DESTINY-Breast04 Trial

ENHERTU was investigated in DESTINY-Breast04, a landmark, phase 3, international trial^1‑3

A phase 3, multicenter, randomized, open-label trial that included patients with^1,3,a:

Unresectable or metastatic HER2-low (HER2 IHC 1+^b or IHC 2+/ISH–) breast cancer
Tumors previously not classified as HER2-positive on any prior pathology testing²

The study design for the DESTINY-Breast04 trial, a randomized 2:1 trial of patients with confirmed HER2-low metastatic breast cancer (IHC 1+ or IHC 2+/ISH–) (N=557)1

The key efficacy endpoints in DESTINY-Breast04 were tested hierarchically¹:

Primary endpoint¹

PFS (BICR)^e in the HR+ population

Key secondary endpoints

PFS (BICR)^e in the overall study population (HR+ and HR–)
OS in the HR+ population
OS in the overall study population (HR+ and HR–)

Select secondary endpoints^3,e,f

Confirmed ORR and DOR in the HR+ population
Confirmed ORR and DOR in the overall study population (HR+ or HR–)

Select exploratory endpoints^4,5

PFS, OS, ORR, and DOR in the HR– population

Stratification factors⁴

HER2 IHC status (IHC 1+ or IHC 2+/ISH–)
Number of prior lines of chemotherapy in the metastatic setting (1 or 2)
HR status/prior CDK4/6 inhibitor (HR+ with prior CDK4/6 inhibitor, HR+ without prior CDK4/6 inhibitor, or HR–)

Patients with HER2-low mBC in DESTINY-Breast04 had 1 or 2 prior lines of chemotherapy in the metastatic setting and, if HR+, were ineligible for or had progressed on endocrine therapy¹

^aPatients had received no prior HER2-directed therapy.³

^bIHC 1+ tumors were ISH– or ISH untested.³

^cTreatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.¹

^d In the control arm, 51.1% of patients received eribulin, 20.1% received capecitabine, 10.3% received nab-paclitaxel, 10.3% received gemcitabine, and 8.2% received paclitaxel.⁴

^eAccording to mRECIST v1.1.³

^fBoth BICR and investigator assessment were performed.³

DESTINY-Breast04 evaluated patients with HER2-low mBC (IHC 1+ and IHC 2+/ISH–)¹

Select patient demographics and clinical characteristics^1,5,g,h

		DESTINY-Breast04 (N=557)
Age, median ≥65 years, %		57 years (range: 28 to 81) 24%
Hormone receptor status, %	HR+	89%
Hormone receptor status, %	HR-	11%
HER2 IHC score, %	1+	58%
HER2 IHC score, %	2+/ISH–	42%
Number of prior lines of endocrine therapy in the metastatic setting in HR+/HER2-low mBC patients (n=494), %	0	9%
	1	31%
	2	33%
	≥3	27%
Prior CDK4/6 inhibitor in HR+/HER2-low mBC patients (n=494), %		70%
Number of prior chemotherapy regimens in the metastatic setting, %	1	58%
	2	41%
Prior lines of systemic therapy in the metastatic setting, medianⁱ		3 (range: 1 to 9)
Sites of metastases, %	Liver metastases	70%
	Lung metastases	33%
	Brain metastases^j	6%

	DESTINY-Breast04 (N=557)
Age, median ≥65 years, %	57 years (range: 28 to 81) 24%
Hormone receptor status, %
HR+	89%
HR-	11%
HER2 IHC score, %
1+	58%
2+/ISH–	42%
Number of prior lines of endocrine therapy in the metastatic setting in HR+/HER2-low mBC patients (n=494), %
0	9%
1	31%
2	33%
≥3	27%
Prior CDK4/6 inhibitor in HR+/HER2-low mBC patients (n=494), %	70%
Number of prior chemotherapy regimens in the metastatic setting, %
1	58%
2	41%
Prior lines of systemic therapy in the metastatic setting, medianⁱ	3 (range: 1 to 9)
Sites of metastases, %
Liver metastases	70%
Lung metastases	33%
Brain metastases^j	6%

Gender: 99.6% were female, 0.4% were male¹
Race/ethnicity: 48% were White, 40% were Asian, 3.8% were Hispanic/Latino, and 2% were Black or African American¹
ECOG PS: 55% had ECOG PS 0 and 45% had ECOG PS 1 at baseline¹
In HR+ cohort, median prior lines of ET: 2 (range: 0 to 9)¹
Early progressors (progression in the neo/adjuvant setting): 3.9%¹

In DESTINY-Breast04, 58% of patients were IHC 1+ and 42% were IHC 2+/ISH−¹

^gPatients with HR-negative mBC were not included in the primary efficacy analysis.⁴

^hIn some instances, percentages do not add up to 100% due to rounding.

ⁱIn the overall study population (N=557), 10% of patients had received 1 prior line of systemic therapy in the metastatic setting, 27% had received 2 prior lines, and 62% had received ≥3 prior lines.⁴

^jPatients with treated brain metastases who were no longer symptomatic and who required no treatment with corticosteroids or anticonvulsants could be included in the study if they had recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.³

BICR, blinded independent central review; CDK4/6, cyclin-dependent kinases 4 and 6; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR–, hormone receptor-negative; HR+, hormone receptor-positive; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; mBC, metastatic breast cancer; mRECIST, Modified Response Evaluation Criteria in Solid Tumors; ORR, objective response rate; OS, overall survival; PS, performance score; PFS, progression-free survival; Q3W, every 3 weeks.

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-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

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-Low Metastatic Breast Cancer

DESTINY-Breast04

The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.

Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).

ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%).

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-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

References

ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Supplement to: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Protocol for: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.

ENHERTU was investigated in DESTINY-Breast04, a landmark, phase 3, international trial1‑3

A phase 3, multicenter, randomized, open-label trial that included patients with1,3,a:

The key efficacy endpoints in DESTINY-Breast04 were tested hierarchically1:

Primary endpoint1

Key secondary endpoints

Select secondary endpoints3,e,f

Select exploratory endpoints4,5

Stratification factors4

DESTINY-Breast04 evaluated patients with HER2-low mBC (IHC 1+ and IHC 2+/ISH–)1

ENHERTU was investigated in DESTINY-Breast04, a landmark, phase 3, international trial^1‑3

A phase 3, multicenter, randomized, open-label trial that included patients with^1,3,a:

The key efficacy endpoints in DESTINY-Breast04 were tested hierarchically¹:

Primary endpoint¹

Select secondary endpoints^3,e,f

Select exploratory endpoints^4,5

Stratification factors⁴

DESTINY-Breast04 evaluated patients with HER2-low mBC (IHC 1+ and IHC 2+/ISH–)¹