Atezolizumab

In combination with atezolizumab or durvalumab Study conducted under the CRADA agreement between NCI and Oryzon April 15, 2025 -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the first patient has been dosed in a Phase I/II trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with immune checkpoint inhibitors (ICI) in first line small cell lung cancer (SCLC) patients with extensive disease, sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. This is the first clinical trial testing the combination of iadademstat with ICI. The trial (NCT06287775), titled “A Phase I Dose Finding and Phase II Randomized Trial of Iadademstat Combined With Immune Checkpoint Inhibition Maintenance After Initial Chemoimmunotherapy in Patients With Extensive-Stage Small Cell Lung Cancer”, 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 Phase I/II clinical study is conducted and sponsored by the NCI, with Dr. Charles Rudin, from the Memorial Sloan Kettering Cancer Center (MSKCC) as the Principal Investigator. The trial will be conducted at a number of prestigious cancer centers in the US, including the MSKCC, the JHU Sidney Kimmel Comprehensive Cancer Center and many others. The trial plans to enroll 45-50 patients and will be carried out under a Cooperative Research and Development Agreement (CRADA) that Oryzon has in place with the NCI. Dr. Carlos Buesa, Oryzon’s CEO, stated: “We are very excited to have the first patient dosed in this study. The biology underlying iadademstat’s ability to make SCLC cells visible to the immune system and to boost significantly the number and the activation of cytotoxic CD8+ T cells is fascinating. Moreover, prior analyses of several Phase III trials in SCLC indicate that low LSD1 expression is a key factor in determining patients' likelihood of responding and surviving. If this trial confirms the preliminary findings reported by researchers at MSKCC and others, it would reinforce the rationale for this combination as a therapeutic option for this critically underserved patient population. In the event of positive results, the company could also initiate a complementary trial to generate additional data in support of a potential accelerated registration strategy.” Founded 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 Iadademstat (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 collaborative Phase II trial with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and 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. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. 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点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”NCCN 2025 微专辑扫描二维码可查看更多内容编者按子宫内膜癌是威胁女性生命健康的三大生殖系统恶性肿瘤之一，其发病率和死亡率在全球范围内呈上升趋势。晚期复发性子宫内膜癌在很大程度上化疗耐药，随后的治疗与获益呈递减状态。因此，免疫治疗逐渐登上子宫内膜癌治疗的舞台[1]。3月28～30日在美国奥兰多召开的美国国立综合癌症网络（NCCN）2025年会上，一项免疫联合化疗治疗原发性晚期或复发性子宫内膜癌疗效的荟萃分析入选大会壁报展示。《肿瘤瞭望》荣幸邀请到湖南省肿瘤医院唐洁教授就上述研究进行点评，现将内容整理如下，以飨读者。研究背景子宫内膜癌的传统治疗方案以化疗为主。近年来的研究表明，免疫治疗联合化疗可显著提升患者生存率和持续缓解率。本研究旨在评估免疫联合化疗在原发性晚期或复发性子宫内膜癌患者中的疗效。研究方法文献检索：系统检索MEDLINE、EMBASE及COCHRANE数据库（截至2024年8月10日），纳入评估免疫联合化疗用于原发性晚期或复发性子宫内膜癌的Ⅱ/Ⅲ期随机对照试验（RCT）。数据提取：由两名研究者独立提取数据，如有分歧则由第三方评审者判定。研究终点：主要终点：无进展生存期（PFS）和总生存期（OS）。统计分析：主要采用随机和固定效应模型进行荟萃分析，使用Mantel-Haenszel方法计算汇总的风险比（HR）和风险差（RD）以及95%置信区间（CI）。通过I2统计量和Cochran’s Q统计量评估研究间的异质性。P<0.05视为具有统计学意义。研究结果检索结果：共纳入五项试验的2 693名患者，包括四项Ⅲ期RCT（AtTEnd、NRG-GY018、RUBY、DUO-E）和一项Ⅱ期RCT（MITO END-3）。其中，668名患者为错配修复缺陷（dMMR）肿瘤患者，2 006名患者为错配修复正常（pMMR）肿瘤患者，19例患者的错配修复状态未确定/无法评估。研究特征（图1）：五项试验均比较了免疫联合化疗（卡铂和紫杉醇）与安慰剂加化疗在原发晚期或复发性子宫内膜癌中的效果：AtTEnd治疗组：阿替利珠单抗+化疗；NRG-GY018治疗组：帕博利珠单抗+化疗；RUBY治疗组：多塔利单抗（dostarlimab）+化疗；DUO-E治疗组：度伐利尤单抗（有/无奥拉帕利）+化疗；MITO END-3治疗组：阿维鲁单抗（avelumab）+化疗。图1. 研究特征荟萃分析结果：与对照组相比，免疫联合化疗组的PFS HR为0.62（95%CI 0.52～0.73；P<0.00001）（图2）；OS HR为0.74（95%CI 0.64～0.85；P<0.0001）（图3）。基于错配修复状态的亚组分析中，在dMMR亚组中，与对照组相比，免疫联合化疗组的PFS HR为0.35（95%CI 0.27～0.44；P<0.00001）（图4）。在pMMR亚组中，与对照组相比，免疫联合化疗组的PFS HR为0.77（95%CI 0.68～0.87；P<0.0001）（图5）。图2. 总体人群PFS结果图3. 总体人群OS结果图4. dMMR亚组PFS结果图5. pMMR亚组PFS结果研究结论在原发性晚期或复发性子宫内膜癌患者中，免疫联合化疗方案相比标准化疗可显著改善总体人群的PFS与OS。亚组分析显示，无论患者MMR状态（dMMR或pMMR），免疫联合化疗均可带来PFS获益。本研究支持将免疫治疗纳入原发性晚期或复发性子宫内膜癌的标准治疗体系。专家点评该荟萃分析为免疫联合化疗在晚期或复发性子宫内膜癌中的应用提供了有力的循证医学证据，具有重要的临床指导价值。研究通过整合五项Ⅱ/Ⅲ期RCT数据，覆盖近2 700例患者，全面评估了不同免疫检查点抑制剂联合化疗的疗效，尤其在MMR状态分层分析中揭示了差异化的治疗获益，为精准治疗奠定了基础。本研究也存在一定局限性：1.长期生存与安全性数据不足：目前OS获益虽显著，但随访时间有限，需关注免疫相关不良反应对长期生活质量的影响，尤其是老年或合并症患者。2.生物标志物的精细化探索：除MMR状态外，未来需整合PD-L1表达或分子分型等多维标志物，以筛选更精准的获益人群。展望未来，临床需规范MMR检测以指导分层治疗，同时探索免疫联合靶向治疗等新策略，优化晚期或复发性子宫内膜癌患者获益，并平衡疗效与毒性风险。唐洁 教授湖南省肿瘤医院妇瘤中心技术总监，妇瘤一科主任 、主任医师、 教授博士、硕士生导师，留美博士、博士后中国抗癌协会卵巢癌专委会委员中国医师协会医学机器人医师分会委员中国临床肿瘤学会（CSCO）妇科肿瘤委员会常委国家癌症中心卵巢癌质控专家委员会委员 中国抗癌协会多学科专委会（MDT）委员中国优生优育妇产科专业委员会委员中国研究型医院妇瘤专委会委员湖南省抗癌协会妇瘤专委会主任委员湖南省高层次卫生人才“225”工程妇科恶性肿瘤学科带头人美国妇科肿瘤协会会员美国临床肿瘤杂志（CLINICAL CANCER RESEARCH）特邀审稿人获得美国执业医师证，在美国THOMAS JEFFERSON大学医院学习和从事妇科临床工作多年获得和主持多个美国卫生部、国家级及省级自然科学基金课题，在国际一流的医学杂志上发表第一或通讯作者的SCI论文30多篇。（上下滑动可查看）参考文献：[1]刘志铭，姜洁.晚期或复发性子宫内膜癌化学治疗:进展、现状与挑战[J].中国癌症防治杂志,202315(5):485-491.摘要原文：Efficacy of Immunochemotherapy in Primary Advanced or Recurrent Endometrial Cancer: A Systematic Review and Meta-Analysis of Phase II/III Randomized Controlled Trials (RCTs)INTRODUCTION:Treatment regimens for endometrial cancer (EC) have historically centered chemotherapy. Recent advancements have begun incorporating immunotherapy in concordance with chemotherapy which have shown shown significant improvement in the survival and durable response rates. Our study explores the efficacy of immunochemotherapy (ICI) regimens in patients with primary advanced or recurrent EC.METHODS:Literature Search: We conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases from inception through August 10th, 2024 Eligibility Criteria. Eligible studies included Phase II/III RCTs utilizing immunochemotherapy in primary advanced or recurrent EC.Data Extraction: Data extraction was independently conducted by two authors; discrepancies were resolved by a third reviewer.Study Outcome Measures: The primary outcomes were progression-free survival (PFS) and overall survival (OS). Data Synthesis and Analysis: The primary meta-analytic approach was a random and fixed effects model using the Mantel-Haenszel (MH) method. This method was used to calculate the estimated pooled hazard ratio (HR) and risk difference (RD) with 95% confidence intervals (CI). Heterogeneity among the studies was assessed using the I² statistic and Cochran’s Q-statistic. A p-value of less than 0.05 was considered statistically significant.RESULTS:Search Results: - A total of 2693 patients were included across five trials: four phase III RCTs (AtTEnd, NRG-GY018, RUBY, DUO-E) and one phase II RCT (MITO END-3). - 668 patients had mismatch repair deficient (dMMR) cancers, 2006 patients had MMR proficient cancers (pMMR), and MMR status was undetermined/inevaluable in 19 casesCharacteristics of the Studies: - All five trials compared immunotherapy combined with chemotherapy (carboplatin and paclitaxel) versus placebo plus in chemotherapy in primary advanced or recurrent EC.- AtTEnd treatment arm: atezolizumab + chemotherapy- NRG-GY018 treatment arm: pembrolizumab + chemotherapy- RUBY treatment arm: dostarlimab + chemotherapy- DUO-E treatment arm: durvalumab with/without olaparib+ chemotherapy- MITO END-3 treatment arm: avelumab + chemotherapy- The PFS HR of the treatment arm 0.62 (95% CI 0.52-0.73; P<0.00001) when compared to the control arm (A).- The OS HR of the treatment arm was 0.74 (95% CI 0.64-0.85; P<0.0001) when compared to the control arm (B).- In a subgroup analysis based on MMR status, in the dMMR cohort, the PFS HRof the treatment arm was 0.35 (95% CI 0.27-0.44; P<0.00001) compared to the control arm (C.)- In the pMMR cohort, the PFS HR of the treatment arm was 0.77 (95% CI 0.68-0.87; P<0.0001) compared to the control arm (D).CONCLUSIONS:This study revealed that the combination of immunotherapy and chemotherapy lead to improvement of PFS and OS in the overall population compared to the standard of care (SOC) chemotherapy. This PFS benefit of immunochemotherapy was also noted in the subgroup analysis of both dMMR and pMMR cohorts. As such, this analysis favors the addition of immunotherapy to SOC treatment of primary advanced or recurrent EC.（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。