Locally Advanced Unresectable Carcinoma

Longest survival follow-up ever reported for a Phase III immunotherapy trial in this setting WILMINGTON, DE, USA I September 16, 2024 I Updated results from the HIMALAYA Phase III trial showed AstraZeneca’s IMFINZI ® (durvalumab) plus IMJUDO ® (tremelimumab-actl) demonstrated a sustained, clinically meaningful overall survival (OS) benefit at five years for patients with unresectable hepatocellular carcinoma (HCC) who had not received prior systemic therapy and were not eligible for localized treatment. These results from HIMALAYA will be presented today at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain (presentation 947MO). At five years of follow-up, this latest exploratory analysis showed that a single priming dose of IMJUDO added toIMFINZI, called the STRIDE regimen (Single Tremelimumab-actl Regular Interval Durvalumab), reduced the risk of death by 24% compared to sorafenib (based on a hazard ratio [HR] of 0.76; 95% confidence interval [CI] 0.65-0.89). An estimated 19.6% of patients treated with the STRIDE regimen were alive at five years versus 9.4% for those treated with sorafenib. In a subgroup analysis of patients in the trial who achieved disease control, defined as complete or partial response or stable disease, 28.7% of those treated with the STRIDE regimen were alive at five years versus 12.7% of patients treated with sorafenib. In addition, an exploratory analysis of depth of response (DpR) showed that more patients treated with the STRIDE regimen experienced deep responses leading to longer survival compared to sorafenib. Lorenza Rimassa, MD, Associate Professor of Medical Oncology, Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy and a lead investigator in the HIMALAYA trial, said: “Treatment with durvalumab plus tremelimumab-actl for patients with advanced liver cancer doubled the overall survival rate at five years, a significant survival advantage over sorafenib that has also become even more pronounced over time. These data reinforce the use of this novel dual immunotherapy regimen and are an important milestone for patients with this devastating disease.” Sarah Manes, Liver Cancers Program Director at Global Liver Institute, said: “Reaching the five-year survival milestone is both clinically significant and emotionally meaningful for people with advanced liver cancer and their families. We are thrilled to see this progress in improving outcomes with new treatment options, bringing new hope for long-term survivorship to patients in our community.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “It is remarkable to see nearly 20 percent of patients with advanced liver cancer treated with the STRIDE regimen alive at five years compared to only about seven percent of patients living that long historically. This is a major step forward, setting a new survival benchmark. This underscores our commitment to following patients for the long term to help us better characterize the enduring clinical benefits of this innovative priming approach with an anti-CTLA-4 antibody added to PD-L1 blockade.” Summary of updated survival results: HIMALAYA The safety profile of the STRIDE regimen was consistent with the known profiles of each medicine, and no new safety signals were observed with longer follow-up. Serious treatment-related adverse events, defined as Grade 3 or 4 and including death, were experienced by 17.5% of patients treated with the STRIDE regimen versus 9.9% of patients treated with sorafenib, with no new events occurring after the primary analysis for STRIDE. IMFINZI in combination with IMJUDO is approved for the treatment of adults with advanced or unresectable HCC in the US, EU (in the 1st-line setting), Japan and several other countries. IMFINZI monotherapy is also approved in Japan in this setting. IMFINZI 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. IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. 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). Please see Full Prescribing Information including Medication Guide for IMFINZI and IMJUDO . Notes Liver cancer Liver cancer, of which HCC is the most common type, is the third-leading cause of cancer death, with nearly 900,000 people worldwide diagnosed each year and a high prevalence in certain regions of Asia. 1-2 An estimated 80-90% of all patients with HCC also have cirrhosis. Chronic liver diseases such as cirrhosis are associated with inflammation that over time can lead to the development of HCC. 3 Advanced-stage HCC prognosis is poor, with a five-year survival rate of only 7%. 4 More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear. 5 The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC. 5 HIMALAYA HIMALAYA is a randomized, open-label, multi-center, global Phase III trial of IMFINZI monotherapy and a regimen comprising a single priming dose of IMJUDO 300 mg added to IMFINZI1500mg followed by IMFINZIevery four weeks (STRIDE regimen) versus sorafenib, a standard-of-care multi-kinase inhibitor. The trial included a total of 1,324 randomized patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue). The trial was conducted in 181 centers across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was OS for the combination versus sorafenib and key secondary endpoints included OS for IMFINZIversus sorafenib, objective response rate and progression-free survival (PFS) for the combination and for IMFINZIalone. 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. IMFINZI is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer (BTC) and in combination with IMJUDO ® (tremelimumab-actl) in unresectable HCC. IMFINZI is also approved as a monotherapy in unresectable HCC in Japan and the EU and in combination with chemotherapy (carboplatin plus paclitaxel) followed by IMFINZI monotherapy in primary advanced or recurrent endometrial cancer that is mismatch repair deficient in the US. In addition to its indications in gastrointestinal (GI) cancers, IMFINZI is the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy. IMFINZI is also approved for the treatment of extensive-stage small cell lung cancer (SCLC) and in combination with a short course of IMJUDO and chemotherapy for the treatment of metastatic NSCLC. In limited-stage SCLC, IMFINZI demonstrated statistically significant and clinically meaningful improvements in the dual primary endpoints of OS and PFS compared to placebo in patients who had not progressed following standard-of-care concurrent chemoradiotherapy in the ADRIATIC Phase III trial. IMFINZI in combination with neoadjuvant platinum-containing chemotherapy before surgery and as adjuvant monotherapy after surgery has been approved for patients in the US and several other countries for the treatment of adult patients with resectable NSCLC and no known epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements. IMFINZI plus chemotherapy followed by IMFINZI alone was recently approved in the US for mismatch repair deficient patients with primary advanced or recurrent endometrial cancer. This regimen was also approved in the EU, in addition to IMFINZI plus chemotherapy followed by IMFINZI and olaparib for mismatch repair proficient patients. In muscle-invasive bladder cancer, IMFINZI in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and the key secondary endpoint of OS versus neoadjuvant chemotherapy in the NIAGARA Phase III trial. Since the first approval in May 2017, more than 220,000 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 SCLC, NSCLC, bladder cancer, breast cancer, several GI and gynecologic cancers other solid tumors. IMJUDO IMJUDO ® (tremelimumab-actl) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). IMJUDO blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In addition to its approved indications in liver and lung cancers, IMJUDOis being tested in combination with IMFINZI across multiple tumor types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE). 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 4.9 million new cancer cases leading to approximately 3.3 million deaths. 6 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. The Company is also assessing rilvegostomig (AZD2936), a PD-1/TIGIT bispecific antibody, in combination with chemotherapy as an adjuvant therapy in BTC and as a 1st-line treatment in patients with HER2-negative, locally advanced unresectable or metastatic gastroesophageal junction cancers. Fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate, is approved in the US, China and several other countries for HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. It also has been assessed in multiple GI settings including BTC in the DESTINY-PanTumor02 Phase II trial, and it was recently approved in the US for the treatment of unresectable or metastatic HER2-positive solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. 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, EU and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Olaparib is developed and commercialized in collaboration with Merck & Co., Inc., known as MSD outside the US and Canada. AstraZeneca is advancing multiple modalities that provide complementary mechanisms for targeting Claudin 18.2, a promising therapeutic target in gastric cancer. These include AZD0901, a potential first-in-class antibody drug conjugate licensed from KYM Biosciences Inc., currently in Phase III development, AZD5863, a novel Claudin 18.2/CD3 T-cell engager bispecific antibody licensed from Harbour 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 IMFINZIas 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 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 SOURCE: AstraZeneca

Promising response rate in patients with low-grade upper tract urothelial cancer (UTUC); complete response (CR) observed in 77% (10/13) of patients who completed the Induction Treatment Phase Padeliporfin VTP safe and efficacious, consistent with prior results and reinforcing initial clinical data from ENLIGHTED Preliminary efficacy data presented in a poster session at ASCO; additional interim analysis expected in 2H 2024 and completion of enrollment anticipated by the end of 2024 TEL AVIV, Israel, June 02, 2024 (GLOBE NEWSWIRE) -- ImPact Biotech, a clinical-stage biotechnology company focused on developing Padeliporfin vascular targeted photodynamic (VTP) therapy to treat a range of solid tumors, today announced additional efficacy and safety data from ENLIGHTED (ENdoluminal LIGHT ActivatED), its ongoing pivotal Phase 3 clinical trial evaluating Padeliporfin VTP in patients with low-grade UTUC. The interim results, which demonstrate Padeliporfin VTP treatment was well-tolerated alongside further efficacy, are being presented today in a poster session at the American Society of Clinical Oncology 2024 Annual Meeting in Chicago, Illinois. “These results emphasize the potential of Padeliporfin VTP as a viable treatment option for patients with low-grade UTUC,” said Vitaly Margulis, M.D., Professor of Urology at UT Southwestern Medical Center. “UTUC is difficult to treat, as it is not easily resectable without inflicting organ damage and current standards of care commonly require onerous treatment regimens that do not match surgery in efficacy. These results highlight Padeliporfin VTP as a compelling alternative to achieve profound efficacy, while sparing the kidney or ureter. I am encouraged by this dataset and look forward to the continued analysis of Padeliporfin VTP and its capacity to alter the treatment paradigm for patients with UTUC.” The Phase 3 ENLIGHTED study is a single arm, non-randomized, open-label, pivotal trial evaluating Padeliporfin VTP for the treatment of low-grade UTUC. Across 29 clinical sites globally, ImPact is targeting enrollment of up to 100 patients with new or recurrent low-grade, non-invasive UTUC of the kidney or ureter. The study consists of two parts – an Induction Treatment Phase (ITP) and Maintenance Treatment Phase (MTP) – across which Padeliporfin, a photosensitizing drug, is administered intravenously and VTP therapy is performed, via an outpatient endoscopy which applies a laser fiber illumination for 10 minutes in the proximity of the tumor, leading to local activation of Padeliporfin in the tumor. ITP consists of one-to-three treatments with VTP therapy at four-week intervals or until a complete response (CR) is achieved; MTP follows with standard-of-care treatment alongside VTP therapy administered every three months for up to 12 months. The study’s primary objective is to assess the response rate to Padeliporfin VTP treatment at the end of ITP, with secondary objectives evaluating safety, tolerability and duration of response. As of January 21, 2024, the data cut-off for this presentation, 17 patients had begun treatment of which 13 had completed ITP and were evaluable for efficacy. Key interim results from the Phase 3 ENLIGHTED study of Padeliporfin VTP: Clinical Profile: Ten of the 13 (77%) response-evaluable patients achieved a CR at the end of ITP. Safety and Tolerability Profile: Padeliporfin VTP was well-tolerated with a safety pro with the previous data obtained from the Phase 1 study and preliminary Phase 3 results. Adverse events (AEs) observed were primarily Grade 1 or 2, mostly gastrointestinal-related. Grade 3 events were observed in 9% of patients. All AEs resolved within two to seven days. There were no Grade 4 or 5 serious adverse events observed. “We are pleased to see Padeliporfin VTP making continued clinical progress in the ENLIGHTED Phase 3 study,” said Eyal Morag, M.D., Chief Medical Officer of ImPact Biotech. “This dataset underscores our conviction that Padeliporfin VTP may provide immense clinical benefit as an alternative that delivers efficacy more in line with surgical intervention than standard-of-care therapeutics but without the associated risk of organ injury or loss. We look forward to the sustained evaluation of Padeliporfin VTP as a differentiated novel treatment in low-grade UTUC and to sharing additional data as this study progresses, as we also seek to explore its potential across other unresectable solid tumors in parallel.” ImPact continues to recruit for the ENLIGHTED study and expects to complete enrollment by the end of 2024. The Company anticipates an interim analysis from this study to be presented in 2H 2024. In addition, ImPact plans to evaluate Padeliporfin VTP in other solid tumors, including pancreatic ductal adenocarcinoma (PDAC), high-grade UTUC and non-small cell lung cancer (NSCLC). At ASCO, the Company also presented a trials-in-progress poster featuring the design of its Phase 1 study in PDAC, which is expected to initiate patient dosing in the coming weeks. The objectives of this two-part, dose-escalation and -expansion study are as follows: in part A, to evaluate safety and tolerability of Padeliporfin VTP in locally advanced, unresectable PDAC; and in Part B, further evaluate preliminary efficacy, with responses defined by conversion from unresectable to resectable, at the recommended dose identified in Part A. About ImPact Biotech ImPact Biotech is an advanced clinical-stage oncology company focused on the development and commercialization of Padeliporfin Vascular Targeted Photodynamic (VTP) therapy, a minimally invasive drug-device combination for selective ablation of unresectable solid tumors. The novel VTP platform delivers non-thermal laser light via optical fibers to locally activate Padeliporfin in the tumor microenvironment. Padeliporfin VTP is currently being evaluated in a pivotal Phase 3 study in low-grade upper tract urothelial carcinoma (UTUC) with earlier stage studies ongoing or planned in high-grade UTUC, pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). The Company has longstanding collaborations with the Weizmann Institute of Science and Memorial Sloan Kettering Cancer Center and operations in the EU, Israel and the US. For more on ImPact Biotech Ltd., visit: and the ENLIGHTED clinical trial website (for the US): . Contacts Global Head of Business Development Guy Schmidt guy.schmidt@impactbiotech.com Precision AQ Josh Rappaport josh.rappaport@precisionaq.com

Combination of novel IL-2 therapeutic AU-007, Bavencio® (avelumab) and aldesleukin in Phase 2 cohort of AU-007 clinical trial to build on compelling preclinical evidence of eradication of solid tumors LARKSPUR, Calif.--(BUSINESS WIRE)-- Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through the development of potentially best-in-class IL-2 therapeutics, today announced a new collaboration and supply agreement with Ares Trading S.A., a Swiss subsidiary of Merck KGaA, Darmstadt, Germany, for use of Bavencio® (avelumab) in a clinical study of its lead human monoclonal antibody candidate, AU-007. Under the terms of the agreement, Merck KGaA, Darmstadt, Germany will provide Aulos with a free supply of Bavencio to evaluate in combination with AU-007 and low-dose, subcutaneous aldesleukin in an additional Phase 2 cohort of Aulos’ Phase 1/2 clinical trial of AU-007 in solid tumor cancers. Bavencio is a human anti-programmed death ligand-1 (PD-L1) antibody approved for use in multiple clinical indications. “We are excited to embark on this clinical trial collaboration with Merck KGaA, Darmstadt, Germany, which will enable our team to further investigate AU-007 in tandem with an anti-PD-L1 antibody, based on positive preclinical results,” said Aron Knickerbocker, Aulos Bioscience’s chief executive officer. “We believe Bavencio may offer distinct mechanistic synergy with AU-007 when compared to other immune checkpoint inhibitors because it is the only approved anti-PD-L1 antibody that has effector function and engages natural killer cells to kill tumor cells by a process known as ADCC, while also interrupting the PD-L1/PD-1 checkpoint that inhibits effector T cells. This unique pro Bavencio, along with the ability of AU-007 and aldesleukin to accelerate the activation and expansion of effector T cells and natural killer cells, holds promise for creating a powerful combination therapeutic regimen that may eradicate tumor cells in multiple cancer types.” AU-007 is the first human IgG1 monoclonal antibody designed using artificial intelligence to enter a human clinical trial. In preclinical studies, strong anti-cancer activity, including complete tumor eradications, was observed when AU-007 was dosed in combination with a single loading dose of human interleukin-2 (hIL-2) and an anti-PD-L1 surrogate of avelumab. A Phase 1/2 study is currently evaluating AU-007 and is enrolling patients with unresectable locally advanced or metastatic cancer at multiple clinical trial site locations in the United States and Australia. Interim data from the Phase 1 portion of the study indicate that AU-007 is the only IL-2 therapy ever to demonstrate an overall trend in decreasing regulatory T cells (Tregs) and eosinophils, with encouraging early signs of anti-tumor activity. Aulos plans to present additional Phase 1 data and preliminary Phase 2 data, with a focus on melanoma and renal cell carcinoma, at an upcoming medical conference. The company anticipates commencing patient enrollment in the Phase 2 cohort studying Bavencio with AU-007 and aldesleukin in the second half of 2024. About AU-007 AU-007 is a computationally designed, human IgG1 monoclonal antibody that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 leverages IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to CD25-containing receptors on eosinophils, as well as vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy. To learn more about the AU-007 Phase 1/2 clinical trial program, including study locations in the United States and Australia, please visit ClinicalTrials.gov (identifier: NCT05267626), (U.S.) and (Australia). About Aulos Aulos Bioscience is an immuno-oncology company working to revolutionize cancer patient care through best-in-class IL-2 therapeutics that direct patients’ immune systems toward killing tumor cells. Matching world-class machine learning from co-founder Biolojic Design with an in-depth understanding of the immune system, Aulos’ initial clinical candidate, AU-007, is a computationally designed human antibody that harnesses the power of IL-2 to induce tumor killing while limiting the immunosuppression and toxicities typically associated with this validated pathway. The company was founded by Biolojic Design and Apple Tree Partners (ATP) and is led by pioneers in the field of artificial intelligence, antibody development and cancer immunotherapies. For more information, visit , X (@AulosBioscience) and LinkedIn.