Ifinatamab deruxtecan

TOKYO, Japan & BASKING RIDGE, NJ, USA I January 30, 2025 I The first patient has been dosed in the TROPION-Lung12 phase 3 trial evaluating the efficacy and safety of adjuvant DATROWAY ® (datopotamab deruxtecan) plus rilvegostomig or rilvegostomig monotherapy versus standard of care in patients with stage 1 adenocarcinoma non-small cell lung cancer (NSCLC) after complete surgical resection who are ctDNA-positive or have other high risk pathological features. DATROWAY is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). Standard treatment for stage 1 NSCLC is tumor resection, but up to 40% of patients may experience disease recurrence. 1,2,3 Tumor resection is typically followed by observation but adjuvant chemotherapy and/or immunotherapy may be offered to patients with stage 1b disease who are identified to be at high risk of relapse. 4 However, novel strategies to identify high risk patients are needed as well as additional treatment options in the adjuvant setting. Research suggests that ctDNA screening may help identify high risk patients who are most likely to benefit from adjuvant therapy. 5,6 “After surgery for early-stage non-small cell lung cancer, there is no established consensus on adjuvant therapy. As a result, patients may either undergo observation or receive adjuvant chemotherapy and/or immunotherapy if they have stage 1b disease and are determined to be at high risk for disease recurrence,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “The TROPION-Lung12 trial will help us better understand the role of DATROWAY in combination with immunotherapy in the adjuvant setting as a potential treatment regimen to help prevent disease recurrence in patients with high risk stage 1 adenocarcinoma following surgery.” “With TROPION-Lung12, we are simultaneously deploying a novel strategy for identifying patients with lung cancer who are at an increased risk of disease recurrence after surgery and evaluating novel treatment options in the adjuvant setting, including rilvegostomig with and without DATROWAY,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “The ambitious approach in this trial underscores our commitment to both enabling more personalized treatment decisions and delivering innovative treatment options to patients with cancer.” About TROPION-Lung12 TROPION-Lung12 is a global, multicenter, three-arm, open-label phase 3 trial where patients will be randomized in a 2:1:2 ratio to evaluate the efficacy and safety of adjuvant DATROWAY (6 mg/kg) in combination with rilvegostomig (750 mg) or rilvegostomig (750 mg) monotherapy versus observation or standard of care adjuvant chemotherapy regimens in those with stage 1 (stage 1a or 1b with tumors < 4 cm) adenocarcinoma NSCLC who are ctDNA-positive (as determined by an investigational ctDNA assay) or have high risk pathological features (as determined by central pathology assessment). The primary endpoint of TROPION-Lung12 is disease-free survival following complete tumor resection as assessed by blinded independent central review in patients treated with adjuvant DATROWAY and rilvegostomig versus those who undergo observation or receive standard of care. Key secondary endpoints include patient-reported physical functions, patient-reported quality of life outcomes, overall survival and safety. TROPION-Lung12 will enroll approximately 660 patients in Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov . Rilvegostomig is AstraZeneca’s PD-1/TIGIT bispecific antibody. The TIGIT component of rilvegostomig is derived from the clinical-stage anti-TIGIT antibody, COM902, developed by Compugen Ltd. (Nasdaq/TASE: CGEN). About Non-Small Cell Lung Cancer Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. 7 NSCLC is the most common type of lung cancer and adenocarcinoma is the most common subtype of NSCLC, accounting for about 40% of all lung cancer cases. 8 For patients with stage 1 NSCLC, standard treatment is tumor resection and observation. 4 For patients with stage 1b disease or those otherwise identified as having a high risk of relapse based on clinical or pathological features, tumor resection may be followed by adjuvant chemotherapy and/or immunotherapy. 4 However, strategies to identify high risk patients are needed as well as more durable and effective treatment options in the adjuvant setting. Research suggests that screening for ctDNA in patients with stage 1 NSCLC may help identify patients most likely to benefit from adjuvant therapy and that combining an immunotherapy with an ADC has the potential to drive deeper and more durable tumor responses. 5,6 TROP2 is a protein broadly expressed in the majority of NSCLC tumors. 9 There is currently no TROP2 directed ADC approved for the treatment of lung cancer. 10,11 About DATROWAY DATROWAY (datopotamab deruxtecan; datopotamab deruxtecan-dlnk in the U.S. only) is a TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, DATROWAY is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. DATROWAY 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, DXd) via tetrapeptide-based cleavable linkers. DATROWAY (6 mg/kg) is approved in Japan and the U.S. for the treatment of adult patients with unresectable or metastatic HR positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease based on the results from the TROPION-Breast01 trial. About the DATROWAY Clinical Development Program A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of DATROWAY across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 negative breast cancer. The program includes eight phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating DATROWAY as a monotherapy and in combination with other anticancer treatments in various settings. 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 DATROWAY 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 DATROWAY. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and DATROWAY, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. DATROWAY U.S. Important Safety Information Indication DATROWAY ® is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic, hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+/ISH−) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Contraindications None. Warnings and Precautions Interstitial Lung Disease/Pneumonitis DATROWAY can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. In TROPION-Breast01, ILD/pneumonitis occurred in 4.2% of patients treated with DATROWAY, including 0.5% of patients with Grade 3-4 ILD/pneumonitis, and 0.3% with fatal ILD/pneumonitis. Six patients (1.7%) permanently discontinued DATROWAY due to ILD/pneumonitis. The median time to onset of ILD/pneumonitis was 3.5 months (range: 1.2 months to 10.8 months). Patients were excluded from TROPION-Breast01 for a history of ILD/pneumonitis requiring treatment with steroids or for ongoing ILD/pneumonitis. Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) during treatment with DATROWAY. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (eg, ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (eg, ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Withhold DATROWAY in patients with suspected ILD/pneumonitis and permanently discontinue DATROWAY if Grade ≥2 ILD/pneumonitis is confirmed. Ocular Adverse Reactions DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision. In TROPION-Breast01, ocular adverse reactions occurred in 51% of patients treated with DATROWAY. Seven patients (1.9%) experienced Grade 3 ocular adverse reactions, including dry eye, keratitis, and blurred vision. The most common (≥5%) ocular adverse reactions were dry eye (27%), keratitis (24%), blepharitis and increased lacrimation (8% each), and meibomian gland dysfunction (7%). Patients with clinically significant corneal disease were excluded from TROPION-Breast01. The median time to onset for ocular adverse reactions was 2.1 months (range: 0.03 months to 23.2 months). Of the patients who experienced ocular adverse reactions, 45% had complete resolution; 9% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to permanent discontinuation of DATROWAY in 0.8% of patients. Advise patients to use preservative-free lubricant eye drops several times daily for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional. Refer patients to an eye care professional for an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at treatment initiation, annually while on treatment, at end of treatment, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular adverse reactions. Monitor patients for ocular adverse reactions during treatment with DATROWAY, and if diagnosis is confirmed, dose delay, dose reduce, or permanently discontinue DATROWAY based on severity. Stomatitis DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis. In the TROPION-Breast01 study, stomatitis occurred in 59% of patients treated with DATROWAY, including 7% of patients with Grade 3-4 events. Median time to first onset was 0.7 months (range: 0.03 months to 8.8 months). Stomatitis led to interruption of DATROWAY in 1.9%, dosage reductions in 13%, and permanent discontinuation in 0.3% of patients. In patients who received DATROWAY, 38% used a mouthwash containing corticosteroid for management or prophylaxis of stomatitis/oral mucositis at any time during the treatment. Advise patients to use a steroid-containing mouthwash for prophylaxis and treatment of stomatitis. Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY. Monitor patients for signs and symptoms of stomatitis. If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue DATROWAY. Embryo-Fetal Toxicity Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells. Advise patients of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose. Adverse Reactions The safety of DATROWAY was evaluated in 360 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH−) breast cancer who received at least one dose of DATROWAY 6 mg/kg in TROPION-Breast01. DATROWAY was administered by intravenous infusion once every three weeks. The median duration of treatment was 6.7 months (range: 0.7 months to 16.1 months) for patients who received DATROWAY. Serious adverse reactions occurred in 15% of patients who received DATROWAY. Serious adverse reactions in >0.5% of patients who received DATROWAY were urinary tract infection (1.9%), COVID-19 infection (1.7%), ILD/pneumonitis (1.1%), acute kidney injury, pulmonary embolism, vomiting, diarrhea, hemiparesis, and anemia (0.6% each). Fatal adverse reactions occurred in 0.3% of patients who received DATROWAY and were due to ILD/pneumonitis. Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 3.1% of patients. Adverse reactions which resulted in permanent discontinuation of DATROWAY in >0.5% of patients included ILD/pneumonitis (1.7%) and fatigue (0.6%). Dosage interruptions of DATROWAY due to an adverse reaction occurred in 22% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 (3.3%), infusion-related reaction (1.4%), ILD/pneumonitis (1.9%), stomatitis (1.9%), fatigue (1.7%), keratitis (1.4%), acute kidney injury (1.1%), and pneumonia (1.1%). Dose reductions of DATROWAY due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reduction in >1% of patients included stomatitis (13%), fatigue (3.1%), nausea (2.5%), and weight decrease (1.9%). The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis (59%), nausea (56%), fatigue (44%), decreased leukocytes (41%), decreased calcium (39%), alopecia (38%), decreased lymphocytes (36%), decreased hemoglobin (35%), constipation (34%), decreased neutrophils (30%), dry eye (27%), vomiting (24%), increased ALT (24%), keratitis (24%), increased AST (23%), and increased alkaline phosphatase (23%). Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included infusion-related reactions (including bronchospasm), ILD/pneumonitis, headache, pruritus, dry skin, dry mouth, conjunctivitis, blepharitis, meibomian gland dysfunction, blurred vision, increased lacrimation, photophobia, visual impairment, skin hyperpigmentation, and madarosis. Use in Specific Populations 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 the Medication Guide . About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 Dziedzic DA, et al. Clin.Lung Cancer . 2016; 17(5): e157–67. 2 Okami J, et al. J Thorac Oncol . 2019;14(2):212–22. 3 Peters S, et al. J Thorac Oncol . 2014;9(11):1675-1684. 4 NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer . Version 3.2025. 5 Abbosh C, et al. Nature . 2023;616(7957):553-62. 6 Xia L, et al. Clin Cancer Res . (2022) 28 (15): 3308–3317. 7 World Health Organization. Global Cancer Observatory: Lung. Accessed January 2025. 8 National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ ® )–Health Professional Version . Accessed January 2025. 9 Mito R, et al. Pathol Int . 2020;70(5):287-294. 10 American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer . Accessed January 2025. 11 Rodríguez-Abreau D, et al. Ann Onc . 2021 Jul;32(7): 881-895. SOURCE: Daiichi Sankyo

TOKYO & BASKING RIDGE, N.J.--( BUSINESS WIRE )--Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) ENHERTU ® (fam-trastuzumab deruxtecan-nxki) has been approved in the U.S. for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. This approval, which is based on results from the DESTINY-Breast06 phase 3 trial presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and published in The New England Journal of Medicine , follows Priority Review and Breakthrough Therapy Designation by the FDA for ENHERTU in this indication. In the DESTINY-Breast06 trial, ENHERTU demonstrated a 36% reduction in the risk of disease progression or death versus chemotherapy in the overall trial population of patients with chemotherapy-naïve HR positive, HER2 low or HER2 ultralow metastatic breast cancer (n=866) (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76; p<0.0001). A median progression-free survival (PFS) of 13.2 months (95% CI: 12.0-15.2) was seen in patients treated with ENHERTU compared to 8.1 months (95% CI: 7.0-9.0) in patients treated with chemotherapy. The confirmed objective response rate (ORR) in the overall trial population was 62.6% (95% CI: 57.6-67.4) in the ENHERTU arm versus 34.4% (95% CI: 29.7-39.4) in the chemotherapy arm as assessed by blinded independent central review (BICR). There were 10 (2.5%) complete responses (CRs) and 236 (60.1%) partial responses (PRs) seen in the ENHERTU arm compared to zero (0%) CRs and 134 (34.4%) PRs in the chemotherapy arm. The median duration of response (DOR) was 14.3 months in the ENHERTU arm (95% CI: 12.5-15.9) versus 8.6 months in the chemotherapy arm (95% CI: 6.9-11.5) as assessed by BICR. In the HER2 low population (n=713) (HR 0.62; 95% CI: 0.52-0.75; p<0.0001), median PFS was 13.2 months (95% CI: 11.4-15.2) in the ENHERTU arm compared to 8.1 months (95% CI: 7.0-9.0) in the chemotherapy arm. Confirmed ORR was 62.0% (95% CI: 56.5-67.3) versus 35.2% (95% CI: 30.0-40.7) in the chemotherapy arm. There were 9 (2.8%) CRs and 193 (59.2%) PRs seen in the ENHERTU arm compared to zero (0%) CRs and 114 (35.2%) PRs in the chemotherapy arm. Median DOR was 14.1 months (95% CI: 11.9-15.9) versus 8.6 months (95% CI: 6.7-11.3) in the chemotherapy arm. An exploratory analysis of the HER2 ultralow population (n=153) (HR 0.76; 95% CI: 0.49-1.17) showed the clinically meaningful improvement in PFS was consistent between patients with HER2 low and HER2 ultralow expression, with 15.1 months (95% CI: 10.0-17.3) reported in the ENHERTU arm and 8.3 months (95% CI: 5.8-15.2) in the chemotherapy arm. Confirmed ORR was 65.7% (95% CI: 53.1-76.8) in the ENHERTU arm and 30.8% (95% CI: 19.9-43.4) in the chemotherapy arm. Median DOR was 14.3 months (95% CI: 11.8-not estimable [NE]) versus 14.1 months (95% CI: 5.9-NE) in the chemotherapy arm. “ Endocrine therapy is typically used in the initial treatment of HR positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes,” said Aditya Bardia, MD, MPH, Program Director of Breast Oncology and Director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center and Investigator in the DESTINY-Breast06 trial. “ With a median progression-free survival exceeding one year and a response rate of more than 60 percent, trastuzumab deruxtecan offers a potential new standard of care for patients with hormone receptor positive, HER2 low or HER2 ultralow metastatic breast cancer following endocrine therapy.” “ We are excited to see more treatment options for these patients which enable more personalized care,” said Krissa Smith, Vice President, Education, Susan G. Komen. “ It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumors that are HER2 low or HER2 ultralow now have more options to consider with their healthcare team.” ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU (5.4 mg/kg) in DESTINY-Breast06. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, decreased blood potassium, diarrhea, vomiting, constipation, decreased appetite, COVID-19 and musculoskeletal pain. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, COVID-19, febrile neutropenia and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients. “ ENHERTU continues to redefine the classification and treatment of HR positive metastatic breast cancer with important new data across the spectrum of HER2 expression,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “ Today’s approval underscores our ongoing commitment to realizing the full potential of this innovative antibody drug conjugate and represents another paradigm shift in how certain breast cancers can be treated.” “ Building on the practice-changing previous approvals for ENHERTU, this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2 expressing metastatic breast cancer,” said Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca. “ The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining with a standard IHC test to identify those who may be eligible for treatment with ENHERTU following endocrine therapy.” 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 . Financial Considerations Following this approval in the U.S., an amount of $175 million is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the HER2 low and HER2 ultralow chemotherapy-naïve breast cancer indication. Sales of ENHERTU in the U.S. are recognized by Daiichi Sankyo. For further details on the financial arrangements, please consult the collaboration agreement from March 2019 . About DESTINY-Breast06 DESTINY-Breast06 is a global, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab paclitaxel) in patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients also were eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting first-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. HER2 IHC status was confirmed by a central laboratory and determined based on the most recent evaluable HER2 IHC sample prior to randomization. In tumor samples from patients screened for trial eligibility, nearly two-thirds of tumors previously assessed as IHC 0 at a local laboratory were re-classified as HER2 low or HER2 ultralow upon central analysis of the archival tumor sample. It was also observed that approximately 85% to 90% patients with HR positive, HER2 negative metastatic breast cancer may have actionable levels of HER2 expression. The primary endpoint of DESTINY-Breast06 is PFS in the HR positive, HER2 low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2 low and HER2 ultralow), OS in patients in the HER2 low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. Analysis of the HER2 ultralow subgroup was not powered to demonstrate statistical significance. DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov . About Breast Cancer and HER2 Expression Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally. 1 In the U.S., more than 300,000 cases of breast cancer are diagnosed annually. 2 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis. 3 HR positive, HER2 negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers. 3 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer. 4 Patients with high levels of HER2 expression (IHC 3+ or IHC2+/ISH+) are classified as HER2 positive and treated with HER2 targeted therapies, representing approximately 15% to 20% of all breast cancers. 5 Historically, tumors that were not classified as HER2 positive were classified as HER2 negative, despite the fact that many of these tumors still carry some level of HER2 expression. 6 Endocrine therapy is widely given consecutively in the early lines of treatment for HR positive metastatic breast cancer. However, after initial therapy, further efficacy with additional endocrine treatment is often limited. 7 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 7,8,9,10 Prior to the approvals of ENHERTU in HER2 low and HER2 ultralow metastatic breast cancer based on the DESTINY-Breast04 and DESTINY-Breast06 trials, there were no targeted therapies approved specifically for these patient populations. 11,12 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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. ENHERTU (5.4 mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) 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 based on the results from the DESTINY-Breast03 trial. ENHERTU (5.4 mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/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 in the U.S. for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial. ENHERTU (5.4 mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. 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 65 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 , DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (5.4 mg/kg) is approved in Brazil, Israel, Russia and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the U.S. may be contingent upon verification and description of clinical benefit in a confirmatory trial. About the ENHERTU Clinical Development Program A comprehensive global clinical 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 DATROWAY ® 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 DATROWAY. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and DATROWAY, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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 (IHC 3+ or ISH 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: – Hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting – 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 (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen Unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options 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. 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 1 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. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU. HER2-Positive 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 10 9 /L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10 9 /L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 10 9 /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 1 level. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients. HER2-Positive 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 20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF 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. HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4. HER2-Positive 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 10 9 /L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 10 9 /L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by 1 level. Adverse Reactions HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINYBreast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (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 1 dose of ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU. Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (1 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%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%). HER2-Low and HER2-Ultralow Metastatic Breast Cancer DESTINY-Breast06 The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast06. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU. Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each). ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (86%), decreased neutrophil count (75%), nausea (70%), decreased hemoglobin (69%), decreased lymphocyte count (66%), fatigue (53%), decreased platelet count (48%), alopecia (48%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (43%), increased aspartate aminotransferase (41%), decreased blood potassium (35%), diarrhea (34%), vomiting (34%), constipation (32%), decreased appetite (26%), COVID-19 (26%), and musculoskeletal pain (24%). 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 once 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 decreased blood potassium (25%). HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated 2 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 HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity 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, decreased blood potassium, 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%). HER2-Positive 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 1 dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m 2 biweekly or paclitaxel (N=7) 80 mg/m 2 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 1 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 decreased blood potassium. 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%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%). HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2). Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in 1 patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%). 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 1741 patients with HER2-positive, HER2-low, or HER2-ultralow breast cancer treated with ENHERTU 5.4 mg/kg, 24% were ≥65 years and 4.9% 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 (61%) as compared to younger patients (52%). Of the 101 patients with HER2-mutant unresectable or metastatic 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 HER2-positive locally advanced or metastatic 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. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were ≥65 years and 9% 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, DXd. 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 an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References: ____________________ 1 Bray F, et al. CA Cancer J Clin . 2024; 10.3322/caac.21834. 2 American Cancer Society. Key Statistics for Breast Cancer . Accessed January 2025. 3 National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes . Accessed January 2025. 4 Iqbal N, et al. Mol Biol Int . 2014;852748. 5 Ahn S, et al. J Pathol Transl Med . 2020;54(1):34-44. 6 Sajjadi E, et al. Cancer Drug Resist . 2022;5(4):882-888. 7 Manohar P, et al. Cancer Biol Med . 2022 Feb 15; 19(2):202–212. 8 Cortes J, et al. Lancet . 2011;377:914-923. 9 Yuan P, et al. Eur J Cancer . 2019;112:57-65. 10 Jerusalem G, et al. JAMA Oncol . 2018;4(10):1367–1374. 11 Modi S, et al. 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