Etoposide

Between December 2024 and July 2025, Oryzon secured financing totaling €52 M, approx. $61 M (€30.0 M from a capital increase, €7.0 M from commercial bank loans, €13.2 M from the EU-IPCEI grant, and €1.8 M from R&D cash-back incentives)Company has terminated the Convertible Bonds financing facility with Nice&GreenClinical trial protocol for vafidemstat’s Phase III PORTICO-2 trial in BPD submitted to the FDAExpansion of ongoing Phase IIb EVOLUTION study with vafidemstat in schizophrenia into other EU countriesNew Phase II trial in preparation: vafidemstat to target aggression in Autism Spectrum DisorderSignificant clinical progress achieved in ongoing iadademstat’s oncology trials in AML (R/R and 1L), MDS and SCLCExpanding iadademstat into non-malignant hematological indications, with a first clinical trial in sickle cell disease MADRID and CAMBRIDGE, Mass., July 30, 2025 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company and a European leader in epigenetics, today reported financial results for the half-year ended June 30, 2025 and provided a corporate update on recent developments. Since last December, the company has secured $61 million in funding, including $35.2 million (€30 million) from a successful capital raise completed in April through a straight equity issuance with no warrants attached. Despite challenging market conditions, the offering attracted strong investor demand and was significantly oversubscribed. “Our successful €30 million capital raise, executed under extraodinarily challenging market conditions, represents a strong vote of confidence in Oryzon’s science, clinical pipeline, and long-term value proposition,” said Dr Carlos Buesa, Oryzon’s Chief Executive Officer. “The proceeds not only reinforce our financial position but also elevate our visibility in the international biotech arena. This funding enables us to advance our clinical programs with renewed momentum and strategic clarity. We are confident that the clinical progress and data to be presented in the coming quarters will further validate the trust placed in us by the investment community.” Dr. Buesa continued, “We are moving closer to becoming a Phase III-stage company, following the submission in June of the Phase III clinical trial protocol for vafidemstat in the treatment of agitation and aggression in Borderline Personality Disorder (BPD) to the FDA. This protocol incorporates all feedback and recommendations received from the agency regarding endpoints. In parallel, additional exploratory data from earlier Phase IIa studies suggest that vafidemstat may also reduce aggression in other patient populations. Building on this, we are now initiating preparations for a new Phase II trial to evaluate vafidemstat in aggression associated with autism spectrum disorder, which will be supported under the recently awarded EU-IPCEI grant. Following the recent financing, we are also expanding the ongoing EVOLUTION trial in schizophrenia, previously conducted exclusively in Spain, into additional European countries. This geographic expansion is designed to accelerate recruitment and further strengthen the robustness of the trial.” “In oncology, we are pleased with the solid progress being made across all ongoing iadademstat clinical trials,” said Dr. Buesa. “This includes the company-sponsored FRIDA trial in relapsed/refractory FLT3-mutated AML, as well as the IIS and CRADA studies in first-line AML, MDS, and small cell lung cancer. We anticipate presenting updates and data from some of these programs at the upcoming ASH-2025 conference this December, marking an important opportunity to share our clinical advances with the broader hematology and oncology community.” Dr. Buesa added, “We are extremely excited to expand iadademstat’s clinical evaluation into non-malignant hematological indications, beginning with sickle cell disease (SCD). In SCD, LSD1 inhibition plays a central mechanistic role in re-inducing fetal hemoglobin, needed to rescue the disease phenotype. Our preliminary data in nonhuman primate models have been highly encouraging compared to other agents in development”. He added,“The SCD market is substantial, as highlighted by Pfizer’s experience with voxelotor (Oxbryta®), which received FDA accelerated approval in 2019. Although the drug was later withdrawn in 2024 due to emerging safety concerns, its initial commercial promise underscored the significant unmet medical need and the market potential in this indication.” First Half and Recent Highlights Vafidemstat: The clinical trial protocol for the PORTICO-2 Phase III trial with vafidemstat in Borderline Personality Disorder (BPD) was submitted to the U.S. Food & Drug Administration (FDA) for approval in June. The primary and key secondary endpoints of the trial have been defined in collaboration with Oryzon’s Clinical Advisory Board (CAB), which comprises leading experts in psychiatric research and clinical trials. PORTICO-2 will use two clinical outcome measures to assess aggression: the STAXI-2 Trait anger scale (a patient-reported outcome) as the primary endpoint, and the Overt Aggression Scale-Modified (OAS-M) (a clinician-rated scale) as a key secondary endpoint. Additional secondary endpoints will assess overall BPD improvement and quality of life. The study will enroll approximately 350 patients, randomized 1:1 to receive vafidemstat or placebo, with a total trial duration of 18 weeks. Subject to FDA’s review of the final data, PORTICO-2 has the potential to be one of the two registrational trials required by the FDA for potential approval of vafidemstat in this indication. FDA approval for the study is expected in 2H25.A dedicated Key Opinion Leader (KOL) webinar with the participation of Dr. Michael Ropacki, Oryzon’s CMO for CNS, and Oryzon’s CAB members was held on July 9 to discuss the PORTICO-2 study design, the substantial unmet medical need in BPD, and the role of aggression as a clinical target. A replay of this event is available at the company’s website, here.Oryzon has announced plans to evaluate vafidemstat for the treatment of aggression in patients with autism spectrum disorder (ASD) in a new Phase II trial. This trial, named HOPE-2, plans to include, inter alia, genetically-defined ASD subpopulations, such as individuals with Phelan-McDermid syndrome, and will initially be conducted in Spain as part of the activities supported by the recently granted Med4Cure IPCEI EU initiative.The EVOLUTION Phase IIb clinical trial evaluating vafidemstat in patients with schizophrenia continues to enroll participants. This study aims to assess the efficacy of vafidemstat, with a primary focus on improving negative symptoms. As secondary endpoints, the trial will evaluate vafidemstat’s efficacy in improving cognitive impairment and positive symptoms in schizophrenia. Based on insights gained from the PORTICO trial, a reassessment of the number of patients needed to obtain a clinically meaningful impact has been conducted, and as a result, the trial is being re-sized to a total number of 84 patients. Initially conducted only in Spain, the trial is now being expanded to include additional EU countries.Oryzon has continued to strengthen its patent portfolio for vafidemstat during this quarter, with additional “Decision to grant” communications from the Canadian and Israel patent offices for patent applications titled “Methods of treating behavior alterations”. The allowed claims cover the use of vafidemstat for the treatment of aggression and social withdrawal. Once issued, these patents will not expire until at least 2038, excluding any potential patent term extension. Corresponding patents have already been granted or allowed in Europe, Australia, Hong Kong, South Korea, Malaysia, the Philippines, and Russia, and additional applications are pending in other countries. Iadademstat: FRIDA, an open-label, multicenter Phase Ib clinical trial of iadademstat in combination with gilteritinib in patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) harboring a FMS-like tyrosine kinase mutation (FLT3mut+), continues to enroll patients. Following the FDA’s new OPTIMUS doctrine, the company continues to explore the minimal dose with clinical activity. The primary objectives of the trial are to evaluate the safety and tolerability of iadademstat in combination with gilteritinib in patients with FLT3mut+ R/R AML and to establish the Recommended Phase 2 Dose (RP2D) for this combination, while the secondary objectives focus on assessing treatment efficacy. The study is being conducted in the U.S. and will accrue up to approximately 45 patients. If successful, Oryzon and the FDA have agreed to hold a meeting to discuss the best plan to further develop this combination in this much-in-need AML population. The company plans to present the next data update from this trial at ASH-2025.The two Phase I dose-finding clinical trials evaluating iadademstat in combination with venetoclax and azacitidine in patients with newly diagnosed AML have continued to actively enroll patients. One trial is sponsored by the National Cancer Institute (NCI) under the Cooperative Research and Development Agreement (CRADA) signed between Oryzon and the NCI, while the other is an Investigator-initiated study (IIS) sponsored by the Oregon Health & Science University (OHSU) Knight Cancer Institute.In addition, the IIS Phase I dose-finding trial of iadademstat in combination with azacitidine in myelodysplastic syndrome (MDS), led by the Medical College of Wisconsin (MCW), has also continued to actively enroll patients.The Phase I/II trial with iadademstat plus immune checkpoint inhibitors (ICI) in first line small cell lung cancer (SCLC) patients with extensive disease, conducted under the CRADA that Oryzon has in place with the NCI, started to enroll patients in April 2025. The trial will evaluate the safety, tolerability, dose finding and efficacy of iadademstat in combination with an ICI, either atezolizumab or durvalumab, in patients with extensive-stage SCLC who have initially received standard of care chemotherapy and immunotherapy. This study is conducted and sponsored by the NCI, with Dr. Charles Rudin from the Memorial Sloan Kettering Cancer Center (MSKCC) as the main PI for the trial. More than 30 sites accross the U.S. participate in the trial, including renowned institutions such as MSKCC, Johns Hopkins, City of Hope, University of Chicago, and many others. The trial plans to enroll 45-50 patients.Beyond oncology, Oryzon has announced plans to evaluate iadademstat in non-malignant hematological disorders, such as sickle cell disease (SCD) and essential thrombocythemia (ET). A clinical trial application (CTA) - the EU equivalent to an IND - for a new Phase Ib trial with iadademstat in SCD has been submitted to the European Medicines Agency (EMA). This trial, named RESTORE (REgulation of Sickling ThrOugh Reprogramming Epigenetics), aims to enroll 40 patients. The primary objectives will be to evaluate the safety and tolerability of iadademstat in adult patients with SCD, and to determine its Recommended Phase 2 dose (RP2D). Secondary objectives include assessing iadademstat’s activity in inducing fetal hemoglobin, among others. CTA approval is expected in September. A second trial, which will evaluate iadademstat in ET, is currently in preparation, with CTA submission to EMA planned for 2H25. Earlier stage programs: ORY-4001, Oryzon’s highly selective histone deacetylase 6 (HDAC6) inhibitor nominated as a clinical candidate for the treatment of certain neurological diseases such as Charcot-Marie-Tooth disease (CMT), Amyotrophic Lateral Sclerosis (ALS) and others, continues to progress through IND enabling studies to prepare it for clinical studies. Financial Update: First half 2025 Financial Results Research and development (R&D) expenses were $3.0 million and $5.8 million for the quarter and six months ended June 30, 2025, compared to $2.3 and $4.9 million for the quarter and six months ended June 30, 2024. General and administrative expenses were $1.4 and $2.7 million for the quarter and six months ended June 30, 2025, compared to $1.2 and $2.1 million for the quarter and six months ended June 30, 2024. Net losses were $1.7 and $3.4 million for the quarter and six months ended June 30, 2025, compared to $1.5 and 2.6 million for the quarter and six months ended June 30, 2024. The result is as expected, given the biotechnology business model where companies in the development phase typically have a long-term maturation period for products and do not have recurrent income. Negative net result was $1.9 million (–$0.03 per share) for the six months ended June 30, 2025, compared to a negative net result of $1.1 million (–$0.02 per share) for the six months ended June 30, 2024. Cash, cash equivalents, and marketable securities totaled $36.5 million as of June 30, 2025. In April 2025, the company raised a capital increase of €30 million, as straight equity with no warranties attached, which will be used to fund clinical development and corporate initiatives. Despite the very adverse market conditions, the financing attracted strong demand and was upsized from the original planned €25 million and ended significantly oversubscribed. A US-based institutional investor anchored the round with a €15 million order, with the remaining demand filled by investors across the US, Europe, and Spain. The capital increase was capped at €30 million by the company’s Board of Directors. In July 2025, the company received the full disbursement of the Important Project of Common European Interest (IPCEI) grant, totaling €13.2 million (approximately $15 million USD), for its VANDAM project. Given the Company’s current treasury needs, the financing agreement between Nice & Green and the Company was terminated in July through a payment of €4.7 million. As a result, Oryzon received 1,340,083 of its own shares, increasing its treasury stock to a total of 2,374,666 shares. ORYZON GENOMICS, S.A.BALANCE SHEET DATA (UNAUDITED)1(Amounts in thousands US $) June 30th, 2025 June 30th, 2024 Cash and cash equivalents36,465 10,787Marketable securities0 0Total Assets162,147 118,474 Deferred revenue0 0Total Stockholders' equity133,869 92,612 ORYZON GENOMICS, S.A. STATEMENTS OF OPERATIONS (UNAUDITED)1 (US $, amounts in thousands except per share data) Three Months Ended June 30th Six Months Ended June 30th 20252024 20252024 Collaboration Revenue00 00 Operating expenses: Research and Development 2,9622,325 5,7604,935 General and administrative 1,3821,222 2,6542,077 Total operating expenses 4,3443,547 8,4147,012 Loss from Operations-4,344-3,547 -8,414-7,012 Other income, net2,6232,061 4,9764,438 Net Loss -1,721-1,486 -3,438-2,574 Net Financial & Tax1,8421,599 1,5691,460 Net Result 121113 -1,869-1,114 Loss per share allocable to common stockholders: Basic 0.000.00 -0.03-0.02 Weighted average Shares outstanding Basic 77,513,03962,214,547 71,165,32561,807,215 1 Spanish GAAP * Exchange Euro/Dollar (1.1720 for 2025 and 1.0705 in 2024) About OryzonFounded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS (Phase III-ready) and iadademstat in oncology (Phase II). The company has other pipeline assets directed against other epigenetic targets like HDAC-6 where a clinical candidate ORY-4001, has been nominated for its possible development in CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com About IadademstatIadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and strong clinical activity in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation & The Lancet Haematology, 2024, 11(7):e487-e498). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations, and in combination with azacitidine and venetoclax in 1L AML in an investigator-initiated study led by OHSU and in a trial sponsored by the U.S. National Cancer Institute (NCI) under the Cooperative Research and Development Agreement (CRADA) signed between Oryzon and the NCI to collaborate on further clinical development of iadademstat in different types of hematologic and solid cancers. Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is in a Phase I/II randomized trial in 1L ED-SCLC in combination with ICI sponsored by NCI and led by the Memorial Sloan Kettering Cancer Center. Oryzon is further expanding the clinical development of iadademstat through additional investigator-initiated studies in oncology, and it has announced plans to expand its clinical development in non-oncological hematology indications like sickle cell disease (protocol submitted) and essential thrombocythemia (trial in preparation). Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. About Vafidemstat Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor. The molecule acts on several levels: it reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has neuroprotective effects. In animal studies vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimer’s disease (AD), to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong, and durable efficacy in several preclinical models of multiple sclerosis (MS). Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE, see Ferrer et al, Psychiatry & Clin Neurosci, 2025, doi.org/10.1111/pcn.13800) and in aggressive/agitated patients with moderate or severe AD (REIMAGINE-AD), with positive clinical results reported in both. Additional finalized Phase IIa clinical trials with vafidemstat include the ETHERAL trial in patients with Mild to Moderate AD, where a significant reduction of the inflammatory biomarker YKL40 was observed after 6 and 12 months of treatment, and the pilot, small-scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where anti-inflammatory activity was also observed. Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients. Vafidemstat is currently advancing as a Phase III-ready asset in Borderline Personality disorder (BPD) following completion of the global, randomized, double blind Phase IIb PORTICO trial (final data presented at ECNP-2024). Following receipt of the minutes from the End-of-Phase II meeting with the FDA to discuss PORTICO’s results, the company announced plans to move forward with a Phase III PORTICO-2 trial in agitation/aggression in BPD (PhIII protocol submitted to FDA). Vafidemstat is also being investigated in a double-blind, randomized, placebo-controlled Phase IIb trial in negative symptoms of schizophrenia (EVOLUTION trial, recruitment ongoing). The company is also deploying a CNS precision medicine approach with vafidemstat in genetically defined patient subpopulations of certain CNS disorders, as well as in neurodevelopmental syndromes, and is evaluating the feasibility of conducting clinical trials in autistic conditions like Fragile X syndrome and Phelan-McDermid syndrome. FORWARD-LOOKING STATEMENTSThis communication contains, or may contain, forward-looking information and statements about Oryzon, including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives, and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates” and similar expressions. Although Oryzon believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon to the Spanish Comisión Nacional del Mercado de Valores (CNMV), which are accessible to the public. Forward-looking statements are not guarantees of future performance and have not been reviewed by the auditors of Oryzon. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon or any of its members, directors, officers, employees, or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon on the date hereof. Except as required by applicable law, Oryzon does not undertake any obligation to publicly update or revise any forward‐looking statements, whether as a result of new information, future events, or otherwise. This document does not constitute an offer or invitation to purchase or subscribe shares in accordance with the provisions of Regulation (EU) 2017/1129 of the European Parliament and of the Council of 14 June 2017, and/or the restated text of the Securities Market Law, approved by Law 6/2023 of 17 March, and its implementing regulations. Nothing in this document constitutes investment advice. In addition, this document does not constitute an offer of purchase, sale or exchange, nor a request for an offer of purchase, sale or exchange of securities, nor a request for any vote or approval in any jurisdiction. The shares of Oryzon Genomics, S.A. may not be offered or sold in the United States of America except pursuant to an effective registration statement under the Securities Act of 1933 or pursuant to a valid exemption from registration. Spain Oryzon IR & Media, Europe & USPatricia Cobo/Mario Cordera Emili Torrell Sandya von der Weid Atrevia Chief BD Officer LifeSci Advisors, LLC +34 91 564 07 25 +34 673 33 97 65 +34 93 515 1313 +41 78 680 05 38pcobo@atrevia.com mcordera@atrevia.com etorrell@oryzon.com svonderweid@lifesciadvisors.com

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca’s supplemental Biologics License Application (sBLA) for IMFINZI® (durvalumab) has been accepted and granted Priority Review in the US for the treatment of patients with resectable, early-stage and locally advanced (Stages II, III, IVA) gastric and gastroesophageal junction (GEJ) cancers. 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 anticipated during the fourth quarter of 2025. IMFINZI was also recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need.2 Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth-highest leading cause of cancer mortality.3 In 2024, there were approximately 6,500 drug-treated patients in the US with early-stage and locally advanced gastric or GEJ cancer. 4 Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “This Priority Review reinforces the potential for a perioperative approach with IMFINZI to transform care for patients with early gastric and gastroesophageal junction cancers, who frequently face disease recurrence or progression even after curative-intent surgery and perioperative chemotherapy. This novel treatment is the only immunotherapy-based regimen to show a statistically significant reduction in the risk of progression, recurrence or death in this setting, and if approved, is poised to change the clinical paradigm." The sBLA is based on data from the MATTERHORN Phase III trial which was presented during the Plenary Session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine. In the trial, patients were treated with neoadjuvant IMFINZI in combination with chemotherapy before surgery, followed by adjuvant IMFINZI in combination with chemotherapy, then IMFINZI monotherapy. In a planned interim analysis, patients treated with the IMFINZI-based perioperative regimen showed a 29% reduction in the risk of disease progression, recurrence or death versus chemotherapy alone (based on an event-free survival [EFS] hazard ratio [HR] of 0.71; 95% confidence interval [CI] 0.58-0.86; P<0.001). Estimated median EFS was not yet reached for the IMFINZI arm versus 32.8 months for the comparator arm. An estimated 78.2% of patients treated with the IMFINZI-based perioperative regimen were event-free at one year, compared to 74.0% in the comparator arm; the estimated 24-month EFS rate was 67.4% versus 58.5%, respectively, signaling a greater magnitude of benefit over time for the IMFINZI-based regimen. For the key secondary endpoint of overall survival (OS), a strong trend was observed in favor of the IMFINZI-based perioperative regimen (HR=0.78; 95% CI 0.62-0.97; P=0.025). The trial will continue to follow OS, which will be formally assessed at the final analysis. The safety profile for IMFINZI and FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy was consistent with the known profiles of each medicine, and the percentage of patients that completed surgery was similar compared to chemotherapy alone. Grade 3 or higher adverse events due to any cause were similar between the two arms. Regulatory applications are currently under review in the EU, Japan and several other countries based on the MATTERHORN results. IMPORTANT SAFETY INFORMATION There are no contraindications for IMFINZI® (durvalumab) or IMJUDO® (tremelimumab-actl). Severe and Fatal Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI and IMJUDO depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI and IMJUDO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis IMFINZI and IMJUDO can cause immune-mediated pneumonitis, which may be fatal. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The incidence of pneumonitis (including radiation pneumonitis) in patients with LS-SCLC following chemoradiation within 42 days prior to initiation of IMFINZI in ADRIATIC was 14% (37/262) in patients receiving IMFINZI and 6% (16/265) in patients receiving placebo. Of the patients who received IMFINZI (262), 0.4% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy. Immune‑mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Immune-Mediated Colitis IMFINZI with IMJUDO and platinum-based chemotherapy can cause immune-mediated colitis, which may be fatal. IMFINZI and IMJUDO can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. Immune‑mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%) adverse reactions. Intestinal perforation has been observed in other studies of IMFINZI and IMJUDO. Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Intestinal perforation and large intestine perforation were reported in 0.1% of patients. Immune-Mediated Hepatitis IMFINZI and IMJUDO can cause immune-mediated hepatitis, which may be fatal. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Immune‑mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.8%), Grade 4 (0.3%) and Grade 3 (4.1%) adverse reactions. Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2%) adverse reactions. Immune-Mediated Endocrinopathies Adrenal Insufficiency : IMFINZI and IMJUDO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.8%) adverse reactions. Hypophysitis : IMFINZI and IMJUDO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. IMFINZI as a Single Agent Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. IMFINZI with IMJUDO Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism) : IMFINZI and IMJUDO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO. Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy. Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. IMFINZI with Carboplatin and Paclitaxel Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis : Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. IMFINZI as a Single Agent Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. IMFINZI with IMJUDO Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including Grade 3 (0.3%) adverse reactions. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI and IMJUDO can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.5%) adverse reactions. Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-Mediated Dermatology Reactions IMFINZI and IMJUDO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and CTLA-4 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Immune-Mediated Pancreatitis IMFINZI in combination with IMJUDO can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI and IMJUDO or were reported with the use of other immune-checkpoint inhibitors. Cardiac/vascular : Myocarditis, pericarditis, vasculitis. Nervous system : Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular : Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal : Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and connective tissue disorders : Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine : Hypoparathyroidism. Other (hematologic/immune) : Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI and IMJUDO based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. Infusion-related reactions occurred in 2.6% (10/388) of patients receiving IMFINZI and IMJUDO. Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on their mechanism of action and data from animal studies, IMFINZI and IMJUDO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and IMJUDO and advise them to use effective contraception during treatment with IMFINZI and IMJUDO and for 3 months after the last dose of IMFINZI and IMJUDO. Lactation There is no information regarding the presence of IMFINZI and IMJUDO in human milk; however, because of the potential for serious adverse reactions in breastfed infants from IMFINZI and IMJUDO, advise women not to breastfeed during treatment and for 3 months after the last dose. Adverse Reactions Unresectable Stage III NSCLC In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), the most common adverse reactions (≥20%) were cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections (26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonia (7%) and pneumonitis/radiation pneumonitis (3.4%). In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), discontinuation due to adverse reactions occurred in 15% of patients in the IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions (≥2%) were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of patients and were similar across arms. Resectable NSCLC In patients with resectable NSCLC in the AEGEAN study, the most common adverse reactions (occurring in ≥20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. In patients with resectable NSCLC in the neoadjuvant phase of the AEGEAN study receiving IMFINZI in combination with platinum-containing chemotherapy (n=401), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients. Serious adverse reactions occurred in 21% of patients. The most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%). Of the 401 IMFINZI treated patients who received neoadjuvant treatment and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. In patients with resectable NSCLC in the adjuvant phase of the AEGEAN study receiving IMFINZI as a single agent (n=265), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 8% of patients. Serious adverse reactions occurred in 13% of patients. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Metastatic NSCLC In patients with mNSCLC in the POSEIDON study receiving IMFINZI and IMJUDO plus platinum-based chemotherapy (n=330), the most common adverse reactions (occurring in ≥20% of patients) were nausea (42%), fatigue (36%), musculoskeletal pain (29%), decreased appetite (28%), rash (27%), and diarrhea (22%). In patients with mNSCLC in the POSEIDON study receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy (n=330), permanent discontinuation of IMFINZI or IMJUDO due to an adverse reaction occurred in 17% of patients. Serious adverse reactions occurred in 44% of patients, with the most frequent serious adverse reactions reported in at least 2% of patients being pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients. Limited-stage Small Cell Lung Cancer In patients with limited-stage SCLC in the ADRIATIC study receiving IMFINZI (n=262), the most common adverse reactions occurring in ≥20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonitis or radiation pneumonitis and pneumonia. In patients with limited-stage SCLC in the ADRIATIC study receiving IMFINZI (n=262), IMFINZI was permanently discontinued due to adverse reactions in 16% of the patients receiving IMFINZI. Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in ≥1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Extensive-stage Small Cell Lung Cancer In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%). In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. Locally Advanced or Metastatic Biliary Tract Cancers In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ≥20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%). In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients). Unresectable Hepatocellular Carcinoma In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), the most common adverse reactions (occurring in ≥20% of patients) were rash (32%), diarrhea (27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%), and abdominal pain (20%). In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), serious adverse reactions occurred in 41% of patients. Serious adverse reactions in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI and IMJUDO, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients. Primary advanced or Recurrent dMMR Endometrial Cancer In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single-agent (n=44), the most common adverse reactions, including laboratory abnormalities (occurring in >20% of patients) were peripheral neuropathy (61%), musculoskeletal pain (59%), nausea (59%), alopecia (52%), fatigue (41%), abdominal pain (39%), constipation (39%), rash (39%), decreased magnesium (36%), increased ALT (32%), increased AST (30%), diarrhea (27%), vomiting (27%), cough (27%), decreased potassium (25%), dyspnea (25%), headache (23%), increased alkaline phosphatase (20%), and decreased appetite (18%). The most common Grade 3 or 4 adverse reactions (≥3%) were constipation (4.5%) and fatigue (4.5%). In patients with advanced or recurrent dMMR endometrial cancer in the DUO-E study receiving IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single-agent (n=44), permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel; the most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%). Muscle-Invasive Bladder Cancer (MIBC) In patients with muscle-invasive bladder cancer (MIBC), the most common adverse reactions, including laboratory abnormalities, in the overall study (occurring in ≥20% of patients) were decreased hemoglobin, decreased neutrophils, increased blood creatinine, decreased sodium, nausea, increased ALT, decreased calcium, decreased platelets, fatigue, increased potassium, decreased lymphocytes, increased AST, constipation, decreased magnesium, decreased appetite, increased alkaline phosphate, rash, pyrexia, diarrhea, vomiting and abdominal pain. In patients with MIBC in the neoadjuvant phase of the NIAGARA study receiving IMFINZI in combination with gemcitabine and cisplatin (n=530), permanent discontinuation of IMFINZI due to an adverse reaction occurred in 9% of patients. Serious adverse reactions occurred in 24% of patients; the most frequent (≥1%) serious adverse reactions were pulmonary embolism (1.9%), febrile neutropenia (1.5%), acute kidney injury (1.3%), thrombocytopenia (1.3%), urinary tract infection (1.3%), and pneumonia (1.3%). Fatal adverse reactions occurred in 1.1% of patients including sepsis, myocardial infarction, and pulmonary embolism (0.2% each). One fatal adverse reaction of pneumonia was reported in 1 (0.2%) patient in the post-surgery phase before adjuvant treatment started. Of the 530 patients in the IMFINZI treatment arm and 526 patients in the chemotherapy treatment arm who received neoadjuvant treatment, 1 (0.2%) patient in each treatment arm did not receive surgery due to adverse reactions. The adverse reaction that led to cancellation of surgery in the IMFINZI treatment arm was interstitial lung disease. In patients with MIBC in the adjuvant phase of the NIAGARA study receiving IMFINZI as a single agent (n=383), permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 5% of patients. Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions (occurring in ≥1% of patients) were urinary tract infection (7%), acute kidney injury (3.7%), hydronephrosis (2.1%), pyelonephritis (2.1%), urosepsis (1.8%) and sepsis (1.6%). Fatal adverse reactions occurred in 1.8% of patients, including COVID-19, severe acute respiratory syndrome, cardiopulmonary failure, gastrointestinal hemorrhage, and chronic hepatic failure (0.3% each). The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients. Indications: IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥4 cm and/or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) as determined by an FDA-approved test. IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by single-agent IMFINZI as adjuvant treatment following radical cystectomy, is indicated for the treatment of adult patients with muscle-invasive bladder cancer (MIBC). Please see additional Important Safety Information throughout and Full Prescribing Information including Medication Guide for IMFINZI and IMJUDO. You may report side effects related to AstraZeneca products. Notes Gastric and gastroesophageal junction cancers Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth-highest leading cause of cancer mortality.3 Nearly one million new patients were diagnosed with gastric cancer in 2022, with approximately 660,000 deaths reported globally.3 In many regions, its incidence has been increasing in patients younger than 50 years old, along with other gastrointestinal (GI) malignancies.5 In 2024, there were approximately 43,000 drug-treated patients in the US, European Union (EU), and Japan with early-stage and locally advanced gastric or GEJ cancer.4 Approximately 62,000 patients in these regions are expected to be newly diagnosed in this setting by 2030.6 GEJ cancer is a type of gastric cancer that arises from and spans the area where the esophagus connects to the stomach.7 Disease recurrence is common in patients with resectable gastric cancer despite undergoing surgery with curative intent and treatment with neoadjuvant/adjuvant chemotherapy. Approximately one in four patients with gastric cancer who undergo surgery develop recurrent disease within one year, and one in four patients do not survive beyond two years, reflecting a high unmet medical need.8-9 Additionally, the five-year survival rate remains poor, with less than half of patients alive at five years.10 MATTERHORN MATTERHORN is a randomized, double-blind, placebo-controlled, multi-center, global Phase III trial evaluating IMFINZI as perioperative treatment for patients with resectable Stage II-IVA gastric and GEJ cancers. Perioperative therapy includes treatment before and after surgery, also known as neoadjuvant/adjuvant therapy. In the trial, 948 patients were randomized to receive a 1500mg fixed dose of IMFINZI plus FLOT chemotherapy or placebo plus FLOT chemotherapy every four weeks for two cycles prior to surgery. This was followed by IMFINZI or placebo every four weeks for up to 12 cycles after surgery (including two cycles of IMFINZI or placebo plus FLOT chemotherapy and 10 additional cycles of IMFINZI or placebo monotherapy). In the MATTERHORN trial, the primary endpoint is EFS, defined as time from randomization until the date of one of the following events (whichever occurred first): RECIST (version 1.1, per blinded independent central review assessment) progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period; RECIST progression/recurrence during the adjuvant period; non-RECIST progression that precludes surgery or requires non-protocol therapy during the neoadjuvant period or discovered during surgery; progression/recurrence confirmed by biopsy post-surgery; or death due to any cause. Key secondary endpoints include pathologic complete response rate, defined as the proportion of patients who have no detectable cancer cells in resected tumor tissue following neoadjuvant therapy, and OS. The trial enrolled participants in 176 centers in 20 countries, including in the US, Canada, Europe, South America and Asia. IMFINZI IMFINZI® (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor's immune-evading tactics and releasing the inhibition of immune responses. In GI cancer, IMFINZI is approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer (BTC) and in combination with IMJUDO® (tremelimumab-actl) in unresectable hepatocellular carcinoma (HCC). IMFINZI is also approved as a monotherapy in unresectable HCC in Japan and the EU. In addition to its indications in GI cancers, IMFINZI is the global standard of care based on OS in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy (CRT). Additionally, IMFINZI is approved as a perioperative treatment in combination with neoadjuvant chemotherapy in resectable NSCLC, and in combination with a short course of IMJUDO and chemotherapy for the treatment of metastatic NSCLC. IMFINZI is also approved for limited-stage small cell lung cancer (SCLC) in patients whose disease has not progressed following concurrent platinum-based CRT; and in combination with chemotherapy for the treatment of extensive-stage SCLC. Perioperative IMFINZI in combination with neoadjuvant chemotherapy is approved in the US and other countries for patients with muscle-invasive bladder cancer based on results from the NIAGARA Phase III trial. Additionally, in May 2025, IMFINZI plus standard-of-care Bacillus Calmette-Guérin induction and maintenance therapy met the primary endpoint of disease-free survival for patients with high-risk non-muscle-invasive bladder cancer in the POTOMAC Phase III trial. IMFINZI in combination with chemotherapy followed by IMFINZI monotherapy is approved as a 1st-line treatment for primary advanced or recurrent endometrial cancer (mismatch repair deficient disease only in the US and EU). IMFINZI in combination with chemotherapy followed by olaparib and IMFINZI is approved for patients with mismatch repair proficient advanced or recurrent endometrial cancer in the EU and Japan. Since the first approval in May 2017, more than 414,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with NSCLC, bladder cancer, breast cancer, ovarian cancer and several GI cancers. AstraZeneca in GI cancers AstraZeneca has a broad development program for the treatment of GI cancers across several medicines and a variety of tumor types and stages of disease. In 2022, GI cancers collectively represented approximately 5 million new cancer cases leading to approximately 3.3 million deaths.11 Within this program, the Company is committed to improving outcomes in gastric, liver, biliary tract, esophageal, pancreatic, and colorectal cancers. In addition to its indications in BTC and HCC, IMFINZI is being assessed in combinations, including with IMJUDO, in liver, esophageal and gastric cancers in an extensive development program spanning early to late-stage disease across settings. Fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate (ADC), is approved in the US and several other countries for HER2-positive advanced gastric cancer. Fam-trastuzumab deruxtecan-nxki is jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. Olaparib, a first-in-class PARP inhibitor, is approved in the US and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Olaparib is developed and commercialized in collaboration with Merck & Co., Inc (MSD outside the US and Canada). The Company is also assessing rilvegostomig (AZD2936), a PD-1/TIGIT bispecific antibody, in combination with chemotherapy as an adjuvant therapy in BTC, in combination with bevacizumab with or without IMJUDO as a 1st-line treatment in patients with advanced HCC, and as a 1st-line treatment in patients with HER2-negative, locally advanced unresectable or metastatic gastric and GEJ cancers. Rilvegostomig is also being evaluated in combination with fam-trastuzumab deruxtecan-nxki in previously untreated, HER2-expressing, locally advanced or metastatic BTC. AstraZeneca is advancing multiple modalities that provide complementary mechanisms for targeting Claudin 18.2, a promising therapeutic target in gastric cancer. These include sonesitatug vedotin, a potential first-in-class ADC licensed from KYM Biosciences Inc., currently in Phase III development; AZD5863, a novel Claudin 18.2/CD3 T-cell engager bispecific antibody licensed from Harbor Biomed in Phase I development; and AZD6422, an armored autologous chimeric antigen receptor T-cell (CAR T) therapy, currently being evaluated in an investigator-initiated trial (IIT) in collaboration with AbelZeta in China. In early development, AstraZeneca is developing two Glypican 3 (GPC3) armored CAR Ts in HCC. AZD5851, currently in Phase I development, is being developed globally, and C-CAR031 / AZD7003 is being co-developed with AbelZeta in China where it is under evaluation in an IIT. AstraZeneca in immuno-oncology (IO) AstraZeneca is a pioneer in introducing the concept of immunotherapy into dedicated clinical areas of high unmet medical need. The Company has a comprehensive and diverse IO portfolio and pipeline anchored in immunotherapies designed to overcome evasion of the anti-tumor immune response and stimulate the body’s immune system to attack tumors. AstraZeneca strives to redefine cancer care and help transform outcomes for patients with IMFINZI as a monotherapy and in combination with IMJUDO as well as other novel immunotherapies and modalities. The Company is also investigating next-generation immunotherapies like bispecific antibodies and therapeutics that harness different aspects of immunity to target cancer, including cell therapy and T-cell engagers. AstraZeneca is pursuing an innovative clinical strategy to bring IO-based therapies that deliver long-term survival to new settings across a wide range of cancer types. The Company is focused on exploring novel combination approaches to help prevent treatment resistance and drive longer immune responses. With an extensive clinical program, the Company also champions the use of IO treatment in earlier disease stages, where there is the greatest potential for cure. 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's innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow the Company on social media @AstraZeneca. References FDA. Priority Review. 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