alopeciap | 26.5 | 9.3 |
Vomiting | 31.1 | 16.3 |
Constipation | 26.5 | 7.8 |
Decreased appetite | 19.5 | 8.2 |
Diarrhea | 19.8 | 8.2 |
Adverse Reactions |
ENHERTU 5.4 mg/kg (n=257) |
|
---|---|---|
Grade 3
(%) |
Grade 4 (%) |
|
Nausea | 6.6 | 0 |
Fatigue | 5.8 | 0 |
Alopeciap | 0.4 | 0 |
Vomiting | 1.2 | 0.4 |
Constipation | 0 | 0 |
Decreased appetite | 1.6 | 0 |
Diarrhea | 1.2 | 0 |
pThis 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
Drug interaction studies1
- Clinical studies: There were no clinically meaningful drug-to-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor), as well as ritonavir (OATP1B/CYP3A 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
- In vitro studies: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP
ALT, alanine aminotransferase; AR, adverse reaction; AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; DXd, deruxtecan; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IQR, interquartile range; mBC, metastatic breast cancer; MATE, multidrug and toxic compound extrusion; MRP1, multidrug resistance protein 1; NCI-CTCAE, National Cancer Institute–Common Terminology Criteria for Adverse Events; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein; PT, preferred term; T-DM1, ado-trastuzumab emtansine.