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For US Healthcare Professionals

DESTINY-Gastric-04 Trial

DESTINY-Gastric04 was a Phase 3, head-to-head trial in patients with 2L HER2+ aGC/GEJ adenocarcinoma1

A multicenter, open-label, global trial vs ramucirumab and paclitaxel1

DESTINY-Gastric02 trial design in adult patients in the United States, Italy, United Kingdom, Belgium, and Spain, single arm (N=79), ENHERTU 6.4 mg/kg once every 3 weeks (21-day cycle), treated until disease progression or unacceptable toxicity DESTINY-Gastric02 trial design in adult patients in the United States, Italy, United Kingdom, Belgium, and Spain, single arm (N=79), ENHERTU 6.4 mg/kg once every 3 weeks (21-day cycle), treated until disease progression or unacceptable toxicity
  • Patients had HER2-positive cancers, defined as IHC 3+ or IHC 2+/ISH+, after progression on a trastuzumab-based therapy
  • Primary endpoint was OS and additional secondary endpoints included PFS, ORR, and DOR
Select patient
characteristics1,2 		ENHERTU
(n=246) 		Ramucirumab and
Paclitaxel
(n=248)
Median age 63.2 64.3
Sex Male 76% 82.7%
Female 24% 17.3%
Race White 47.2% 52.4%
Black 0% 0.8%
Asian 41.1% 39.1%
Other 11.4% 7.7%
Multiple 0.4% 0%
ECOG PSa 0 39.4% 35.5%
1 60.2% 63.7%
2 0.4% 0.4%
Primary tumor
site 		Stomach 62.2% 60.1%
Gastroesophageal junction 37.8% 39.9%
Any post-trial
systemic
treatmentb 		Yesc 51.2% 47.6%
ENHERTU 1.2% 21.0%
Other HER2-directed ADC 2.0% 4.8%
Select patient
characteristics1,2 		ENHERTU
(n=246) 		Ramucir-
umab
and
Paclitaxel
(n=248)
Median age 63.2 64.3
Sex
Male 76% 82.7%
Female 24% 17.3%
Race
White 47.2% 52.4%
Black 0% 0.8%
Asian 41.1% 39.1%
Other 11.4% 7.7%
Multiple 0.4% 0%
ECOG PSa
0 39.4% 35.5%
1 60.2% 63.7%
2 0.4% 0.4%
Primary tumor site
Stomach 62.2% 60.1%
Gastroesophageal junction 37.8% 39.9%
Any post-trial systemic treatmentb
Yesc 51.2% 47.6%
ENHERTU 1.2% 21.0%
Other HER2-directed ADC 2.0% 4.8%

Data shown above for select patient characteristics may not total 100% due to rounding.

a1 patient in the ramucirumab + paclitaxel arm did not have ECOG PS data.1

bPatients may have been treated with more than 1 type of post-trial systemic treatment.2

cOther post-trial systemic treatments were utilized in addition to ENHERTU and other HER2-directed ADC.2

 

Interim efficacy results in DESTINY-Gastric04 were consistent with DESTINY-Gastric011,3

  • Efficacy data were based on a cutoff date of October 24, 2024. Median duration of follow-up was 16.8 months with ENHERTU and 14.4 months with ramucirumab and paclitaxel1
  • These data are from a prespecified interim analysis of an ongoing clinical trial. A final analysis is planned when the trial has completed1

OS: Primary endpoint1,a

Confirmed objective response rate (42%) of ENHERTU from DESTINY-Gastric02 Confirmed objective response rate (42%) of ENHERTU from DESTINY-Gastric02

Secondary endpoints1

6.7 months
mPFSb

(95% CI: 5.6, 7.1) vs 5.6 months (95% CI: 4.9, 5.8) with ramucirumab and paclitaxel (HR=0.74; 95% CI: 0.59, 0.92; P=0.007)c

44.3% confirmed
ORRd

(n=104/235; 95% CI: 37.8, 50.9) vs 29.1% (n=69/237; 95% CI: 23.4, 35.3) with ramucirumab and paclitaxel; P<0.001e,f

3% CR (n=7) vs 1.3% (n=3) with ramucirumab and paclitaxelg

41.3% PR (n=97) vs 27.8% (n=66) with ramucirumab and paclitaxel

7.4 months
mDORb

(95% CI: 5.7, 10.1) vs 5.3 months (95% CI: 4.1, 5.7) with ramucirumab and paclitaxel

These studies represent additional data to the safety and efficacy data in the PI and further support the approved 2L use of ENHERTU for eligible patients with HER2+ advanced gastric/GEJ adenocarcinoma

aMedian OS and OS rates at specified timepoints were calculated using Kaplan-Meier analysis. CI for the median was computed using the Brookmeyer-Crowley method. CIs for OS rates at specific timepoints were calculated using the Greenwood formulation.1

bMedian PFS was calculated using Kaplan-Meier analysis. CI for the median was computed using the Brookmeyer-Crowley method. Estimates and CIs at the specified time points were calculated using Kaplan-Meier analysis.1

cTwo-sided P-value was calculated using a stratified log-rank test, and the stratified Cox proportional hazards model was adjusted for the HER2 status (IHC 3+ or IHC 2+/ISH+) stratification factor.1

dORR-eligible patients were those who were randomized at least 77 days (ie, 2 × 6 weeks − 1 week) before the data cutoff date of the interim analysis. Confirmed ORR and DCR were calculated using the number of eligible patients as the denominator (ENHERTU, n=235; ramucirumab and paclitaxel, n=237).1

eCI calculated based on Clopper-Pearson method for single proportion.1

fP-value calculated using the Cochran-Mantel-Haenszel test adjusted for the HER2 status (IHC 3+ or IHC 2+/ISH+) stratification factor.1

gComplete response patients without target lesions at baseline were included.1

 

In DESTINY-Gastric04, safety results were consistent with DESTINY-Gastric011,3

No Grade 4 or 5 ILD/pneumonitis was observed with ENHERTU in DESTINY-Gastric04 (n=244)1

All grades Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
% (n)1 13.9 (34) 2.9 (7) 10.7 (26) 0.4 (1) 0 0
% (n)1
All grades 13.9 (34)
Grade 1 2.9 (7)
Grade 2 10.7 (26)
Grade 3 0.4 (1)
Grade 4 0
Grade 5 0
  • All reported left ventricular dysfunction cases were Grade ≤3 (Grade 2, n=3/6; Grade 3, n=3/6)

The most common (≥10%) treatment-emergent adverse reactions in DESTINY-Gastric04, including lab abnormalities, were1:

Adverse reaction ENHERTU
(n=244) 		Ramucirumab and
Paclitaxel
(n=233)
All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%)
Fatiguea 48.0 7.0 37.8 2.6
Neutropeniab 48.0 28.7 48.9 35.6
Nausea 44.3 4.9 14.2 0
Anemiac 31.1 13.9 33.0 13.7
Decreased appetite 29.1 2.0 18.0 1.3
Leukopeniad 26.6 7.4 22.3 12.4
Thrombocytopeniae 26.6 8.6 13.7 3.0
Diarrhea 25.8 1.2 20.2 2.1
Alopecia 24.2 0 26.6 0
Aminotransferase level increasedf 21.7 2.0 9.4 0.4
Vomiting 20.1 2.9 6.9 0.4
ILD or pneumonitisg 13.9 0.4 1.3 1.3
Weight decreased 11.1 1.2 3.9 0.4
Constipation 10.7 0 5.2 0
Lymphopeniah 10.2 2.0 5.6 1.3
Adverse reaction All Grades (%)
ENHERTU
(n=244) 		Ramucir-
umab and
Paclitaxel
(n=233)
Fatiguea 48.0 37.8
Neutropen-
iab 		48.0 48.9
Nausea 44.3 14.2
Anemiac 31.1 33.0
Decreased appetite 29.1 18.0
Leukopen-
iad 		26.6 22.3
Thrombocy-
topeniae 		26.6 13.7
Diarrhea 25.8 20.2
Alopecia 24.2 26.6
Aminotran-
sferase level increasedf 		21.7 9.4
Vomiting 20.1 6.9
ILD or pneumoni-
tisg 		13.9 1.3
Weight decreased 11.1 3.9
Constipat-
ion 		10.7 5.2
Lymphope-
niah 		10.2 5.6
Adverse reaction Grade 3 or 4 (%)
ENHERTU
(n=244) 		Ramucir-
umab and
Paclitaxel
(n=233)
Fatiguea 7.0 2.6
Neutropen-
iab 		28.7 35.6
Nausea 4.9 0
Anemiac 13.9 13.7
Decreased appetite 2.0 1.3
Leukopen-
iad 		7.4 12.4
Thrombocy-
topeniae 		8.6 3.0
Diarrhea 1.2 2.1
Alopecia 0 0
Aminotran-
sferase level increasedf 		2.0 0.4
Vomiting 2.9 0.4
ILD or pneumoni-
tisg 		0.4 1.3
Weight decreased 1.2 0.4
Constipat-
ion 		0 0
Lymphope-
niah 		2.0 1.3
  • Median treatment duration was 5.4 months (range: 0.7-30.3) in patients treated with ENHERTU and 4.6 months (range: 0.9-34.9) in patients treated with ramucirumab and paclitaxel1

Shown are adverse events that emerged or worsened after the initiation of a trial drug until 47 days after the last dose of a trial drug. Adverse events that occurred in at least 10% of the patients with any grade of drug-related adverse event in either treatment group are listed according to preferred or grouped term. Adverse events were coded with the use of the Medical Dictionary for Regulatory Activities, version 27.1, and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. If a patient had more than one event according to a preferred term or grouped term, the patient was counted once at each level of summation.1

a Group term of fatigue includes fatigue, asthenia, malaise, and lethargy.1

b Group term of neutropenia includes neutrophil count decreased and neutropenia.1

c Group term of anemia includes hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.1

d Group term of leukopenia includes white blood cell count decreased and leukopenia.1

e Group term of thrombocytopenia includes platelet count decreased and thrombocytopenia.1

f Group term of aminotransferase level increased includes aminotransferase levels increased, aspartate aminotransferase increased, alanine aminotransferase increased, γ-glutamyltransferase increased, liver function test abnormal, hepatic function abnormal, and liver function test increased.1

gInterstitial lung disease includes all events that were considered by the adjudication committee as being related to a trial drug.1

hThe group term lymphopenia includes lymphocyte count decreased and lymphopenia.1

2L, second line; CI, confidence interval; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ILD, interstitial lung disease; ISH, in situ hybridization; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.

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 locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

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.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

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.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% 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.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

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

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least 1 dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in 1 patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).

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 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • 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 locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

References
  • Shitara K, Van Cutsem E, Gümüş M, et al; DESTINY-Gastric04 Trial Investigators. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med. 2025;1-12. doi:10.1056/NEJMoa2503119
  • Shitara K, Van Cutsem E, Gümüş M, et al; DESTINY-Gastric04 Trial Investigators. Supplement to: Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med. 2025;1-29. doi:10.1056/NEJMoa2503119
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
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