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ENHERTU (fam-trastuzumab deruxtecan-nxki) Logo
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Additional Data

Patient-reported outcomes of health-related quality of life in DESTINY-Breast031

PROs of HRQoL were prespecified secondary endpoints in DESTINY-Breast03 and were assessed throughout the study

PROs of HRQoL were prespecified secondary endpoints in DESTINY-Breast03 and were assessed throughout the study PROs of HRQoL were prespecified secondary endpoints in DESTINY-Breast03 and were assessed throughout the study

Primary endpoint

  • PFS (BICR)

Key secondary endpoint

  • OS

Secondary endpoints

  • ORR (BICR and investigator)
  • DOR (BICR)
  • PFS (investigator)
  • Safety
  • HEOR outcomes (PROs and hospitalization rates)

PRO endpoint assessment schedulee:

  • Cycle 1
  • Cycle 2
  • Cycle 3
  • Every 2
    cycles
    (cycle 5, 7, 9,
    etc)
  • Every 2 cycles
    (cycle 5, 7, 9, etc)
  • EOT
  • 40-day
    follow-up
  • 3-month
    follow-up

Reprinted from Annals of Oncology, Vol. 34(7), Curigliano G, Dunton K, Rosenlund M, et al., Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study, Pages No. 569-577, Copyright 2023, with permission from Elsevier.

aHER2 IHC 3+ or IHC 2+/ISH+ based on central confirmation.

bProgression during or <6 months after completing adjuvant therapy involving trastuzumab and a taxane.

cFour patients were randomly assigned but not treated.

dTwo patients were randomly assigned but not treated.

e1 cycle, 21 days; ENHERTU or T-DM1 administered on day 1 of each cycle; questionnaires completed before treatment on day 1 of cycles indicated.

HRQoL for patients was assessed across several measurements

Primary and secondary PRO assessment instruments and variables of interest

Measurements
EORTC QLQ-C30

Oncology-specific Quality of Life Questionnaire Core 30

Measurements
  • Global health status (GHS)/quality of life (QoL)f
  • Physical functioningg
  • Emotional functioningg
  • Social functioningg
  • Pain symptomsg
EORTC QLQ-BR45

Breast cancer–specific instrument

Measurements
  • Arm symptomsg
  • Breast symptomsg
EQ-5D-5L

EuroQol 5-dimension 5-level
questionnaire visual
analogue scale

Measurements
  • Visual analogue scale (VAS)g
  • Analyses included change from baseline, time to definitive deterioration, and hospitalization-related endpoints
  • Most patients in both treatment groups completed the QoL questionnaires as prescribed in the trial
    • >97% compliance at baseline
    • >82% compliance from cycles 3-27
    • >90% compliance at the follow-up

Patients who had discontinued the trial were not included in further PRO assessments.

fPrimary PRO variable of interest.

gSecondary PRO variable of interest.

HRQoL was assessed using 3 PRO measures in DESTINY-Breast031

Median time to definitive deterioration in patient-reported QoL measures in DESTINY-Breast03

Median time to definitive deterioration in patient-reported QoL measures in DESTINY-Breast03 Median time to definitive deterioration in patient-reported QoL measures in DESTINY-Breast03
  • Time to definitive deterioration was defined as the number of days between the date of randomization and the date of the assessment at which the definitive deterioration event (a prespecified, ≥10-point change from baseline of the specific score in the direction of deterioration [positive for symptom scales, negative for all others], and deterioration on two or more consecutive visits or at last visit), is first seen

Reprinted from Annals of Oncology, Vol. 34(7), Curigliano G, Dunton K, Rosenlund M, et al., Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study, Pages No. 569-577, Copyright 2023, with permission from Elsevier.

PRO measures are reported such that a high GHS/QoL or VAS score represents a high QoL, a high score on functional scales represents a high level of functioning, and a high score on symptom scales represents a high level of symptomatology. Time to definitive deterioration was defined as the number of days between the date of randomization and the date of the assessment at which the definitive deterioration event is first observed (ie, a change exceeding +10 points for symptom scales, or a change exceeding –10 points for GHS, VAS, and functional scales, with deterioration on two or more consecutive visits or at last visit). P values are not adjusted for multiple testing.

hPrimary PRO variable of interest.

iSecondary PRO variable of interest.

EORTC QLQ-C30 GHS was assessed over time in DESTINY-Breast031

EORTC QLQ-C30 GHS change from baseline over time in patients treated with ENHERTU and T-DM1

EORTC QLQ-C30 GHS change from baseline over time in patients treated with ENHERTU and T-DM1 EORTC QLQ-C30 GHS change from baseline over time in patients treated with ENHERTU and T-DM1
  • Scores range from 0 to 100; the investigators considered a higher score to represent higher (“better”) GHS/overall QoL

Limitations: The EORTC QLQ-C30 is not all-inclusive and does not include adequate assessment of additional expected treatment-related symptoms or overall side effect bother from the patient perspective. The results should be interpreted with caution due to the open-label design of the study and because time to definitive deterioration may be confounded by events not related to disease/treatment

Reprinted from Annals of Oncology, Vol. 34(7), Curigliano G, Dunton K, Rosenlund M, et al., Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study, Pages No. 569-577, Copyright 2023, with permission from Elsevier.

BICR, blinded independent central review; CI, confidence interval; DOR, duration of response; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of treatment; EQ-5D-5L, EuroQoL 5-dimension, 5-level questionnaire; GHS, global health status; HEOR, health economics and outcomes research; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HRQoL, health-related quality of life; IHC, immunohistochemistry; ISH, in situ hybridization; NE, not evaluable; ORR, objective response rate; OS, overall survival; PRO, patient-reported outcome; Q3W, every 3 weeks; QLQ-BR45, Quality of Life Breast Cancer questionnaire; QLQ-C30, Quality of Life Questionnaire Core 30; QoL, quality of life; TDD, time to definitive deterioration; T-DM1, ado-trastuzumab emtansine; VAS, visual analogue scale.

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
Reference
  • Curigliano G, Dunton K, Rosenlund M, et al. Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Ann Oncol. 2023;34(7):569-577.
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