• First ENHERTU trial in Western patients with gastric cancer
• Efficacy and safety results consistent with pivotal DESTINY-Gastric01 trial; will support ongoing discussions with global health authorities

TOKYO & MUNICH & BASKING RIDGE, N.J.--(BUSINESS WIRE)--Detailed results from the positive DESTINY-Gastric02 phase 2 trial showed that ENHERTU^� (trastuzumab deruxtecan), the Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca HER2 directed antibody drug conjugate (ADC), provided a clinically meaningful and durable tumor response in patients with HER2 positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with a trastuzumab-containing regimen. Results were presented during a late-breaking Mini Oral presentation at the European Society for Medical Oncology (#ESMO21) 2021 Virtual Congress (#LBA55).

Gastric cancer is associated with a poor prognosis, particularly in the advanced stages of the disease, with only 5% to 10% of metastatic patients surviving five years globally.^1,2 Approximately one in five gastric cancers are HER2 positive.^3,4 After progression on first-line HER2 targeted systemic treatment, second-line treatment options in the metastatic setting are limited in certain parts of the world, driving a need for HER2 targeted therapies for these patients.^1,5,6

In the primary analysis of DESTINY-Gastric02, the first trial of ENHERTU specifically in Western patients with HER2 positive metastatic gastric cancer or GEJ adenocarcinoma, ENHERTU (6.4 mg/kg) demonstrated a confirmed overall response rate (ORR) of 38.0% (n=30; CI: 27.3-49.6) as assessed by independent central review (ICR). Out of a total of 79 patients treated with ENHERTU, three (3.8%) complete responses (CR) and 27 (34.2%) partial responses (PR) were observed. These results were consistent with those from the pivotal DESTINY-Gastric01 phase 2 trial, previously published in The New England Journal of Medicine, which evaluated ENHERTU in patients from Japan and South Korea with HER2 positive advanced gastric or GEJ adenocarcinoma who had progressed on two or more prior treatment regimens, including trastuzumab, a fluoropyrimidine and platinum-containing chemotherapy.⁷

After a median follow-up of 5.7 months, the median duration of response (DoR) of ENHERTU was 8.1 months (95% CI: 4.1-NE). The median progression-free survival (PFS) was 5.5 months (95% CI: 4.2-7.3). An exploratory endpoint of confirmed disease control rate (DCR) of 81% (95% CI: 70.6-89.0) was seen.

The overall safety profile of ENHERTU in DESTINY-Gastric02 was consistent with that seen in DESTINY-Gastric01. The most common grade 3 or higher drug-related treatment-emergent adverse events seen in DESTINY-Gastric02 were anemia (7.6%), neutropenia (7.6%), nausea (3.8%), fatigue (3.8%), vomiting (1.3%), diarrhea (1.3%), decreased appetite (1.3%) and decreased platelet count (1.3%). Seven patients (8.9%) discontinued treatment due to drug-related treatment-emergent adverse events. There were six cases (7.6%) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (83%) were low grade (grade 1 or grade 2), with one grade 5 (ILD or pneumonitis-related death).

�While the benefit of a HER2 targeted therapy in the first-line metastatic gastric cancer setting has been well-established, the disease will eventually progress,� said Eric Van Cutsem, MD, PhD, Full Professor and Division Head of Digestive Oncology, University Hospitals Leuven, Belgium. �The positive results of DESTINY-Gastric02 show a strong response rate and reinforce the established efficacy and safety profile of ENHERTU in patients who are in need of additional therapeutic options.�

�The encouraging results from DESTINY-Gastric02 are consistent with those previously seen in the pivotal DESTINY-Gastric01 trial,� said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. �This additional data will support our ongoing discussions with global health authorities as we work toward ENHERTU becoming an option for patients with HER2 positive metastatic gastric cancer.�

�The data from DESTINY-Gastric02 reaffirm the clinical significance of the potential benefit of ENHERTU in patients with advanced gastric cancer,� said Susan Galbraith, MD, PhD, RCP, RCR, Executive Vice President, Oncology R&D, AstraZeneca. �Patients often experience disease progression following initial therapies, and then face limited treatment options, so today�s news brings hope to both patients and treating physicians.�

About DESTINY-Gastric02

DESTINY-Gastric02 is an open-label, single-arm, phase 2 trial in Western patients evaluating the safety and efficacy of ENHERTU (6.4 mg/kg) in patients with HER2 positive metastatic and/or unresectable gastric or GEJ adenocarcinoma whose disease has progressed on or after a trastuzumab-containing regimen. The primary endpoint of DESTINY-Gastric02 is confirmed ORR based on ICR. Secondary endpoints include PFS, overall survival, DoR and safety. DESTINY-Gastric02 enrolled 79 patients at multiple sites in North America and Europe. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Positive Gastric Cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality, with a five-year global survival rate of 5% to 10% for advanced or metastatic disease.^1,2,8 There were approximately one million new cases of gastric cancer and 768,000 deaths reported worldwide in 2020.⁹ Incidence rates for gastric cancer are markedly higher in eastern Asia, where approximately half of all cases occur.^1,8,9,10 Gastric cancer is typically diagnosed in the advanced stage but even when diagnosed in earlier stages of the disease the survival rate remains modest.^5,11,12

Approximately one in five gastric cancers are HER2 positive.^3,4 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers.⁴ HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification.⁴

Recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy.¹⁰ For patients with metastatic gastric cancer that progress following initial treatment with a trastuzumab-based regimen, treatment options are limited, and in many regions in the world there are no additional HER2 directed medicines available.^1,5,6

About ENHERTU

ENHERTU^� (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo�s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca�s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in Canada, EU, Israel, Japan, UK and U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is also approved in Israel, Japan and U.S. for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

ENHERTU was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the �ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers,� based on data from both the DESTINY-Gastric01 and DESTINY-CRC01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2 mutant cohort of the DESTINY-Lung01 trial.

In May 2020, ENHERTU received Breakthrough Therapy Designation in the U.S. for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information for ENHERTU

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

  This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

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.

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. 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

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer

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).

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. 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.

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer

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.

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 the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. 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. 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

Metastatic Breast Cancer

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (?20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer

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 count 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.

Contacts

Media:

Global:
Victoria Amari

Daiichi Sankyo, Inc.

[email protected]
+1 908 900 3010 (mobile)

US:
Don Murphy

Daiichi Sankyo, Inc.

[email protected]
+1 917 817 2649 (mobile)

EU:
Lydia Worms

Daiichi Sankyo Europe GmbH

[email protected]
+49 (89) 7808751 (office)

+49 176 11780861 (mobile)

Japan:
Masashi Kawase

Daiichi Sankyo Co., Ltd.

[email protected]
+81 3 6225 1126 (office)

Investor Relations Contact:
[email protected]

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