Gemcitabine Hydrochloride

– Expert Insights on Clinical Relevance and Scientific Rationale– The replay of the event is available on the Investor Relations section of the Actuate website CHICAGO and FORT WORTH, Texas, June 02, 2025 (GLOBE NEWSWIRE) — Actuate Therapeutics, Inc. (NASDAQ: ACTU) (“Actuate” or the “Company”), a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), today announced key takeaways from its Key Opinion Leader (KOL) event held on May 31, 2025 discussing the positive topline results from the Phase 2 (Actuate-1801 Part 3B) trial of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The study met its primary endpoint, demonstrating a clinically meaningful increase in median overall survival (mOS) of 10.1 months compared to 7.2 months (p = 0.01), with a 37% reduction in the risk of death (HR = 0.63). The elraglusib/GnP arm also doubled the 12-month survival rate in 44.1% of patients compared to GnP alone (22.3%), with a favorable safety profile. The KOL event followed the presentation of topline trial data during an oral session at the American Society of Clinical Oncology (ASCO) Annual Meeting. The event featured a fireside discussion with leading mPDAC clinicians, all with direct participation in the elraglusib clinical trial program: Colin Weekes, MD, PhD, Massachusetts General Hospital; Devalingam Mahalingam, MD, Northwestern University Feinberg School of Medicine; Rachna Shroff, MD, MS, FASCO, University of Arizona Cancer Center; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic College of Medicine and Science. The panelists highlighted the implications of the Phase 2 Actuate 1801 Part 3β results in the broader context of the unmet need in mPDAC, the unique immune-modulating mechanism of elraglusib, and its potential to reshape the treatment landscape, as follows. Daniel Schmitt, President & Chief Executive Officer of Actuate said, “The reception we received at ASCO confirms what we already believed – this data has the potential to change the trajectory of mPDAC treatment. As our KOLs highlighted in the panel discussion, there is a clear need for new drugs, like elraglusib, with new mechanistic pathways, and which can be successfully combined without overlapping toxicities for treatment of this devastating disease. As these thought leaders pointed out, due to a number of negative trials, there has been quite some time since we’ve had anything that improves outcomes for patients with these chemotherapy backbones. The thought leaders further highlighted the importance of the overall survival benefit and noted the magnitude of that benefit in the elraglusib trial is actually substantial. We are now laser-focused on turning this promise into patient access. With a clear survival benefit, favorable safety profile, and strong scientific rationale, we look forward to advancing elraglusib development and initiating regulatory discussions with both the FDA and EMA.” Key highlights from the ASCO oral presentation: In addition to the improved mOS and one-year survival rate, a continued survival benefit was also observed at eighteen and twenty-four months (survival rates of 19.7% vs 4.4% and 13.8% vs 0% in the elraglusib/GnP combination arm vs the GnP arm, respectively). The elraglusib/GnP combination treatment also resulted in numerically improved overall response rates (29.0% in the elraglusib/GnP combination arm vs 21.8% in the GnP arm) and improvements in median progression-free survival and median duration of response of 5.6 months vs 5.1 months, and 5.5 months vs 4.0 months in the elraglusib/GnP combination arms vs GnP arms, respectively. The trial also met its primary safety endpoint. Treatment-emergent adverse events (TEAEs) and Serious Adverse Events (SAEs) in the elraglusib/GnP combination arm were similar to those observed in the GnP arm, indicating a favorable risk-benefit profile for the elraglusib/GnP combination. Treatment-related adverse events (TRAEs) were mostly Grade 1-2, with the most frequent TRAEs observed (in about two-thirds of patients) being transient visual impairments that were reversible and non-progressive While Grade 3 or higher neutropenia was observed, similar rates of febrile neutropenia and sepsis were observed in both treatment arms. Pre-dose cytokine analysis that suggested lower baseline levels of key immune modulators, including CCL3, IL-1α, IL-18, TGF-β, and TRAIL R3, were correlated with improved 1-year survival. Increased CD8-positive and granzyme B-positive T cells, increased NK cells, and decreased myeloid-derived suppressor cells were observed in tumor biopsies only from elraglusib-treated patients. This exploratory result confirms elraglusib proposed immune modulating mechanism of action in patients with mPDAC. Treatment-related adverse events (TRAEs) were mostly Grade 1-2, with the most frequent TRAEs observed (in about two-thirds of patients) being transient visual impairments that were reversible and non-progressive While Grade 3 or higher neutropenia was observed, similar rates of febrile neutropenia and sepsis were observed in both treatment arms. About Actuate-1801 Part 3β Study The Actuate-1801 Part 3β study (NCT03678883) is a randomized, controlled Phase 2 trial of elraglusib with GnP versus GnP alone in first-line mPDAC. The trial enrolled 286 mPDAC patients with no prior systemic treatment for metastatic disease, who were randomized 2:1 to the elraglusib treatment arm (elraglusib + GnP) or the control arm (GnP alone). Elraglusib is administered at a dose of 9.3 mg/kg by IV infusion on Day 1 of each week of a 28-day cycle. The primary endpoint for this study is median overall survival, with OS summarized throughout the study by estimates of 1-year survival. Secondary endpoints are DCR, ORR, PFS, and AE. Inhibition of GSK-3β may inhibit tumor growth and improve survival through several complimentary mechanisms that include enhancement of chemotherapy activity, activation of innate anti-tumor immunity, and regulation of gene expression, leading to alterations in tumor metabolism and Epithelial-to-Mesenchymal Transition (EMT). About Actuate Therapeutics, Inc. Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers. Actuate’s lead investigational drug, elraglusib (a novel GSK-3β inhibitor), targets molecular pathways in cancer that are involved in promoting tumor growth and resistance to conventional cancer drugs such as chemotherapy through the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and DNA Damage Response (DDR). Elraglusib may also mediate anti-tumor immunity through the regulation of multiple immune checkpoints and immune cell function. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com. Forward-Looking Statements This press release contains forward-looking statements about us, including our and other parties’ clinical trials and development plans, and our industry. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would,” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements related to present facts or current conditions or of historical facts, contained in this press release are forward-looking statements. Accordingly, these statements involve estimates, assumptions, substantial risks and uncertainties which could cause actual results to differ materially from those expressed in them, including but not limited to that preliminary and unpublished data may be subject to change and further interpretation following the availability of more data or following a more comprehensive review of the data and should not be relied upon as a final analysis; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities and within the medical community; clinical and preclinical drug development involves a lengthy and expensive process with uncertain timelines and outcomes, results of prior preclinical studies and early clinical trials are not necessarily predictive of future results, and elraglusib may not achieve positive clinical results or favorable preclinical results, and we may not be able to make regulatory submissions or receive regulatory approval on a timely basis, if at all; that we may not successfully enroll additional patients or establish or advance plans for further development, including through conversations with the FDA or EMA and the standards such bodies may impose for such development; that elraglusib could be associated with side effects, adverse events or other properties or safety risks, which could delay or preclude regulatory approval, cause us to suspend or discontinue clinical trials or result in other negative consequences; our reliance on third parties to conduct our non-clinical studies and our clinical trials; our reliance on third-party licensors and ability to preserve and protect our intellectual property rights; that we face significant competition from other biotechnology and pharmaceutical companies; our ability to fund development activities, including because our financial condition raises substantial doubt as to our ability to continue as a going concern and we require additional capital to finance our operations beyond the second quarter of fiscal year 2025, and a failure to obtain this necessary capital in the near term on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our development programs, commercialization efforts or other operations. In addition, any forward-looking statements are qualified in their entirety by reference to the factors discussed under the heading “Item 1A. Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2024, filed with the SEC on March 13, 2025, our Quarterly Report on Form 10-Q for the quarter ended March 31, 2025, filed with the SEC on May 15, 2025, and other filings with the SEC. Because the risk factors referred to above could cause actual results or outcomes to differ materially from those expressed in any forward-looking statements made by us or on our behalf, you should not place undue reliance on any forward-looking statements. Further, any forward-looking statement speaks only as of the date on which it is made. New factors emerge from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Unless legally required, we do not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date of this press release or to reflect the occurrence of unanticipated events. Investor Contact Mike Moyer Managing Director LifeSci Advisors, LLC mmoyer@lifesciadvisors.com

编者按：鼻咽癌是我国华南地区及其他东南亚国家高发的恶性肿瘤，带来了较大的疾病负担和健康威胁。其中复发/转移性鼻咽癌（R/M NPC）患者的治疗选择十分有限。近年来，免疫检查点抑制剂（ICIs）为此类患者带来了新的治疗选择，而我国自主研发的ICIs也表现抢眼。在2025年ASCO大会的口头报告环节中，中山大学肿瘤防治中心麦海强教授汇报了一项塔戈利单抗（Tagitanlimab）联合GP用于R/M NPC一线治疗III期研究取得了积极结果，并在接受《肿瘤瞭望》的采访中进一步分享其研究成果，展望塔戈利单抗对我国NPC临床实践的影响。01《肿瘤瞭望》：请您介绍一下复发/转移性鼻咽癌（R/M NPC）的诊疗现状？免疫检查点抑制剂在此类患者治疗中展现了怎样的应用潜力？麦海强 教授中山大学肿瘤防治中心鼻咽癌（NPC）是极具“中国特色”的恶性肿瘤，具有显著的地理分布特征，全球每年约有超过13万新发病例，其中超过70%发生在东亚、东南亚和北非地区，超过一半发生在中国，且主要在我国华南地区[1-2]。NPC对放射线和化疗较为敏感，以放化疗（CRT）为主的综合治疗模式已成为NPC患者治疗的重要手段，但仍有部分（约10%~30%）患者因放疗抵抗、化疗耐药或其他原因发生局部复发或远处转移[3-4]。目前，复发/转移性鼻咽癌（R/M NPC）的一线治疗方案以GP（吉西他滨+顺铂）为主，但临床治疗获益较为有限，中位无进展生存期（PFS）仅为7.0个月，中位总生存期（OS）仅为1～2年[5-6]。因此，R/M NPC患者仍存在巨大未被满足的治疗需求，亟需新的治疗药物，以更好地控制疾病，提高治疗的生存获益。NPC往往与EBV慢性感染相关，因此肿瘤中存在大量的淋巴细胞浸润及PD-L1表达升高[7]，可能是免疫治疗的敏感性肿瘤。近年来，针对PD-1/PD-L1的免疫检查点抑制剂（ICs）在R/M NPC领域取得了不少突破性进展，多项III期临床试验探讨了ICIs在R/M NPC患者中的作用，贯穿于一线及后线治疗，并获得国内外指南共识的推荐[8-9]。开发更多中国原创的、疗效和安全性俱佳、可及性更好的免疫治疗方案，可为R/M NPC患者提供更多治疗选择，满足更多的临床治疗需求。02《肿瘤瞭望》：塔戈利单抗是我国自主研发的PD-L1单抗，目前已获批上市用于治疗复发或转移性鼻咽癌。此次ASCO大会上，塔戈利单抗联合吉西他滨/顺铂（GP）治疗R/M NPC的随机对照研究（摘要号：6004）入选口头报告。能否介绍一下该研究所取得的主要结果，尤其是该联合方案的疗效和安全性？麦海强 教授中山大学肿瘤防治中心塔戈利单抗是我国自主研发的PD-L1免疫检查点抑制剂，通过定点突变技术对药物Fc段进行优化，消除了ADCC和CDC效应，具有稳定性高、免疫逃逸低等药物优势。既往发表于《柳叶刀》子刊Lancet Reg Health West Pac的II期研究显示，在经过多重治疗且肿瘤负荷较高（肝转移43.9%，≥3线化疗31.8%）的R/M NPC患者中，塔戈利单抗单药治疗的客观缓解率（ORR）仍可达26.5%，中位PFS和OS分别为2.8个月和16.2个月，且安全性良好[10]。随后，我们进一步开展了这项III期临床研究[11]，旨在评价塔戈利单抗联合GP作为R/M NPC患者一线治疗的疗效和安全性。此次ASCO大会口头报告披露的数据显示到达主要研究终点：与单独化疗组相比，塔戈利单抗联合化疗组具有更长的PFS（NR vs 7.9个月），疾病进展或死亡风险显著降低53%（HR 0.47，95％CI：0.33-0.66，单侧P＜0.0001）；而且在不同亚组中，塔戈利单抗联合化疗均有一致获益。△独立评审中心（IRC）评估的PFS（中期分析） △独立评审中心（IRC）评估的PFS亚组分析在肿瘤缓解方面，与单独化疗组相比，塔戈利单抗联合化疗组具有更高的ORR（81.7% vs 74.5%）；中位持续治疗缓解时间（DoR）延长近1倍（11.7 vs 5.8个月；HR 0.48，95％CI：0.32-0.70）。OS数据尚未成熟，但已显示出塔戈利单抗联合化疗组的获益趋势，目前死亡风险降低38%（HR 0.62，95％CI：0.32-1.22）；此外，安全性与既往报道一致，患者的治疗耐受性良好。△两组患者的肿瘤缓解情况△两组患者的安全性汇总和常见TRAEs03《肿瘤瞭望》：基于这些研究结果，您认为塔戈利单抗将如何进一步影响鼻咽癌治疗的临床实践？未来还有哪些研究方向值得进一步探讨？麦海强 教授中山大学肿瘤防治中心基于上述II期研究，塔戈利单抗已经于2024年12月获得中国国家药品监督管理总局（NMPA）批准上市，用于治疗既往接受过2线及以上化疗失败的复发或转移性鼻咽癌患者，这是全球首个获批上市用于治疗鼻咽癌的PD-L1单抗。而基于这项ASCO报道的III期研究，2025年1月，NMPA进一步批准塔戈利单抗联合顺铂和吉西他滨用于复发或转移性鼻咽癌的一线治疗。至此，塔戈利单抗为R/M NPC患者构筑了完整的治疗防线，从联合化疗的一线治疗，到单药的后线治疗，将在我国鼻咽癌的临床实践中进一步发挥重要作用，从而改善改善R/M NPC患者的生存预后。塔戈利单抗在NPC领域还有不少探索方向。以往的PD-1抑制剂相关研究中，PD-L1高表达被认为是ICIs免疫治疗敏感的生物标志物，但在既往研究中，PD-L1抑制剂塔戈利单抗联合化疗在不同PD-L1表达水平患者中均有PFS获益，其背后机制值得进一步探讨。此次报告的研究显示，EBV-DNA清除能够预测PFS，第1周期治疗后EBV DNA 从阳性转为阴性的患者，相较于EBV DNA阳性患者具有更好的PFS（12.2 vs 6.9个月，HR 0.46）。再者，TIL，TMB、dMMR/MSI-H等其他生物标志物在塔戈利单抗中是否也具有临床应用价值，期待有更多探索性分析或转化研究。△基线EBV-DNA阳性患者中C2D1转阴和持续阳性患者的PFS差异此外，塔戈利单抗联合放疗、抗体偶联药物（ADC）等不同联合治疗方案，能否进一步提高疗效，也是未来可以研究的方向。参考文献上下滑动查看更多内容[1]Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022;135(5):584-590.[2]Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.[3]Huang T, Su N, Zhang X, et al. Systemic chemotherapy and sequential locoregional radiotherapy in initially metastatic nasopharyngeal carcinoma: Retrospective analysis with 821 cases. Head Neck. 2020;42(8):1970-1980.[4]Lu T, Chen Y, Li J, et al. High Soluble Programmed Death-Ligand 1 Predicts Poor Prognosis in Patients with Nasopharyngeal Carcinoma. Onco Targets Ther. 2020;13:1757-1765.[5]Lee AW, Ma BB, Ng WT, Chan AT. Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective. J Clin Oncol. 2015;33(29):3356-3364.[6]Hong S, Zhang Y, Yu G, et al. Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study. J Clin Oncol. 2021;39(29):3273-3282.[7]Ahmed MM, Gebriel MG, Morad EA, et al. Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. Appl Immunohistochem Mol Morphol. 2021;29(6):401-408. doi:10.1097/PAI.0000000000000903[8]中国临床肿瘤学会（CSCO）指南工作委员会.CSCO鼻咽癌诊疗指南（2025）.人民卫生出版社.[9]Colevas AD, Cmelak AJ, Pfister DG, et al. NCCN Guidelines® Insights: Head and Neck Cancers, Version 2.2025. J Natl Compr Canc Netw. 2025;23(2):2-11. doi:10.6004/jnccn.2025.0007[10]Shi Y, Qin X, Peng X, et al. Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. Lancet Reg Health West Pac. 2022;31:100617. Published 2022 Oct 10. doi:10.1016/j.lanwpc.2022.100617[11]Shi Y, et al.Tagitanlimab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC): Results from a randomized, double-blind, phase 3 study.ASCO 2025,abstract 6004.麦海强 教授中山大学二级教授，一级主任医师，博士生导师中山大学肿瘤防治中心院长助理、鼻咽科主任中山大学附属肿瘤医院甘肃医院副院长国家杰出青年基金获得者国家万人计划科技创新领军人才科技部中青年科技创新领军人才中国肿瘤青年科学家教育部新世纪优秀人才广东省科技创新领军人才广东省医学领军人才中国抗癌协会鼻咽癌整合康复专委会主任委员国家癌症中心鼻咽癌质控专家委员会副主任委员美国MD Anderson 癌症中心质子治疗中心学术委员会委员中国抗癌协会青年理事会常务理事中国临床肿瘤协会（CSCO）鼻咽癌专家委员会常委广东省临床医学学会鼻咽癌精准治疗专委会主任委员广东省医学会肿瘤精准诊疗分会候任主任委员中国抗癌协会鼻咽癌专业委员会常委中华医学会放射肿瘤治疗分会鼻咽癌学组委员中国生物医学工程学会精确放疗技术分会常委中国医学装备协会离子放射治疗分会常委（来源：《肿瘤瞭望》编辑部）声 明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。