AstraZeneca Pharmaceuticals LP

In-licensed SYN-2510/IMM2510, a potentially best-in-class PD-L1xVEGF bispecific antibody, and SYN-27M/IMM27M, a next-generation ADCC-enhanced anti-CTLA-4 antibodyEntered into a 15-year lease for our cell therapy manufacturing facility to AstraZeneca Pharmaceuticals LP DALLAS, Aug. 13, 2024 (GLOBE NEWSWIRE) -- Instil Bio, Inc. (“Instil”) (Nasdaq: TIL), a clinical-stage biopharmaceutical company focused on developing a pipeline of novel therapies, today reported its second quarter 2024 financial results and provided a corporate update. “We have expanded our pipeline with a pair of clinical-stage, potentially best-in-class therapeutics by in-licensing SYN-2510 and SYN-27M,” said Bronson Crouch, CEO of Instil. “By executing a 15-year lease of our Tarzana cell therapy manufacturing facility, we have strengthened our financial foundation to support Instil’s near-term clinical development of these assets.” Recent Highlights: In-licensed SYN-2510 and SYN-27M: In August 2024, SynBioTx, Inc., a wholly owned subsidiary of Instil, entered into a license and collaboration agreement with ImmuneOnco (HKEX:1541) for the exclusive global development and commercialization rights outside of Greater China of SYN-2510, a potentially best-in-class PD-L1xVEGF bispecific antibody, and SYN-27M, a next-generation ADCC-enhanced CTLA-4 antibody. SYN-2510 and SYN-27M have completed Phase 1a dose escalation studies in multiple solid tumor types in China, and ImmuneOnco is continuing patient enrollment in both programs to support dose optimization and dose expansion. Executed lease of our cell therapy manufacturing facility to AstraZeneca Pharmaceuticals LP: In July 2024, Instil reported the execution of a lease of its U.S. cell therapy manufacturing facility to AstraZeneca Pharmaceuticals LP. Under the terms of the agreement, initial base rent is greater than $7.5 million annually, and escalates at 3% per annum, with the tenant also required to pay certain operating expenses and tax expenses, subject to certain rent abatement in the first year of the 15-year lease term. Exploring further opportunities to in-license or acquire novel therapeutic candidates: Instil continues to explore further opportunities to in-license or otherwise acquire novel therapeutic candidates with first-in-class or best-in-class potential.Cash runway expected beyond 2026. Second Quarter 2024 Financial and Operating Results: As of June 30, 2024, Instil had cash, cash equivalents, marketable securities and long-term investments of $152.6 million, which consisted of $6.8 million in cash and cash equivalents, $141.8 million in marketable securities, and $4.0 million in long-term investments, compared to $175.0 million in cash, cash equivalents, marketable securities and long-term investments as of December 31, 2023, consisting of $9.2 million in cash and cash equivalents, $1.5 million in restricted cash, $141.2 million in marketable securities, and $23.2 million in long-term investments. Instil expects that its cash, cash equivalents, marketable securities and long-term investments as of June 30, 2024 will enable it to fund its operating plan beyond 2026. Research and development expenses were $2.9 million and $10.2 million for the three and six months ended June 30, 2024, respectively, compared to $8.5 million and $29.1 million for the three and six months ended June 30, 2023, respectively. General and administrative expenses were $10.7 million and $23.1 million for the three and six months ended June 30, 2024, respectively, compared to $11.5 million and $24.7 million for the three and six months ended June 30, 2023, respectively. Restructuring and impairment charges were $0.5 million and $4.8 million for the three and six months ended June 30, 2024, respectively, compared to $1.0 million and $25.6 million for three and six months ended June 30, 2023, respectively. Net loss per share, basic and diluted were $2.29 and $6.03 for the three and six months ended June 30, 2024, respectively, compared to $2.87 and $11.64 for the three and six months ended June 30, 2023, respectively. Non-GAAP net loss per share, basic and diluted, were $1.57 and $3.95 for the three and six months ended June 30, 2024, respectively, compared to $2.03 and $6.33 for the three and six months ended June 30, 2023, respectively. Note Regarding Use of Non-GAAP Financial Measures In this press release, Instil has presented certain financial information that has not been prepared in accordance with U.S. generally accepted accounting principles (“GAAP”). These non-GAAP financial measures include non-GAAP net loss and non-GAAP net loss per share, which are defined as net loss and net loss per share, respectively, excluding non-cash stock-based compensation expense and restructuring and impairment charges. Instil believes that these non-GAAP financial measures, when considered together with the GAAP figures, can enhance an overall understanding of Instil’s financial performance. The non-GAAP financial measures are included with the intent of providing investors with a more complete understanding of Instil’s operating results. In addition, these non-GAAP financial measures are among the indicators Instil’s management uses for planning purposes and to measure Instil’s performance. These non-GAAP financial measures should be considered in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The non-GAAP financial measures used by Instil may be calculated differently from, and therefore may not be comparable to, non-GAAP financial measures used by other companies. Please refer to the below reconciliation of these non-GAAP financial measures to the comparable GAAP financial measures. About Instil Bio Instil Bio is a clinical-stage biopharmaceutical company focused on developing a pipeline of novel therapies. Instil’s lead asset, SYN-2510, is a novel and differentiated PD-L1xVEGF bispecific antibody in development for the treatment of multiple solid tumor cancers. For more information visit www.instilbio.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipates,” “believes,” “expects,” “expected,” “exploring,” “future,” “intends,” “may,” “plans,” “potential,” “projects,” and “will” or similar expressions are intended to identify forward-looking statements. Forward-looking statements include express or implied statements regarding our expectations with respect to the license and collaboration agreement with ImmuneOnco, the therapeutic potential of SYN-2510 and SYN-27M, clinical development of SYN-2510 and SYN-27M and the generation of clinical data for SYN-2510 and SYN-27M; concerning or implying our ability to acquire and develop additional product candidates; our research, development and regulatory plans for our product candidates; our expectations regarding our capital position, resources, and balance sheet and the expected impact of the lease of our U.S. manufacturing facility with respect thereto, and the potential impact thereof on the development of any product candidates; and other statements that are not historical fact. Forward-looking statements are based on management's current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements, including risks and uncertainties associated with acquiring additional product candidates, the costly and time-consuming drug product development process and the uncertainty of clinical success; the risks inherent in relying on collaborators and other third parties, including for manufacturing and generating clinical data, and the ability to rely on any such data from clinical trials in China in regulatory filings submitted to regulatory authorities outside of China; the risks and uncertainties related to successfully initiating, enrolling, completing and reporting data from clinical studies, particularly collaborator-led clinical trials, as well as the risks that results obtained in any clinical trials to date may not be indicative of results obtained in ongoing or future trials and that our product candidates may otherwise not be effective treatments in their planned indications; risks related to macroeconomic conditions, including as a result of international conflicts and U.S.-China trade and political tensions, as well as interest rates, inflation, and other factors, which could materially and adversely affect our business and operations; the risks and uncertainties associated with the time-consuming and uncertain regulatory approval process and the sufficiency of our cash resources; and other risks and uncertainties affecting us and our plans and development programs, including those discussed in the section titled “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2024 to be filed with the SEC, as well as our other filings with the SEC. Additional information will be made available in other filings that we make from time to time with the SEC. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements speak only as the date hereof, and we disclaim any obligation to update these statements except as may be required by law. Contacts: Investor Relations:1-972-499-3350 investorrelations@instilbio.comwww.instilbio.com INSTIL BIO, INC.SELECTED FINANCIAL DATA (Unaudited; in thousands, except share and per share amounts)Selected Condensed Consolidated Balance Sheet Data June 30, 2024 December 31, 2023Cash, cash equivalents, restricted cash, marketable securities and long-term investments$152,578 $175,018Total assets$294,316 $325,630Total liabilities$99,297 $99,801Total stockholders’ equity$195,019 $225,829 Condensed Consolidated Statements of Operations Three Months Ended Six Months Ended June 30, June 30, 2024 2023 2024 2023 Operating expenses: Research and development$2,921 $8,459 $10,177 $29,129 General and administrative 10,706 11,518 23,130 24,740 Restructuring and impairment charges 508 1,010 4,783 25,564 Total operating expenses 14,135 20,987 38,090 79,433 Loss from operations (14,135) (20,987) (38,090) (79,433)Interest income 1,919 2,287 3,981 4,358 Interest expense (1,999) (590) (3,980) (1,226)Other (expense) income, net (702) 628 (1,130) 571 Net loss$(14,917) $(18,662) $(39,219) $(75,730)Net loss per share, basic and diluted$(2.29) $(2.87) $(6.03) $(11.64)Weighted-average shares used in computing net loss per share, basic and diluted 6,503,913 6,503,913 6,503,913 6,503,913 INSTIL BIO, INC.Reconciliation of GAAP to Non-GAAP Net Loss and Net Loss per Share (Unaudited; in thousands, except share and per share amounts) Three Months Ended Six Months Ended June 30, June 30, 2024 2023 2024 2023 Net loss$(14,917) $(18,662) $(39,219) $(75,730)Adjustments: Non-cash stock-based compensation expense 4,173 4,413 8,688 8,943 Restructuring and impairment charges 508 1,010 4,783 25,564 Non-GAAP net loss$(10,236) $(13,239) $(25,748) $(41,223)Net loss per share, basic and diluted$(2.29) $(2.87) $(6.03) $(11.64)Adjustments: Non-cash stock-based compensation expense per share 0.64 0.68 1.34 1.38 Restructuring and impairment charges per share 0.08 0.16 0.74 3.93 Non-GAAP net loss per share, basic and diluted*$(1.57) $(2.03) $(3.95) $(6.33)Weighted-average shares outstanding, basic and diluted 6,503,913 6,503,913 6,503,913 6,503,913 * Non-GAAP net loss per share, basic and diluted may not total due to rounding.

WILMINGTON, Del.--( BUSINESS WIRE )--Positive high-level results from an interim analysis of the AMPLIFY Phase III trial showed a fixed duration of AstraZeneca’s CALQUENCE ® (acalabrutinib) in combination with venetoclax, with or without obinutuzumab, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemoimmunotherapy in previously untreated adult patients with chronic lymphocytic leukemia (CLL). For the secondary endpoint of overall survival (OS), a trend was observed in favor of CALQUENCE in combination with venetoclax, with or without obinutuzumab, versus standard-of-care chemoimmunotherapy. The OS data were not mature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint. CLL is caused by the abnormal production of white blood cells and is the most prevalent type of leukemia in adults worldwide, with numbers anticipated to grow. 1-3 In the first-line setting, approximately 40,000 patients are treated with the current standard of care. 4 Although CLL is considered an incurable cancer, patients often live with the disease for many years, and may remain on continuous treatment. 5 Jennifer R. Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the trial, said: “ The AMPLIFY results demonstrate the potential of acalabrutinib and venetoclax with or without obinutuzumab to be effective and well-tolerated fixed-duration treatment options for patients with chronic lymphocytic leukemia. This is an important advance in this setting as fixed-duration regimens allow those living with this chronic disease to take breaks from their treatment, thereby decreasing the possibility of long-term adverse events and drug resistance and improving quality of life.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “ The progression-free survival and overall survival results from the AMPLIFY Phase III trial demonstrate the potential of including a BTK inhibitor in a fixed-duration regimen and reinforce our leadership in advancing science for patients with chronic lymphocytic leukemia. If approved, CALQUENCE would become the only second-generation BTK inhibitor available as both a treat-to-progression and fixed-duration treatment, providing more options for patients and their healthcare providers.” The safety and tolerability were consistent with the known safety profile of each medicine. No new safety signals were identified, with low rates of cardiac toxicity observed. The data will be presented at a forthcoming medical meeting and shared with global regulatory authorities. INDICATIONS AND USAGE CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. CALQUENCE is also indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE ® (acalabrutinib) tablets Serious and Opportunistic Infections Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE. Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly. Hemorrhage Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding. Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Cytopenias Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted. Second Primary Malignancies Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure. Cardiac Arrhythmias Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate. Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE. Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE. ADVERSE REACTIONS The most common adverse reactions (≥20%) of any grade in patients with relapsed or refractory MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%). *Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions. Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients. The most common adverse reactions (≥30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea. *Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions. In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively). Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times ULN occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively. In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in >5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection. Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE. DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE. Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor. Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co-administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours. SPECIFIC POPULATIONS Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for 1 week following the last dose of CALQUENCE. It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for 2 weeks after the last dose. Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Please see full Prescribing Information , including Patient Information . Notes CLL In CLL, there is an accumulation of abnormal lymphocytes within the bone marrow and in blood and lymph nodes. 1 Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain. 6 As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets. This could result in anemia, infection and bleeding. 1 B-cell receptor signaling through BTK is one of the essential survival pathways for CLL. AMPLIFY AMPLIFY is a randomized, global, multi-center, open-label Phase III trial evaluating the efficacy and safety of CALQUENCE in combination with venetoclax with and without obinutuzumab compared to investigator's choice of chemoimmunotherapy in adult patients with previously untreated CLL without del(17p) or TP53 mutation. 7 Patients were randomized 1:1:1 to receive either CALQUENCE in combination with venetoclax, CALQUENCE in combination with venetoclax plus obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy. 7 The primary endpoint is PFS in the CALQUENCE and venetoclax arm as assessed by an Independent Review Committee (IRC) and PFS in this arm assessed by investigators (INV) is a key secondary endpoint. IRC and INV assessed PFS in the CALQUENCE , venetoclax and obinutuzumab arm as a key secondary endpoint. Other key secondary endpoints include OS, event-free survival, overall response rate, duration of response and time to next treatment. 7 The trial includes 27 countries across North and South America, Europe, Asia and Oceania. 7 The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic. 7 Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalization and death compared to the general population. 8 CALQUENCE CALQUENCE (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity. 9 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion. CALQUENCE has been used to treat more than 80,000 patients worldwide 10 and is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in the EU and many other countries worldwide and approved in China for relapsed or refractory CLL and SLL. CALQUENCE is also approved in the US, China and several other countries for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. CALQUENCE is not currently approved for the treatment of MCL in Japan or the EU. As part of an extensive clinical development program, CALQUENCE is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma. AstraZeneca in hematology AstraZeneca is pushing the boundaries of science to redefine care in hematology. Our goal is to help transform the lives of patients living with malignant, rare and other related hematologic diseases through innovative medicines and approaches that are shaped by insights from patients, caregivers and physicians. In addition to our marketed products, we are spearheading the development of novel therapies designed to target underlying drivers of disease across six scientific platforms. Our recent acquisitions of Alexion, with expertise in rare, non-malignant blood disorders, and Gracell Biotechnologies Inc., focused on cell therapies for hematologic malignancies, expand our hematology pipeline and enable us to reach more patients with high unmet needs through the end-to-end development and delivery of novel therapies. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version: General Information About Chronic Lymphocytic Leukemia. Available online. Accessed July 2024. American Cancer Society. What is Chronic Lymphocytic Leukemia? Available online. Accessed July 2024. Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015;126(23):871. Cerner CancerMPact and DRG databases. Reflects epidemiology estimates across G8 countries (Cerner CancerMPact for G7: US, EU, Japan; DRG database for China). Accessed July 2024. American Cancer Society. After Chronic Lymphocytic Leukemia Treatment. Available at: https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/after-treatment/follow-up . Accessed July 2024. American Cancer Society. Signs and Symptoms of Chronic Lymphocytic Leukemia. Available online. Accessed July 2024. ClinicalTrials.gov. Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL (AMPLIFY). Available at: https://clinicaltrials.gov/study/NCT03836261 . Accessed July 2024. Dube S, et al. Continued Increased Risk of COVID-19 Hospitalisation and Death in Immunocompromised Individuals Despite Receipt of ≥4 Vaccine Doses: Updated 2023 Results from INFORM, a Retrospective Health Database Study in England. Poster P0409 at ECCMID 2024. Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol . 2016;9(21). Data on File, REF-236261. AstraZeneca Pharmaceuticals LP. US-92135 Last Updated 7/24

If approved, AstraZeneca and Daiichi Sankyo’s ENHERTU will potentially be the first HER2-directed treatment and antibody drug conjugate to receive a tumor-agnostic indication Application based on results from DESTINY-PanTumor02 trial and supported by additional ENHERTU data Submission to be reviewed under FDA Real-Time Oncology Review and Project Orbis WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca Pharmaceuticals LP and Daiichi Sankyo's supplemental Biologics License Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki) has been accepted and granted Priority Review in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior treatment or who have no satisfactory alternative treatment options. The sBLA is based on data from the ongoing DESTINY-PanTumor02 Phase II trial where ENHERTU demonstrated clinically meaningful and durable responses leading to a clinically meaningful survival benefit in previously treated patients across HER2-expressing metastatic solid tumors, including biliary tract, bladder, cervical, endometrial, ovarian cancers, and other tumors. Data from other supporting trials in patients with HER2-positive IHC3+ tumors in the ENHERTU clinical development program, including DESTINY-Lung01 and DESTINY-CRC02, were also included in the submission. ENHERTU is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance.1 The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the second quarter of 2024. Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Today’s Priority Review for the first tumor-agnostic submission for ENHERTU reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers. Biomarkers for HER2 expression are already established in breast and gastric cancers, but we must now define them across tumor types. We will continue working closely with the FDA to bring this potential first tumor-agnostic HER2-targeted medicine and biomarker to patients as quickly as possible.” Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “The clinical benefit seen across HER2-expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the ENHERTU clinical development program continues to demonstrate the potential of this medicine beyond its approved indications. If approved, ENHERTU could become the first HER2-directed therapy and antibody drug conjugate with a tumor-agnostic indication, providing patients with a potential new treatment option.” The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA which are designed to bring safe and effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners. Results from DESTINY-PanTumor02 were presented at the 2023 European Society for Medical Oncology Congress and simultaneously published in the Journal of Clinical Oncology.2 The safety pro across the trials was consistent with previous clinical trials of ENHERTU with no new safety concerns identified. The Priority Review follows receipt of Breakthrough Therapy Designation (BTD) in the US in August 2023 for ENHERTU in metastatic HER2-positive solid tumors. 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. Notes HER2 expression in solid tumors HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.3,4 In some cancers, HER2 expression is amplified or the cells have activating mutations.3,5 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.6 While HER2-directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2-expressing solid tumor types.4,7,8 HER2 is an emerging biomarker in solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.5 Testing is not routinely performed in these additional tumor types and as a result, available literature is limited. In these solid tumors, HER2-positive expression, classified as IHC 3+, has been observed at rates from 1% to 28%.9,10 There is an unmet need for effective therapies for certain HER2-expressing solid tumors, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2-directed therapies for these cancers.4,11 DESTINY-PanTumor02 DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg) for the treatment of previously treated HER2-expressing tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer or other tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed objective response rate (ORR) as assessed by investigator. Secondary endpoints include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, tolerability and pharmacokinetics. DESTINY-PanTumor02 has enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov. DESTINY-Lung01 DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg or 6.4mg/kg) in patients with HER2-mutant (cohort 2, n=91) or HER2-overexpressing (defined as IHC 3+ or IHC 2+) [cohort 1 and 1a, n=90] unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov. DESTINY-CRC02 DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter Phase II trial evaluating the efficacy and safety of two doses (5.4mg/kg or 6.4mg/kg) of ENHERTU in patients with locally advanced, unresectable or metastatic HER2-positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4mg/kg or 6.4mg/kg of ENHERTU. In the second stage, additional patients (n=42) were enrolled in the 5.4mg/kg arm. The primary endpoint is confirmed ORR as assessed by blinded independent central review. Secondary endpoints include DoR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. DESTINY-CRC02 enrolled 122 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov. ENHERTU ENHERTU 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 (5.4mg/kg) is approved in more than 55 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 (5.4mg/kg) is approved in more than 45 countries for the treatment of adult patients with unresectable or metastatic HER2-low (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 (5.4mg/kg) is approved in more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer 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 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4mg/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 trial and/or DESTINY-Gastric02 trial. ENHERTU development program A comprehensive clinical development program is underway globally, evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. Daiichi Sankyo collaboration Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit and follow the Company on Social Media @AstraZeneca. References FDA. Priority Review. Available at: . Accessed January 2024. Meric-Bernstam F, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2023 Oct;42:47-58. ASCO. Breast Cancer. Available at: . Accessed January 2024. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014; 852748. Omar N, et al. HER2-an emerging biomarker in non-breast and non-gastric cancers. Pathogenesis. 2015;2(3):1-9. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21): 4099-4105. National Cancer Institute. Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer. Available at: . Accessed January 2024. Siena S, et al. Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) Oncogene in Colorectal Cancer. Ann Oncol. 2018 May;29(5):1108-1119. Yan M, et al. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015 Mar;34(1):157-64. Buza N, et al. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Modern Pathology. 2013 Dec;26(12):1605-12. Meric-Bernstam F, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentere, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019 Apr;20(4):518-530. US-84753 Last Updated 01/24