Leucovorin Calcium

- Zolbetuximab is currently the first and only therapy approved in the European Union to target claudin 18.2, a biomarker positively expressed by 38% of patients with advanced gastric cancer1,2 - Treatment with the claudin 18.2-targeted monoclonal antibody shown to significantly extend both progression-free survival and overall survival in Phase 3 trials1,2 TOKYO, Sept. 20, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") today announced that the European Commission (EC) has approved VYLOY™ (zolbetuximab) in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive. The European Medicines Agency has recommended that zolbetuximab's designation as an orphan medicinal product be maintained in recognition of the poor survival outcomes associated with gastric and GEJ cancers. Zolbetuximab is currently the first and only approved monoclonal antibody specifically designed to target gastric tumor cells that express the biomarker CLDN18.2, offering a more personalized approach to cancer treatment. In the zolbetuximab Phase 3 clinical trials, approximately 38% of adult patients with advanced and metastatic gastric and GEJ cancers had tumors that were CLDN18.2 positive.1,2 By binding to CLDN18.2 expressed on tumor cell membranes, zolbetuximab results in antibody-dependent cellular cytotoxicity, complement dependent cytotoxicity and tumor growth inhibition.3 Zorana Maravic, Chief Executive Officer of Digestive Cancers Europe (DiCE): "Sadly, due to similar symptoms to more common stomach conditions, gastric and gastroesophageal junction cancers are often diagnosed at the advanced or metastatic stage when treatment options have traditionally been relatively limited. Ensuring timely diagnosis, followed by personalized treatment and care, will be essential to better survival and quality of life for patients." Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Senior Vice President and Head of Immuno-Oncology Development, Astellas: "We are delighted to bring zolbetuximab, a first-in-class targeted treatment option, to patients in Europe where gastric and gastroesophageal cancers are the sixth leading cause of cancer-related death. With zolbetuximab, we're entering a new era in precision medicine for these advanced cancers, underpinning our ongoing commitment to pioneering scientific discovery that can advance patient outcomes." Data from the Phase 3 SPOTLIGHT and GLOW clinical trials, which supported the European Marketing Authorization, showed that treatment with zolbetuximab provided statistically significant improvements in progression-free survival (PFS) and overall survival (OS) compared to other standard of care chemotherapies in eligible patients with gastric and GEJ cancers.1,2 In the SPOTLIGHT trial, a median PFS of 10.61 months was achieved with zolbetuximab plus mFOLFOX6 as first-line treatment, versus 8.67 months with placebo plus mFOLFOX6. The median OS was 18.23 months versus 15.54 months in the respective treatment groups.1 Similar efficacy findings were seen in the GLOW trial where median PFS was 8.21 months versus 6.80 months, and median OS 14.39 months versus 12.16 months, with zolbetuximab plus CAPOX, compared to placebo plus CAPOX, respectively.2 In both the SPOTLIGHT and GLOW trials, the incidence of serious treatment emergent adverse events (TEAEs) was similar in the zolbetuximab treatment groups compared to the controls. The most common all-grade TEAEs reported in the zolbetuximab treatment groups were nausea, vomiting and decreased appetite.1,2 The European Marketing Authorization for zolbetuximab is valid in all 27 EU member states as well as Iceland, Liechtenstein, and Norway, and is aligned to the recently updated ESMO Gastric Cancer Living Guidelines which state that the addition of zolbetuximab to chemotherapy can be considered for patients with CLDN18.2 positive, HER-2 negative tumors in the first-line metastatic disease setting.4 Astellas is working closely with local regulatory authorities and health technology assessment bodies across the EU to ensure that patients who may gain benefit from zolbetuximab are able to access the novel treatment as soon as possible. This regulatory approval for zolbetuximab follows the August 2024 approval by the UK Medicines and Healthcare products Regulatory Agency and the March 2024 approval by Japan's Ministry of Health, Labour and Welfare.5,6 Astellas has submitted further applications for zolbetuximab to other regulatory agencies around the world with reviews ongoing. Astellas has already reflected the impact from this result in its financial forecast for the current fiscal year ending March 31, 2025. About Zolbetuximab Zolbetuximab is a claudin 18.2-directed cytolytic antibody investigated in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive. In both the SPOTLIGHT and GLOW Phase 3 clinical trials, approximately 38% of patients screened had tumors that were CLDN18.2 positive, defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 immunohistochemical staining, assessed and confirmed using an in-vitro companion diagnostic test or medical device.1,2 Astellas collaborated with Roche on the VENTANA® CLDN18 (43-14A) RxDx Assay that, upon approval, is intended to be used by a pathologist or laboratory to identify patients eligible for targeted treatment with zolbetuximab.7 This immunohistochemistry based companion diagnostic test is currently under review by the notified body. As an investigational first-in-class monoclonal antibody (mAb), zolbetuximab targets and binds to CLDN18.2, a transmembrane protein expressed on cancer cells. In pre-clinical studies, zolbetuximab reduced the number of CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, leading to tumor growth inhibition.3 About Locally Advanced Unresectable Metastatic Gastric and Gastroesophageal Junction Cancer Gastric and gastroesophageal junction (G/GEJ) cancers are known to be histologically similar, are recommended to be managed in the same way in treatment guidelines, and frequently display aligned responses to treatment.2,8 Across Europe, over 135,000 new cases of G/GEJ cancer were diagnosed in 2022.9 G/GEJ cancer is the sixth most common cause of cancer-related mortality in Europe, responsible for 95,431 deaths in 2022.9,10 GEJ adenocarcinomas start in the first two inches (5 cm) where the esophagus joins the stomach.11 The average five-year survival rate for patients in Europe with G/GEJ cancer is 26% across all stages of the disease, driving the need for new therapeutic options that can slow disease progression and extend lives.12 Because early-stage cancer symptoms frequently overlap with more common stomach-related conditions, G/GEJ cancers are often diagnosed in the advanced or metastatic stage, or once they have spread from the tumor's origin to other body tissues or organs.13 Early signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, bloating of the stomach after meals, and loss of appetite.13,14 Signs of more advanced G/GEJ cancer can include unexplained weight loss, weakness and fatigue, sensation of food getting stuck in the throat while eating, vomiting blood or having blood in the stool.13,14,15 Risk factors associated with G/GEJ cancer can include older age, male gender, family history, H. pylori infection, smoking, and gastroesophageal reflux disease (GERD).16,17 INVESTIGATIONAL STUDIES About the SPOTLIGHT Phase 3 Clinical Trial SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus mFOLFOX6 (a combination chemotherapy regimen that includes oxaliplatin, leucovorin, and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 565 patients at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America, and Asia. The primary endpoint is progression-free survival (PFS) of participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability, and quality-of-life parameters.1 Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19, 2023, and were subsequently published in The Lancet on April 14, 2023.1 For more information, please visit clinicaltrials.gov under Identifier NCT03504397. About the GLOW Phase 3 Clinical Trial GLOW is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX as a first-line treatment in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors were CLDN18.2 positive. The study enrolled 507 patients at 166 study locations in the U.S., Canada, United Kingdom, Europe, South America, and Asia, including Japan. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability, and quality-of-life parameters.2 Data from the GLOW study were initially presented at the March 2023 ASCO Plenary Series with an updated oral presentation at the 2023 ASCO Annual Meeting on June 3, 2023, and were subsequently published in Nature Medicine on July 31, 2023.2 For more information, please visit clinicaltrials.gov under Identifier NCT03653507. Investigational Pipeline in CLDN18.2 An expanded Phase 2 trial of zolbetuximab in metastatic pancreatic adenocarcinoma is in progress and recruiting patients. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2 positive tumors (defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining based on a validated immunohistochemistry assay). For more information, please visit clinicaltrials.gov under Identifier NCT03816163. In addition to zolbetuximab, ASP2138 is under development in our Primary Focus Immuno-Oncology area and is currently recruiting patients. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and CLDN18.2, and it is currently in a Phase 1/1b study in participants with metastatic or locally advanced unresectable gastric or GEJ adenocarcinoma or metastatic pancreatic adenocarcinoma whose tumors have CLDN18.2 expression. The safety and efficacy of the agent under investigation have not been established for the uses being considered. For more information, please visit clinicaltrials.gov under Identifier NCT05365581. There is no guarantee that the agent(s) will receive regulatory approval and become commercially available for the uses being investigated. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. SOURCE Astellas Pharma Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AUSTIN, Texas--( BUSINESS WIRE )-- Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA and genetic testing, announced that new data from the GALAXY arm of the ongoing CIRCULATE-Japan trial was released today at the 2024 Congress of the European Society for Medical Oncology (ESMO) in Barcelona, Spain. GALAXY is one of the largest and most comprehensive prospective studies of circulating tumor DNA (ctDNA) testing in resectable colorectal cancer (CRC). This latest analysis, which will also be published in Nature Medicine on September 16, provides the first evidence of the ability of Signatera-based molecular residual disease (MRD) detection to predict overall survival (OS). The data also demonstrates Signatera’s ability to predict adjuvant chemotherapy (ACT) benefit in resectable CRC, with ctDNA clearance as an indicator of a superior survival benefit compared to no clearance. In the study, 2,240 patients with stage II–IV CRC were monitored using Signatera after curative-intent surgery with a median follow-up of 23 months. Key takeaways include: Signatera status was predictive of overall survival. Signatera-positivity in the post-op MRD window was found to be significantly associated with worse OS compared to Signatera-negative patients (HR: 9.68, p-value < 0.01) with a 36-month OS of 71.80% vs. 96.0%, respectively. This 10x advantage in overall survival compares favorably to all known guideline-recommended biomarkers that have HRs for overall survival in a range of 1-4. Signatera status was predictive of an overall survival benefit from adjuvant chemotherapy. High-risk stage II and stage III-IV patients who were Signatera-positive after surgery and received ACT demonstrated superior OS (adjusted HR: 0.53, p-value = 0.05), corresponding to a 50% reduction in the risk of death when treated with ACT. By comparison, the MOSAIC trial 1 , which was the last practice-changing study in adjuvant CRC, demonstrated a 16% reduction in risk of death (HR: 0.84, p-value = 0.05). Signatera-negative patients did not derive an OS benefit from ACT (adjusted HR: 0.53, p-value = 0.13). Signatera status remained the most significant predictor of recurrence. Signatera-positivity after surgery was the single most significant prognostic factor associated with inferior DFS (HR 12.08, p-value <0.01) and OS (HR 9.87, p-value <0.01) in a multivariate analysis that included all clinicopathologic risk factors currently in use. This is also reflected by the 36-month DFS difference between Signatera-positive and Signatera-negative patients at 16.7% (95% CI: 12.1–21.9%) versus 83.5% (95% CI: 81.2%–85.6%), respectively. The association of Signatera-positivity with a significantly increased risk for recurrence was observed across all pathologic stages. Sustained Signatera clearance after ACT was associated with improved survival. Patients who clear ctDNA and remained Signatera-negative (referred to as “sustained clearance”) had superior survival benefit with 24-month OS of 100%. This compares to patients who cleared ctDNA for a period of time but later become Signatera-positive (referred to as “transient clearance”), with 24-month OS of 82%, and patients who did not achieve ctDNA clearance, with 24-month OS of 61%. This finding further supports the utility of sustained ctDNA clearance as a surrogate endpoint for long-term outcomes. “ We now have compelling prospective evidence from a large trial of more than 2,200 patients that clearly reinforces the link between MRD status and overall survival,” said Yoshiaki Nakamura, MD, PhD, co-author of the paper and principal investigator of the study from the National Cancer Center Hospital East in Kashiwa, Chiba, Japan. “ These findings suggest that Signatera can predict post-surgical outcomes for colorectal cancer patients with great precision, redefining the future of personalized medicine and providing the potential to significantly improve outcomes for a greater number of patients.” “ The GALAXY data released today builds on an earlier analysis from the same study that was published in Nature Medicine in 2023,” said Minetta Liu, MD, chief medical officer of oncology at Natera. “ Introducing 36-month, first-of-its-kind data on overall survival is an important milestone that reinforces the potential to improve outcomes for patients diagnosed with colorectal cancer. The updated data affirms ctDNA status as a critical measure both for prognosis and for predicting which patients may truly benefit from adjuvant chemotherapy.” About Signatera Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer, ovarian cancer and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 70 peer-reviewed papers. About Natera Natera™ is a global leader in cell-free DNA and genetic testing, dedicated to oncology, women’s health, and organ health. We aim to make personalized genetic testing and diagnostics part of the standard of care to protect health, and inform earlier, more targeted interventions that help lead to longer, healthier lives. Natera’s tests are validated by more than 200 peer-reviewed publications that demonstrate high accuracy. Natera operates ISO 13485-certified and CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in Austin, Texas and San Carlos, California. For more information, visit www.natera.com . Forward-Looking Statements All statements other than statements of historical facts contained in this press release are forward-looking statements and are not a representation that Natera’s plans, estimates, or expectations will be achieved. These forward-looking statements represent Natera’s expectations as of the date of this press release, and Natera disclaims any obligation to update the forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including with respect to whether the results of clinical or other studies will support the use of our product offerings, the impact of results of such studies, our expectations of the reliability, accuracy and performance of our tests, or of the benefits of our tests and product offerings to patients, providers and payers. Additional risks and uncertainties are discussed in greater detail in "Risk Factors" in Natera’s recent filings on Forms 10-K and 10-Q and in other filings Natera makes with the SEC from time to time. These documents are available at www.natera.com/investors and www.sec.gov . References Thierry André et al., Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial. JCO 27, 3109-3116(2009). DOI:10.1200/JCO.2008.20.6771