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    • Efficacy data

    In DESTINY-Breast03, a head-to-head study vs T-DM1,

    ENHERTU demonstrated superior PFS vs T-DM11

    PRIMARY ENDPOINT (MAY 2021)

    hazard ratio: 0.28

    (95% Cl: 0.22, 0.37); P<0.0001

    NR mPFS with ENHERTU (95% Cl: 18.5 months, NE)

    vs 6.8 months with T-DM1 (95% Cl: 5.6, 8.2)1,2,a,b

    EXPLORATORY ANALYSIS (JULY 2022)
    • These data are from an exploratory PFS analysis conducted in July 2022, which was based on an open-label study and was not tested for statistical significance or powered to show a difference between treatment arms. Therefore, the clinical significance of these data is not known. Statistical significance of PFS was determined at the May 2021 analysis1-3

    Progression-free survival3,c

    Median progression free survival of ENHERTU (28.8 months) and T-DM1 (6.8 months) from DESTINY-Breast03
    Median progression free survival of ENHERTU (28.8 months) and T-DM1 (6.8 months) from DESTINY-Breast03

    aMedian duration of follow-up for PFS (BICR) at the May 2021 analysis: 16.2 months (range: 0-32.7) for ENHERTU and 15.3 months (range: 0-31.3) for T-DM1.2

    bThe stratified log-rank test P value is compared with the allocated alpha of 0.0002 for this interim analysis (with 73% of the planned number of events for final analysis).1

    cMedian duration of follow-up for PFS (BICR) at the July 2022 analysis: 28.4 months (IQR: 22.1-32.9) for ENHERTU and 26.5 months (IQR: 14.5-31.3) for T-DM1.3

    In DESTINY-Breast03, a head-to-head study vs T-DM1,

    ENHERTU demonstrated superior OS vs T-DM11

    KEY SECONDARY ENDPOINT (JULY 2022)

    HAZARD RATIO: 0.64

    (95% Cl: 0.47, 0.87); P=0.0037

    NR mOS with ENHERTU (95% Cl: 40.5 months, NE)

    vs NR with T-DM1 (95% Cl: 34.0 months, NE)1,3,d

    EXPLORATORY ANALYSIS (NOVEMBER 2023)
    • These data are from an exploratory OS analysis conducted in November 2023, which was based on an open-label study and was not tested for statistical significance or powered to show a difference between treatment arms. Therefore, the clinical significance of these data is not known. Statistical significance of OS was determined at the July 2022 analysis1,3,4

    Overall survival4,e

    Overall survival rate of ENHERTU (77.4%) and T-DM1 (69.9%) from DESTINY-Breast03
    Overall survival rate of ENHERTU (77.4%) and T-DM1 (69.9%) from DESTINY-Breast03

    dThe stratified log-rank test P value is compared with the allocated alpha of 0.013 for this interim analysis (with 68% of the planned number of events for final analysis).1

    eMedian duration of follow-up at the November 2023 analysis: 43 months (range: 0-62.9) for ENHERTU and 35.4 months (range: 0-60.9) for T-DM1.4

    In DESTINY-Breast03, a head-to-head study vs T-DM1,

    ENHERTU delivered 82.1% confirmed ORR5

    • The DESTINY-Breast03 study protocol did not power ORR—a secondary endpoint—to detect treatment effect differences between arms. Therefore, the clinical significance of these data is not known

    SECONDARY ENDPOINT (MAY 2021)

    82.7% confirmed ORR with ENHERTU (n=205/248; 95% CI: 77.4, 87.2; 15.7% CR [n=39] + 66.9% PR [n=166]) and 36.1% with T-DM1 (n=87/241; 95% CI: 30.0, 42.5; 8.3% CR [n=20] + 27.8% PR [n=67])2,3,f

    EXPLORATORY ANALYSIS (JULY 2022)

    Confirmed objective response rate1,5,g

    Confirmed objective response rate of ENHERTU (82.1%) and T-DM1 (36.7%) from DESTINY-Breast03
    Confirmed objective response rate of ENHERTU (82.1%) and T-DM1 (36.7%) from DESTINY-Breast03
    • ~98% of patients had disease control with ENHERTU (21.1% CR [n=52] + 61.0% PR [n=150] + 15.4% SD [n=38])

    1 OUT OF EVERY 5 patients achieved a complete response with ENHERTU

    fAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline (n=248 patients randomized to receive ENHERTU; n=241 for T-DM1).2

    gAnalysis was performed based on the patients with measurable disease assessed by BICR at baseline (n=246 patients randomized to receive ENHERTU; n=240 for T-DM1).5

    In DESTINY-Breast03, a head-to-head study vs T-DM1,

    The majority of patients had a tumor response with ENHERTU3

    EXPLORATORY ANALYSIS (MAY 2021)
    • The DESTINY-Breast03 study protocol did not power best percent change in the sum of the diameter of measurable tumors—an exploratory endpoint—to detect treatment effect differences between arms. Therefore, the clinical significance of these data is not known

    Best percent change from baseline in the sum of diameters of measurable tumors

    Best percent change from baseline in the sum of diameters of measurable tumors
    Best percent change from baseline in the sum of diameters of measurable tumors

    hOnly subjects with measurable disease at baseline and at least one postbaseline target lesion assessment are included.

    In DESTINY-Breast03, a head-to-head study vs T-DM1,

    Consistent PFS results were observed with ENHERTU in prespecified exploratory patient subgroups2

    EXPLORATORY ANALYSIS (MAY 2021)
    A table demonstrating that similar mPFS results were observed in the initial analysis of DESTINY-Breast03 in prespecified exploratory patient subgroups; NR with ENHERTU (n=87/261) vs. 6.8 months with T-DM1 (n=158/263)
    A table demonstrating that similar mPFS results were observed in the initial analysis of DESTINY-Breast03 in prespecified exploratory patient subgroups; NR with ENHERTU (n=87/261) vs. 6.8 months with T-DM1 (n=158/263)
    • The DESTINY-Breast03 study protocol did not power the prespecified exploratory patient subgroup analysis to detect treatment effect differences between subgroups. Therefore, the clinical significance of these data is not known
    NCCN GUIDELINES® PREFERRED

    THE ONLY NCCN CATEGORY 1, Preferred Option in 2L HER2+ mBC6
    NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends fam-trastuzumab deruxtecan-nxki (ENHERTU) as the only Category 1, preferred 2L option for recurrent unresectable (local or regional) or stage IV HER2+ breast cancer6,i

    NCCN Clinical Practice
    Guidelines in Oncology (NCCN Guidelines®) Preferred

    THE ONLY NCCN CATEGORY 1, Preferred Option in 2L HER2+ mBC6
    NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommends fam-trastuzumab deruxtecan-nxki (ENHERTU) as the only Category 1, preferred 2L option for recurrent unresectable (local or regional) or stage IV HER2+ breast cancer6,i

    iFam-trastuzumab deruxtecan-nxki may be considered in the first-line setting as an option for select patients (ie, those with rapid progression within 6 months of neoadjuvant or adjuvant therapy [12 months for pertuzumab-containing regimens]).6

    2L, second line; BICR, blinded independent central review; CI, confidence interval; CR, complete response; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR-, hormone receptor negative; HR+, hormone receptor positive; IQR, interquartile range; mBC, metastatic breast cancer; mOS, median overall survival; mPFS, median progression-free survival; NCCN, National Comprehensive Cancer Network® (NCCN®); NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; T-DM1, ado-trastuzumab emtansine.

    IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS Expand

    WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

    • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
    • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
    INDICATION

    ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:

    • In the metastatic setting, or
    • In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy

    Contraindications

    None.

    Warnings and Precautions

    Interstitial Lung Disease / Pneumonitis

    Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

    Neutropenia

    Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients.

    Left Ventricular Dysfunction

    Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

    Embryo-Fetal Toxicity

    ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

    Additional Dose Modifications

    Thrombocytopenia

    For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by 1 level.

    Adverse Reactions

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    The pooled safety population 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, and other clinical trials. Among these patients, 67% were exposed for >6 months and 38% were exposed for >1 year. 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 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 1 dose of ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU.

    Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (1 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 (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).

    Use in Specific Populations

    • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. 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.
    • Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
    • Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
    • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
    • Geriatric Use: Of the 1741 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 24% were ≥65 years and 4.9% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (61%) as compared to younger patients (52%).
    • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
    • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

    To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

    Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

    INDICATION

    ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:

    • In the metastatic setting, or
    • In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy
    References
    • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
    • Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154.
    • Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117.
    • Cortés J, Hurvitz SA, Im S-A, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024;30(8):2208-2215.
    • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed January 31, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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