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DESTINY-Gastric02 Trial

ENHERTU was evaluated in a 2L trial in patients in the US and Europe with HER2+ advanced gastric or GEJ adenocarcinoma

A multicenter, open-label, single-arm Phase 2 trial1,2

Adult patients in the United States, Italy, the United Kingdom, Belgium, and Spain with HER2+ unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who had disease progression during or after treatment with a trastuzumab-based regimen

Single arm (N=79)

ENHERTU
6.4 mg/kg once every 3 weeks (21-day cycle)

Patients were treated until disease progression or withdrawal from treatment for other reasons

  • Primary endpoint was confirmed ORR assessed by ICR and secondary endpoints included PFS assessed by ICR, OS, DOR by ICR, safety, and patient-reported outcomes1
Select patient characteristics1 ENHERTU
(N=79)
Median age (range) 60.7 (20.3, 77.8)
Sex Male 72.2%
Female 27.8%
Race White 87.3%
Black or African American 1.3%
Asian 5.1%
Native Hawaiian or Pacific Islander 1.3%
Other 3.8%
Missing 1.3%
ECOG PS 0 36.7%
1 63.3%
Primary tumor site Gastric 34.2%
Gastroesophageal junction 65.8%
Histological subtype Adenocarcinomaa 98.7%
Intestinal 24.1%
Diffuse 1.3%
Mixed 1.3%
Unknown 72.2%

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

a1 patient had non-adenocarcinoma histological subtype.1

 

DESTINY-Gastric02 shows consistent efficacy and safety results with DESTINY-Gastric011,3,4

Confirmed ORR: Primary endpoint1,b

Confirmed objective response rate (41.8%) of ENHERTU from DESTINY-Gastric02 Confirmed objective response rate (41.8%) of ENHERTU from DESTINY-Gastric02

Secondary endpoints1

12.1 months mOS

12.1 months
mOS

8.1 months
mDOR

5.6 months
mPFS

12.1 months mOS

5.6 months mPFS

  • Efficacy data based on a cutoff date of November 8, 2021. Median duration of follow-up was 10.2 months1

b Based on full analysis set.1

c Based on responders (n=33); 18 patients were censored (reasons: initiating new anticancer therapy, event after missing two consecutive assessments, ongoing without event, and adequate tumor assessment no longer available).1

d Based on 51 events (44 PD, 7 deaths).1

 

Most common (≥10%) all Grades TEAEs in DESTINY-Gastric02 (N=79)1

Treatment-emergent
adverse events
All Grades (%) Grade ≥3 (%)
Nausea 67.1 7.6
Vomiting 44.3 2.5
Fatigue 41.8 3.8
Anemia 38.0 13.9
Diarrhea 36.7 1.3
Decreased weight 35.4 3.8
Decreased appetite 32.9 5.1
Constipation 29.1 0
Alopecia 24.1 0
Decreased platelet count 17.7 2.5
Abdominal pain 16.5 2.5
Increased aspartate aminotransferase 16.5 1.3
Hypokalemia 16.5 1.3
Decreased neutrophil count 16.5 7.6
Asthenia 15.2 1.3
Increased blood alkaline phosphatase 11.4 1.3
Cough 11.4 1.3
Pyrexia 11.4 0
Decreased white blood cell count 11.4 6.3
Increased alanine aminotransferase 10.1 1.3
Epistaxis 10.1 0
Gastroesophageal reflux disease 10.1 0
Hypoalbuminemia 10.1 0
Neutropenia 10.1 5.1
Pneumonitis 10.1 1.3
  • Median treatment duration with ENHERTU was 4.3 months (range, 0.7-22.1)1

ILD and pneumonitis, including Grade 5 cases, have been reported with ENHERTU1,e

  • ILD includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis3
  • ILD and pneumonitis, including fatal cases, have been reported with ENHERTU1
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All
Grades
% (n)1 2.5 (2) 5.1 (4) 0 0 2.5 (2) 10.1 (8)
% (n)1
Grade 1 2.5 (2)
Grade 2 5.1 (4)
Grade 3 0
Grade 4 0
Grade 5 2.5 (2)
All Grades 10.1 (8)

e Grade 5=fatal cases.

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; ICR, independent committee review; ILD, interstitial lung disease; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; TEAE, treatment-emergent adverse event.

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 gastric or gastroesophageal junction 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 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.

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 one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

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.

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 one 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 one 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 one 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 hypokalemia. 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%), hypokalemia (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 locally advanced or metastatic HER2‑positive 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. 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 gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

References
  • Ku G, di Bartolomeo M, Smyth E, et al. Updated analysis of DESTINY-Gastric02: a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in Western patients with HER2-positive unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen. Presented at: ESMO 2022 Annual Meeting; September 9-13, 2022; Paris, France.
  • DS-8201a in HER2-positive gastric cancer that cannot be surgically removed or has spread (DESTINY-Gastric02). ClinicalTrials.gov identifier: NCT04014075. Updated May 3, 2023. Accessed May 31, 2023. https://clinicaltrials.gov/ct2/show/record/NCT04014075
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2022.
  • Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430.
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