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Efficacy Data

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

ENHERTU demonstrated 28.8 months mPFS in 2L in patients with HER2+ mBC (6.8 months with T-DM1)1

  • Initial analysis of mPFS (BICR; primary endpoint): NR mPFS with ENHERTU (95% CI: 18.5, NE) vs 6.8 months with T-DM1 (95% CI: 5.6, 8.2); HR: 0.28 (95% CI: 0.22, 0.37; P<0.0001)2,a,b
UPDATED ANALYSIS

Progression-free survival1,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
  • The updated exploratory PFS analysis was not tested for statistical significance and not powered to show a difference between treatment arms

aMedian duration of follow-up for PFS (BICR) at initial data cutoff: 16.2 months (range: 0-32.7) for ENHERTU and 15.3 months (range: 0-31.3) for T-DM1.3

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).2

cMedian duration of follow-up for PFS (BICR) at updated analysis: 28.4 months (IQR: 22.1-32.9) for ENHERTU and 26.5 months (IQR: 14.5-31.3) for T-DM1.1

Initial analysis: similar mPFS results were observed in prespecified exploratory patient subgroups in the ENHERTU arm3

  • Prespecified exploratory patient subgroups analyses were not powered to detect treatment effect differences between subgroups

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

Superior overall survival with ENHERTU vs T-DM12

UPDATED ANALYSIS
  • mOS (key secondary endpoint): NR mOS with ENHERTU (95% CI: 40.5 months, NE) vs NR with T-DM1 (95% CI: 34.0 months, NE); HR: 0.64 (95% CI: 0.47, 0.87; P=0.0037d)2,3

Overall survival1,2,d

Immature overall survival rate (77.4%) of ENHERTU and T-DM1 (69.9%) from DESTINY-Breast03
Immature overall survival rate (77.4%) of ENHERTU and T-DM1 (69.9%) from DESTINY-Breast03
  • The 24-month landmark analysis is based on Kaplan-Meier estimates and is descriptive only; the DESTINY-Breast03 trial was not powered to assess a statistical difference between treatment groups at this time point

36% reduction in risk of death with ENHERTU over T-DM1 in 2L (key secondary endpoint; HR: 0.64; 95% CI: 0.47, 0.87; P=0.0037d)2

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).2

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

ENHERTU delivered 82.1% confirmed ORR, more than double the 36.7% T-DM1 response4

  • Initial analysis of confirmed ORR (BICR; secondary endpoint)2,e:
    • 82.7% with ENHERTU (n=205/248; 95% CI: 77.4, 87.2; 15.7% CR [n=39] + 66.9% PR [n=166])
    • 36.1% with T-DM1 (n=87/241; 95% CI: 30.0, 42.5; 8.3% CR [n=20] + 27.8% PR [n=67])
UPDATED ANALYSIS

Confirmed objective response rate4,f

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
  • ORR was not tested for statistical significance and not powered to show a difference between treatment arms
  • ~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 have achieved a complete response with ENHERTU

eAnalysis 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

fAnalysis 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).4

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

The majority of patients had a tumor response with ENHERTU3

Initial analysis: best percent change from baseline in the sum of diameters of measurable tumors (exploratory endpoint)

Tumor response of ENHERTU and T-DM1 from DESTINY-Breast03
Tumor response of ENHERTU and T-DM1 from DESTINY-Breast03

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

NCCN GUIDELINES® PREFERRED

THE ONLY CATEGORY 1, Preferred Option in 2L HER2+ mBC5
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 cancer5,h

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

THE ONLY CATEGORY 1, Preferred Option in 2L HER2+ mBC5
NCCN Guidelines® recommends
fam-trastuzumab deruxtecan-nxki (ENHERTU) as Category 1, preferred option as second-line therapy for recurrent unresectable (local or regional) or stage IV HER2+ disease5,h

hFam-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]).5

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.

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 one 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 1.0% 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 one 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 one 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 63% of patients. Seventeen 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% 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 3.8% of patients, of which 0.6% were Grade 3.

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 one 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 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, and other clinical trials. Among these patients, 65% 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 nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).

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 intravenously once every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).

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 (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 1287 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.8% 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 (59%) as compared to younger patients (49%).
  • 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
  • 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.
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
  • 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.
  • 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.2.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 11, 2024. 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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