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Daiichi Sankyo and AstraZeneca’s ENHERTU met pre-specified criteria for objective response rate and duration of response TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Positive topline results from an analysis of the ongoing DESTINY-PanTumor02 phase 2 trial showed treatment with Daiichi Sankyo and AstraZeneca’s ENHERTU® (trastuzumab deruxtecan) met the pre-specified target for objective response rate (ORR) and demonstrated durable response across multiple HER2 expressing advanced solid tumors in heavily pre-treated patients. ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. The DESTINY-PanTumor02 phase 2 trial is evaluating the efficacy and safety of ENHERTU in patients with previously-treated locally advanced, unresectable or metastatic HER2 expressing solid tumors not eligible for curative therapy, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic and rare cancers. The primary endpoint of the trial is investigator-assessed confirmed ORR and investigator-assessed duration of response (DoR) is a key secondary endpoint. The data will be presented at an upcoming medical meeting and shared with global regulatory authorities. HER2 is a tyrosine kinase receptor protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.1,2 In some cancer cells, HER2 expression is amplified or the cells have activating mutations.1,3 While HER2 directed therapies have been used to treat breast, gastric and lung cancers, more research is needed in evaluating their potential in treating other HER2 expressing tumor types.2,4,5,6 “The clinically meaningful responses seen in the DESTINY-PanTumor02 trial reaffirm our belief in the potential of ENHERTU across multiple HER2 expressing cancers,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The results seen so far across multiple cohorts of the trial will inform next steps of our broad development program as we look to bring this important medicine to as many patients as quickly as possible.” “ENHERTU has already demonstrated its potential to improve outcomes for patients with HER2 targetable breast, gastric and lung cancers, and these positive initial results in other tumor settings with significant unmet need are very encouraging,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “The DESTINY-PanTumor02 results mark an important step forward in our understanding of the potential role of ENHERTU across multiple HER2 expressing tumor types.” The safety pro in patients treated with ENHERTU in the DESTINY-PanTumor02 trial was consistent with that seen in other trials of ENHERTU with no new safety signals identified.​ About DESTINY-PanTumor02 DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) for the treatment of HER2 expressing tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and rare tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, disease control rate, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. DESTINY-PanTumor02 has enrolled 268 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov. 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 more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (ISH)-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. ENHERTU (5.4 mg/kg) is approved under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4 mg/kg) is approved in more than 30 countries 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 based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials. 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. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway. 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 the manufacturing and supply of ENHERTU and datopotamab deruxtecan. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and DS-6000, a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, each ADC targets and delivers a cytotoxic payload inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. ENHERTU U.S. Important Safety Information 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 a prior anti-HER2-based regimen either: In the metastatic setting, or In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy This indication is approved under accelerated approval based on objective 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. 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. Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg) In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23). 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 >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level. Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg) In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients. 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. Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg) In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3. 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 Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg) The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%). HER2-Positive Metastatic Breast Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30). Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), hypokalemia (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), respiratory infection (22%), headache (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%). HER2-Low Metastatic Breast Cancer DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and hypokalemia (25%). Unresectable or Metastatic HER2-Mutant NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients with unresectable or metastatic HER2-mutant NSCLC who received ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months. Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%). ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, hypokalemia, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%). Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) 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 883 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.6% were ≥75 years. No overall differences in efficacy within clinical studies 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 (60%) as compared to younger patients (48%). Of the 101 patients with unresectable or metastatic HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. 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 see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit . References: 1 ASCO. Breast Cancer. Accessed March 2023. 2 Iqbal N, et al. Mol Biol Int. 2014;852748. 3 Omar N, et al. Pathogenesis. 2015;2(3):1-9. 4 Wu VS, et al. J Steroid Biochem Mol Biol. 2015;153;45-53. 5 American Cancer Society. Targeted Drug Therapy for Stomach Cancer. Accessed March 2023. 6 National Cancer Institute. Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer. Accessed March 2023. View source version on businesswire.com: Contacts Global: Jennifer Brennan Daiichi Sankyo, Inc. jbrennan2@dsi.com +1 908 900 3183 (mobile) Japan: Koji Ogiwara Daiichi Sankyo Co., Ltd. ogiwara.koji.ay@daiichisankyo.co.jp +81 3 6225 1126 (office) Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp Source: Daiichi Sankyo View this news release online at:

TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo (TSE: 4568) today announced that the first patient has been dosed in the global, randomized TROPION-Lung07 phase 3 trial evaluating datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum chemotherapy, in patients with previously untreated advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with PD-L1 expression less than 50% (TPS<50%) and without actionable genomic alterations. Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). Among patients with NSCLC, nearly half are diagnosed at an advanced stage and generally have a poor prognosis.1,2,3 While first-line treatment with pembrolizumab or other checkpoint inhibitors, with or without chemotherapy, has improved outcomes in patients with NSCLC without actionable genomic alterations, disease progression still occurs in the majority of patients.4,5 “Metastatic non-squamous non-small cell lung cancer remains a challenge because the majority of patients experience disease progression following their initial treatment, underscoring the need for more effective treatment options in the first-line setting,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “The TROPION-Lung07 trial will assess the potential of the combination of datopotamab deruxtecan and pembrolizumab with and without chemotherapy, to evaluate whether this combination may be a more effective standard treatment option than the current standard of care for patients in the first-line setting.” “The combination of datopotamab deruxtecan with a checkpoint inhibitor with or without chemotherapy, has shown increased activity and a manageable safety pro early trials, including TROPION-Lung02,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “With this initiation, TROPION-Lung07 becomes the third phase 3 trial in our evaluation of these investigational combinations for the first-line treatment of patients with non-small cell lung cancer, across PD-L1 segments and tumor histologies.” TROPION-Lung07 is the third clinical trial collaboration and supply agreement between Daiichi Sankyo and AstraZeneca with a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab. Previous clinical trial collaboration agreements were entered in October 2021 for the TROPION-Lung08 phase 3 trial and May 2020 for the TROPION-Lung02 phase 1b trial. About TROPION-Lung07 TROPION-Lung07 is a global, randomized, open-label, phase 3 trial assessing the efficacy and safety of datopotamab deruxtecan in combination with pembrolizumab with or without platinum chemotherapy compared with pembrolizumab and platinum chemotherapy in patients with previously untreated, advanced or metastatic non-squamous NSCLC with less than 50% programmed death-ligand (PD-L1) expression (tumor proportion score [TPS] < 50%) and without actionable genomic alterations. Eligible participants in the three-arm study will be randomized in a 1:1:1 ratio to the following intervention arms: Arm A (datopotamab deruxtecan [6 mg/kg] plus pembrolizumab 200 mg IV plus platinum chemotherapy every three weeks), Arm B (datopotamab deruxtecan [6 mg/kg] plus pembrolizumab 200 mg IV every three weeks), and Arm C (pembrolizumab 200 mg IV plus pemetrexed [500 mg/m2] plus platinum chemotherapy every three weeks). The primary endpoints of TROPION-Lung07 are progression-free survival (PFS) as assessed by blinded independent central review and overall survival. Secondary endpoints include objective response rate, duration of response, time to response, disease control rate as assessed by both investigator and blinded independent central review, PFS as assessed by investigator, PFS2 and safety. TROPION-Lung07 will enroll approximately 975 patients at sites in North America, South America, Europe, Asia and Oceania. For more information visit ClinicalTrials.gov. About Non-Small Cell Lung Cancer Without Actionable Genomic Alterations Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide.1 NSCLC is diagnosed at an advanced stage in nearly 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.6,7,8 While the introduction of targeted therapies and checkpoint inhibitors in recent years have improved outcomes for patients with advanced NSCLC, the majority of tumors do not have known actionable genomic alterations.7,8,9,10 The current standard of care in the first-line treatment of patients with advanced NSCLC without actionable genomic alterations consists of checkpoint inhibitors with or without platinum-based chemotherapy based on PD-L1 expression. While these therapies may improve survival, at least 40% to 60% of patients experience disease progression, underscoring the need for new therapeutic approaches and options.11,12,13,14 TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is widely expressed in several types of tumors, including NSCLC.15,16,17,18 TROP2 is expressed across all lung cancer subtypes with the highest expression seen in the majority of adenocarcinoma and squamous cell carcinoma (the most common forms of NSCLC).19 No TROP2 directed therapies are currently approved for the treatment of patients with NSCLC.19,20,21 About Datopotamab Deruxtecan (Dato-DXd) Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers. A comprehensive development program called TROPION is underway globally with more than 10 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumors including NSCLC, triple negative breast cancer and HR positive, HER2 low or negative breast cancer. Trials in combination with other anticancer treatments are also underway. About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of datopotamab deruxtecan. About the DXd ADC Portfolio of Daiichi Sankyo The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and DS-6000, a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute. Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit: . References: 1 Siegel R, et al. CA Cancer J Clin. 2021;71:7-33. 2 Centers for Disease Control and Prevention. U.S. Cancer Statistics Data Visualizations Tool. Accessed January 2023. 3 Hardstock F, et al. BMC Cancer. 2020;20(1):260. 4 Shields MD, et al. Am Soc Clin Oncol Educ Book. 2021;41:1-23. 5 Walsh RJ, et al. Ther Adv Med Oncol. 2020;12:1758835920937902. 6 World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Accessed January 2023. 7 Chen R, et al. J Hematol Oncol. 2020;13(1):58. 8 Majeed U, et al. J Hematol Oncol. 2021;14(1):108. 9 Adib E, et al. Genome Med. 2022;14(1):39. 10 Bubendorf L, et al. Eur Respir Rev. 2017;26(144):170007. 11 Paz-Ares L, et al. J Thorac Oncol. 2020 Oct;15(10):1657-1669. 12 Mok TSK, et al. Lancet. 2019 May 4;393(10183):1819-1830. 13 Brahmer J.R. et al. KEYNOTE-024 5-year OS update. ESMO 2021 Virtual Congress. 2021 Sept 16 – 20; Abstract LBA51. 14 Rodríguez-Abreu D et al. Ann Onc. 2021 Jul;32(7):881-895. 15 McDougall ARA, et al. Devel Dynamics. 2015;244:99-109. 16 Shvartsur A, et al. Genes Cancer. 2015;6(3-4):84-105. 17 Inamura K, et al. Oncotarget. 2017; 8(17):28725-28735. 18 Goldenberg DM, et al. Oncotarget. 2018;9(48):28989-29006. 19 Mito R, et al. Pathol Int. 2020;70(5):287-294. 20 Zaman S, et al. Onco Targets Ther. 2019;12:1781-1790. 21 American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Accessed January 2023.