• First HER2 directed medicine approved for patients with gastric cancer in a decade

TOKYO & MUNICH & BASKING RIDGE, N.J.--(BUSINESS WIRE)--Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca?s?ENHERTU^??(fam-trastuzumab deruxtecan-nxki) has been approved in the U.S. for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. In the U.S., gastric cancer is more frequently diagnosed in the advanced stage, with only approximately 5% of patients surviving five years.^1,2?Approximately one in five gastric cancers are HER2 positive.³ ?Patients with metastatic HER2 positive gastric cancer with progression following first-line treatment have historically faced poor outcomes, including low response to treatment and rapid disease progression,? said Ronan Kelly, MD, MBA, Director of the Charles A. Sammons Cancer Center and the W.W. Caruth, Jr. Chair of Immunology at Baylor University Medical Center, Dallas, Texas. ?This approval represents the first time a HER2 directed medicine has demonstrated a significant improvement in survival compared to chemotherapy for patients following initial treatment in the metastatic setting and it has the potential to become the new standard of care for this patient population.? Regular approval by the U.S. Food and Drug Administration (FDA) was based on the positive results from the randomized pivotal?DESTINY-Gastric01?phase 2 trial, in which ENHERTU?demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and objective response rate (ORR) versus chemotherapy (irinotecan or paclitaxel) in patients with advanced gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine and a platinum-containing chemotherapy. ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. In the DESTINY-Gastric01 trial, patients (n=126) in the ENHERTU treatment arm had a 41% reduction in the risk of death versus patients (n=62) treated with chemotherapy (based on a hazard ratio [HR] of 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) at a pre-specified interim analysis with a median OS of 12.5 months [95% CI 9.6-14.3] versus 8.4 months [95% CI 6.9-10.7] with chemotherapy. Confirmed ORR, assessed by independent central review, was a major efficacy outcome. Results showed a confirmed ORR of 40.5% [95% CI 31.8-49.6] with ENHERTU compared to 11.3% [95% CI 4.7-21.9] with chemotherapy. Patients treated with ENHERTU had a 7.9% complete response rate (n=10) and a 32.5% partial response rate (n=41) compared to a complete response rate of 0% (n=0) and a partial response rate of 11.3% (n=7) for patients treated with chemotherapy.?Additionally,^?ENHERTU showed a median duration of response (DoR) of 11.3 months [95% CI 5.6-NR] versus 3.9 months [95% CI 3.0-4.9] with chemotherapy. ENHERTU also demonstrated a median progression-free survival (PFS) of 5.6 months [95% CI 4.3-6.9] compared to 3.5 months [95% CI 2.0-4.3] (HR=0.47; 95% CI 0.31-0.71) with chemotherapy. Results from the DESTINY-Gastric01 trial were presented at the 2020 American Society of Clinical Oncology (ASCO) meeting and published in?The New England Journal of Medicine.⁴ ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. The most common adverse reactions (=20%), including laboratory abnormalities, were hemoglobin decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia. 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, interstitial lung disease occurred in 10% of patients. Median time to first onset of ILD was 2.8 months (range: 1.2 to 21.0). ?ENHERTU is the first antibody drug conjugate to receive approval in the U.S. for the treatment of patients with metastatic gastric cancer, and represents a major advance in managing this difficult-to-treat disease,? said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. ?This second indication in the U.S. represents an important step forward in our ambitious plan to accelerate the development of ENHERTU across a broad range of HER2 targetable cancers.? ?Today?s approval of ENHERTU represents the first HER2 directed medicine approved in a decade for patients with HER2 positive metastatic gastric cancer,? said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca. ?The results from the DESTINY-Gastric01 trial highlight the potential to change clinical practice, showing a forty-one percent improvement in survival and a response rate more than three times higher with ENHERTU compared to chemotherapy. We are thrilled to bring this important medicine to more patients and physicians in the U.S.? This is the second regulatory approval for ENHERTU in the U.S. ENHERTU?is also approved in the U.S. under accelerated approval, and in Japan, under the conditional early approval system, 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 DESTINY-Breast01 trial. ENHERTU is also approved in Japan for HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy based on the DESTINY-Gastric01 trial. ENHERTU previously received Priority Review and Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of patients with previously treated HER2 positive metastatic gastric cancer, as well as Orphan Drug Designation (ODD) for patients with gastric cancer, including gastroesophageal junction cancer. Two additional phase 2 trials,?DESTINY-Gastric02?and?DESTINY-Gastric03, are underway, further evaluating the use of ENHERTU in patients with HER2 positive metastatic gastric cancer. Daiichi Sankyo and AstraZeneca are committed to ensuring that patients in the U.S. who are prescribed ENHERTU can access the medication and receive necessary financial support. Provider and patient support, reimbursement and distribution for ENHERTU in the U.S. will be accessible by visiting?www.ENHERTU4U.com?or calling 1-833-ENHERTU (1-833-364-3788). Please visit?www.ENHERTU.com?for full?Prescribing Information, including Boxed WARNINGS, and?Medication Guide. About Gastric Cancer Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease; there were approximately one million new cases reported in 2020 and more than 768,000 deaths.^2,5?In the U.S., it is estimated that 27,600 new cases of gastric cancer were diagnosed in 2020 and more than 11,000 people died from the disease.⁶ Approximately one in five gastric cancers are HER2 positive.³?HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancer. Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease, the survival rate remains modest.¹?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. For patients with metastatic gastric cancer that progresses following initial treatment with a trastuzumab-based regimen, there were previously no other approved HER2 targeted medicines prior to the approval of ENHERTU.³ About DESTINY-Gastric01 DESTINY-Gastric01 is an open-label, multi-center, randomized, pivotal phase 2 trial evaluating the safety and efficacy of ENHERTU (6.4 mg/kg) versus investigator?s choice of chemotherapy?in a primary cohort of 188 patients from Japan and South Korea with HER2 positive (defined as IHC3+ or IHC2+/ISH+), advanced gastric or GEJ adenocarcinoma who had progressed on two or more prior treatment regimens including trastuzumab, a fluoropyrimidine and platinum-containing chemotherapy. Patients were randomized 2:1 to receive ENHERTU?or investigator?s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with ENHERTU 6.4mg/kg once every three weeks or chemotherapy. The main efficacy outcome measures were ORR assessed by independent central review according to RECIST v1.1 and OS in the intent-to-treat population. Additional efficacy outcome measures were PFS and DoR. About ENHERTU ENHERTU^??(trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S.) is a HER2 directed antibody drug conjugate (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. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (?payload?) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. ENHERTU is comprised of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. ENHERTU (5.4 mg/kg)?is approved in the U.S. under accelerated approval, and in Japan, under the conditional early approval system, 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 DESTINY-Breast01 trial, and received a CHMP positive opinion in December 2020 as monotherapy 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. ENHERTU (6.4 mg/kg) is also approved in the U.S. and Japan for the treatment of previously treated patients with HER2 positive metastatic gastric cancer based on the DESTINY-Gastric01 trial. About the ENHERTU Clinical Development Program A comprehensive development program is underway globally with nine pivotal trials evaluating the efficacy and safety of ENHERTU?monotherapy across multiple HER2 targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. In May 2020, ENHERTU received BTD in the U.S. for the treatment of patients with metastatic non-small cell lung cancer whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy. In March 2020, the European Medicines Agency?s CHMP granted ENHERTU?accelerated assessment for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens. About the Collaboration between Daiichi Sankyo and AstraZeneca Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2 directed ADC) in?March 2019, and datopotamab deruxtecan (Dato-DXd; DS-1062; a TROP2 directed ADC) in?July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. 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.

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 5.4mg/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.
• Geriatric Use:?Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were =65 years and 5% were =75 years. No overall differences in efficacy 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 (53%) as compared to younger patients (42%). 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.