ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate that is now approved for use in adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.¹

In the clinical trial DESTINY-Gastric01, ENHERTU achieved significantly longer overall survival versus chemotherapy (irinotecan or paclitaxel)^1,2*:

• 12.5-month mOS† (95% CI: 9.6, 14.3) vs 8.4 months (95% CI: 6.9, 10.7) with chemotherapy; HR=0.59‡; 95% CI: 0.39, 0.88; P=0.00971§

• 40.5% confirmed ORR‖ (n=51/126; 95% CI¶: 31.8, 49.6) vs 11.3% (n=7/62; 95%CI¶: 4.7, 21.9) with chemotherapy; P<0.00011**

ENHERTU has Boxed WARNINGS for Interstitial Lung Disease/Pneumonitis and Embryo-Fetal Toxicity. In the attachment, please see Important Safety Information and full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

*OS was evaluated following a statistically significant outcome of ORR. Interim OS analyses were conducted after all patients had tumor assessment at approximately 24 weeks or discontinued the study. Data cutoff date November 8, 2019.1,2

†Median based on Kaplan-Meier estimate; 95% CI for median calculated using Brookmeyer-Crowley method.

‡Based on the stratified Cox proportional hazards regression model (stratified by region).

§Based on the stratified log-rank test (stratified by region).

‖Confirmed ORR was assessed by ICR and defined as a response (CR+PR according to RECIST v1.1) as confirmed on a follow-up scan ≥4 weeks after an initial response as designated by ICR.1,2

¶95% exact binomial confidence interval.

**Based on the stratified Cochran-Mantel-Haenszel test (stratified by region).

††Patients in the chemotherapy arm received either irinotecan monotherapy 150 mg/m2 IV every 2 weeks or paclitaxel monotherapy 80 mg/m2 IV weekly.1

ENHERTU was assessed in a multicenter, open-label, randomized, phase 2 trial in Japan and South Korea of 188 adult patients with HER2+ locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who had progressed on ≥2 prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy regimen. Patients in the ENHERTU arm received 6.4 mg/kg IV once every 3 weeks^†† until unacceptable toxicity or disease progression. The major efficacy outcomes were ORR assessed by ICR according to RECIST v1.1 and OS. Additional efficacy outcomes were PFS and DOR.^1,2

Important Safety Information

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. In DESTINY-Gastric01, of the 125 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 21.0). 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. Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. In DESTINY-Gastric01, of the 125 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. 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. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3°C or a sustained temperature of ≥38°C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level. 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. In DESTINY-Gastric01, of the 125 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. 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. 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. 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 at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 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. 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 once every three 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) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group. 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 hemoglobin decreased (75%), white blood cell decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (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 following 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 at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following 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. • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor. 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 for full Prescribing Information, including Boxed WARNINGS, and Medication Guide. aGC, advanced gastric cancer; CI, confidence interval; CR, complete response; DOR, duration of response; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; ICR, independent central review; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors.

References:

1. ENHERTU. Package insert. Daiichi Sankyo, Inc; 2021.

2. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430.

3. Curea FG, Hebbar M, Ilie SM, et al. Current targeted therapies in HER2-positive gastric adenocarcinoma. Cancer Biother Radiopharm. 2017;32(10):351‐363.

4. Zhao D, Klempner SJ, Chao J. Progress and challenges in HER2-positive gastroesophageal adenocarcinoma. J Hematol Oncol. 2019;12(1):50.

5. HCPCS Quarterly Update. Centers for Medicare & Medicaid Services. Updated October 15, 2020. Accessed October 19, 2020. https://www.cms.gov/ Medicare/Coding/HCPCSReleaseCodeSets/HCPCS-Quarterly-Update

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ENHERTU^® is a registered trademark of Daiichi Sankyo Company, Limited.

© 2021 Daiichi Sankyo, Inc. and AstraZeneca. PP-US-ENG-0289  01/21