Adebrelimab

Esophageal squamous cell carcinomaThe Chinese Academy of Sciences' Center for Systems Biology recently published a research article in Nature Medicine titled "Neoadjuvant Adebrelimab in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma: A Phase 1b Trial," which reports on the results of the world’s first-ever neoadjuvant mono-immunotherapy Phase 1b clinical trial of locally advanced esophageal squamous cell carcinoma. The study proposes new strategies for predicting tumor immunotherapy efficacy based on multi-omics studies. Neoadjuvant immunotherapyEsophageal cancer is one of the most prevalent malignant tumors of the digestive tract worldwide, with over 90% of cases comprising esophageal squamous cell carcinomas (ESCC), representing nearly 60% of new cases globally. It ranks fourth among common cancers in terms of mortality. Unfortunately, most patients with esophageal cancer are in the locally advanced stage at the time of diagnosis. The current standard clinical treatment methods are neoadjuvant chemoradiotherapy or chemotherapy after surgery. However, these treatments have limited efficacy, leading to local recurrence or distant metastasis and ultimately compromising patient survival rates. Recent years have seen the emergence of immunotherapy, represented by checkpoint inhibitors, which has demonstrated positive therapeutic effects in advanced solid tumors. Its application has gradually extended from second-line maintenance treatment to neoadjuvant treatment. However, the safety and benefits of neoadjuvant mono-immunotherapy for esophageal squamous cell carcinoma have not yet been reported, and there is no clear biological marker for predicting the efficacy of such immunotherapy. To explore the safety and effectiveness of neoadjuvant mono-immunotherapy for patients with locally advanced resectable esophageal squamous cell carcinoma, the researchers carried out a prospective, single-center, single-arm, nonrandomized Phase 1b clinical trial (NATION-1907, registered number NCT04215471). NATION-1907 study design30 patients with stage II-IV resectable esophageal squamous cell carcinoma who underwent surgery after neoadjuvant treatment with Adebrelimab (anti-PD-L1 antibody) were enrolled for the study. Based on assessments of safety and effectiveness, the rate of major pathological response (MPR, tumor shrinkage ≥90%) and overall survival (OS) were elicited. Tumor tissues and blood samples of enrolled patients before and after treatment were collected to integrate genome and transcriptome sequencing, TCR sequencing, and multiple immunofluorescence techniques. The study compared the different molecular characteristics of the sensitive and insensitive groups to explore the potential mechanisms of treatment response and resistance. Safety, efficacy and biomarkersIn the safety evaluation of the study, no adverse reactions over Grade 3 were observed, and 24% of patients achieved major pathological remission (MPR), with 2-year overall survival (OS) at 92% and 2-year disease-free survival (RFS) at 100%. Both treatment adverse reactions and 2-year survival status assessment demonstrated that the neoadjuvant anti-PD-L1 monotherapy adopted in this study was significantly better than neoadjuvant chemotherapy or chemoradiotherapy (compared with CMISG1701 clinical study), showing good safety and efficacy of the treatment regimen. Preliminary efficacyTo compare well responders and poor responders, the research team further analyzed potential biomarkers associated with efficacy stratification. Although no significantly correlated mutation features were identified at the genome variation level, the researchers constructed an "IFN/EMT score" consisting of 12 characteristic genes based on transcriptome data. The score could significantly distinguish patients in different treatment response groups. Further integrative analysis of immune cell composition and enriched cancer-related pathways defined three immune microenvironment phenotypes: immune-enriched, tumor-proliferation, and fibroblast-enriched. Immune-enriched patients exhibited more significant tumor shrinkage compared to the other two types, and the response group had a higher proportion of immune-enriched patients. Immune-enriched TME phenotype in responsive patients.The analysis of non-responsive patients found that their tumors harbored higher densities of immunosuppressive cells such as M2 macrophages and fibroblasts. These patients may require a combination of immune-suppressing strategies to benefit from immunotherapy. Using multiple immunofluorescence staining techniques, the research team further characterized the spatial distribution of the microenvironment in 2 non-responsive patients, classified as immune-excluded and immune-suppressive. In immune-excluded tumors, immune cells accumulated at the tumor margin with limited infiltration into the core, while the immune-suppressive tumor core accumulated more pro-tumor macrophages and fewer B cells. By analyzing the immune repertoire (TCR-seq) of tumor tissues and peripheral blood mononuclear cells (PBMCs), the researchers found that T cell receptor (TCR) diversity in PBMCs and the clonality of tumor-infiltrating T cells (TILs) were positively correlated with treatment response. This suggests that the degree of immune activation in peripheral blood and the infiltration of T cells into the tumor microenvironment may play important roles in predicting the efficacy of immunotherapy. Mechanism of pre-existing T cells in response to neoadjuvant Adebrelimab blockade.The study provides evidence of the safety and effectiveness of neoadjuvant mono-immunotherapy using Adebrelimab in treating locally advanced resectable esophageal squamous cell carcinoma. It also suggests new approaches for predicting the efficacy of tumor immunotherapy through multi-omics studies. The "IFN/EMT score," derived from transcriptome data, immune microenvironment phenotypes, and TCR repertoire analysis, may serve as a potential biomarker for predicting immunotherapy efficacy in patients with esophageal squamous cell carcinoma. These findings establish a foundation for optimizing and personalizing immunotherapy strategies for patients with this type of cancer. Reference: Yin, J., Yuan, J., Li, Y. et al. Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial. Nat Med (2023). The content above comes from the network. if any infringement, please contact us to modify.

2025年2月18日，广州医科大学附属第一医院钟南山院士团队开展的一项探索诱导化疗联合卡瑞利珠单抗和阿帕替尼（“双艾”组合）治疗广泛期小细胞肺癌（ES-SCLC）的多中心临床研究发表于《自然》子刊、国际知名医学期刊《信号转导与靶向治疗》（Signal Transduction and Targeted Therapy，简称STTT，IF：40.8） [1]。本研究创新性地提出了诱导化疗（EC），即在未经治疗的ES-SCLC患者中，先化疗两个疗程，再联合“双艾”组合，探索性研究其抗肿瘤活性及潜在生物标志物。 该研究结果显示，诱导化疗后联合“双艾”组合治疗显示出可控的安全性和良好的抗肿瘤活性，客观缓解率（ORR）达到88.9%，疾病控制率（DCR）为97.2%，中位无进展生存期（PFS）为7.3个月，中位总生存期（OS）为17.3个月，为ES-SCLC的治疗提供了新的思路和新希望。 诱导化疗联合“双艾”组合治疗广泛期小细胞肺癌研究登上《STTT》 01 研究背景 ES-SCLC是一种恶性程度高、进展迅速的肺癌亚型。尽管传统化疗联合免疫治疗在一定程度上改善了患者的生存期，其中位生存期仍仅为12-15个月[2-5]，治疗效果有限。因此，临床亟需新的治疗策略。近年研究发现，抗血管生成药物可能通过改善肿瘤微环境增强免疫治疗效果。免疫检查点抑制剂（ICIs）联合抗血管内皮生长因子受体（VEGFR）抑制剂及化疗的治疗策略在肺癌患者中显示出良好疗效[6-9]。然而，大多数SCLC患者病灶属于中央型，靠近或侵袭大血管，抗血管药物的一线使用存在较高的出血风险。既往针对SCLC的抗VEGFR联合治疗方案通常排除了大血管侵犯或高出血风险的患者，这限制了抗血管生成联合策略在ES-SCLC患者中的广泛应用。 卡瑞利珠单抗（商品名：艾瑞卡®）是恒瑞医药自主研发的一款人源化PD-1单克隆抗体，于2019年5月获NMPA批准上市，目前已获批9个适应症，涵盖肺癌、肝癌、食管癌、鼻咽癌以及淋巴瘤五大瘤种，为获批适应症和覆盖瘤种数量领先的国产PD-1产品。阿帕替尼（商品名：艾坦®）是恒瑞医药开发的一款针对血管内皮生长因子受体（VEGFR）的小分子酪氨酸激酶抑制剂，于2014年10月获NMPA批准上市，目前已在胃癌、肝癌和乳腺癌治疗领域获批4项适应症。 本研究首次探索了“诱导化疗后+卡瑞利珠单抗+阿帕替尼+化疗”四联方案在ES-SCLC中的疗效与安全性。 02 研究设计 研究设计 本研究为单臂试验（ClinicalTrials.gov NCT05001412），采用了一种创新的治疗方案：患者首先接受2个周期的依托泊苷和卡铂（EC）诱导化疗，随后进行2-4个周期的“双艾”组合联合EC治疗，最后进入“双艾”组合的维持治疗阶段。该方案旨在通过诱导化疗缩小肿瘤并减少抗血管生成药物可能引起的出血风险，同时通过免疫治疗和抗血管生成药物的协同作用增强抗肿瘤效果。主要终点为安全性，次要终点包括ORR、缓解持续时间（DoR）、PFS和OS。通过靶向测序和全转录组测序（WTS）探索生物标志物。 03 研究结果 1 患者特征与治疗流程 2021年1月21日至2022年8月20日期间，共纳入40例患者并接受了诱导EC治疗。40例患者可评估安全性，36例患者可评估肿瘤缓解情况。在40例患者中，中位年龄为60岁（范围：40-73岁），36例（90.0%）为男性。所有40例患者（100%）均为Ⅳ期疾病。大多数患者为中央型小细胞肺癌（33/40，82.5%），ECOG PS为1（31/40，77.5%）。 表1 患者基线特征 图1 患者流程表 2 安全性 在整个治疗过程中，安全性整体可控。未观察到阿帕替尼相关的≥3级出血事件。 3 疗效 在36例可评估的患者中，总体ORR为88.9%（95% CI：73.9%-96.9%），其中32例（88.9%）患者部分缓解（PR），3例（8.3%）患者病情稳定（SD）（表2）。DCR为97.2%（95% CI：85.5%-100%）。中位PFS为7.3个月（95% CI：6.6-9.2）。中位OS为17.3个月（95% CI：11.8-未达到）。12个月OS率为63.4%（95% CI：45.4%-76.9%）（图2）。 表2 抗肿瘤活性 图2 临床结果 4 生物标志物探索 基线组织样本来自30例患者，用于靶向基因测序，以及21例患者，用于WTS。TP53（97%）和RB1（90%）是最常突变的基因。在诱导治疗期间和整个治疗过程中，未观察到基因组突变与反应（完全缓解/部分缓解）之间有显著相关性。 RB1突变与较长的PFS相关（P<0.001；HR，0.10；95% CI：0.02-0.45），而PTPRD突变（P=0.02；HR，3.85；95% CI：1.17-12.67）和mTOR信号通路基因突变（P=0.005；HR，3.97；95% CI：1.43-11.06）与较短的PFS相关。在SPTA1突变的患者中观察到PFS有缩短的趋势（P=0.06；HR，2.22；95% CI：0.94-5.25）（图3）。高水平的自然杀伤（NK）细胞（P=0.002；HR，0.08；95% CI：0.01-0.61）和干扰素（P=0.004；HR，0.13；95% CI：0.03-0.63）与较长的PFS相关，而高水平的癌症相关成纤维细胞（P=0.001；HR，5.55；95% CI：1.74-17.69）与较短的PFS相关（图4）。 图3 基于基因组改变的治疗反应 图4 基于TMB、HRD和肿瘤微环境状态的治疗反应 04 临床意义与未来方向 ES-SCLC的治疗一直是肺癌领域的难点，尤其大血管侵犯或高出血风险的患者，既往联合抗血管的研究均会排除此类基线较差的患者，本研究创新性采用2周期诱导化疗，缩瘤，让血管和肿瘤分离后，再联合抗血管，首次证实了诱导化疗联合“双艾”组合在ES-SCLC患者治疗中具有可控的安全性和良好的抗肿瘤活性。本研究中入组的患者更符合临床实践，且患者基线情况更差，所有可评估血管侵犯的患者均有大血管侵犯情况，研究结果显示安全性良好，无出血发生，整体AE耐受，因此本方案有望为这一难治性肺癌亚型的治疗提供新的选择。尽管该研究为单臂试验，缺乏对照组，但其结果为进一步的随机对照试验奠定了基础。未来，随着更多临床数据的积累和生物标志物的验证，我们期待这一治疗方案在未来的临床实践中得到广泛应用，为更多患者带来福音。 参考文献： 1. Liu, M., Qiu, G., Guan, W. et al.Induction chemotherapy followed by camrelizumab plus apatinib and chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, single-arm trial. Sig Transduct Target Ther 10, 65 (2025). https://doi.org/10.1038/s41392-025-02153-7. 2. Leora Horn, at el. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. 3. Luis Paz-Ares, at el. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23;394(10212):1929-1939. 4. Jie Wang, at el. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022 Jun;23(6):739-747. 5. Ying Cheng, at el. Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial. JAMA. 2022 Sep 27;328(12):1223-1232. 6. Socinski, M. A. et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N. Engl. J. Med 378, 2288–2301 (2018). 7. Tiseo, M. et al. Italian, multicenter, phase III, randomized study of cisplatin plusetoposide with or without bevacizumab as first-line treatment in extensivedisease small-cell lung cancer: the GOIRC-AIFA FARM6PMFJM trial. J. Clin. Oncol.35, 1281–1287 (2017). 8. Cheng, Y. et al. Benmelstobart, anlotinib and chemotherapy in extensive-stagesmall-cell lung cancer: a randomized phase 3 trial. Nat. Med 30, 2967–2976 (2024). 9. Zhao, Y. et al. Camrelizumab combined with chemotherapy followed by maintenance camrelizumab and apatinib as first-line therapy for extensive-stage small cell lung cancer: A phase II, single-arm, exploratory study. J. Clin. Oncol. 42, abstr.e20107–e20107 (2024). 声明： 1.本新闻旨在分享学术前沿动态，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2.恒瑞医药不对任何药品和/或适应症作推荐。 3.本新闻中涉及的信息仅供参考，请遵从医生或其他医疗卫生专业人士的意见或指导。医疗卫生专业人士作出的任何与治疗有关的决定应根据患者的具体情况并遵照药品说明书。 撰稿：肿瘤中央医学事务部 排版：程梦真 责编：李玉莹 往期精选 |  研发创新  | 全球首个超长效PCSK9单抗！恒瑞降脂创新药瑞卡西单抗获批上市 慢病创新里程碑！恒瑞首个自免创新药夫那奇珠单抗获批上市 |  国际化  | 海外BD再下一城！恒瑞医药DLL3 ADC创新药SHR-4849实现海外独家许可 海外BD再传捷报！恒瑞医药GLP-1类创新药组合实现海外许可 |  重磅奖项  | 喜报！恒瑞医药荣获2023年度国家科技进步奖 恒瑞医药连续六年入选全球制药企业50强榜单！ |  社会公益  | “健康中国行·重走长征路”项目启动仪式圆满举行！恒瑞提供公益支持，助力健康中国 恒瑞医药集团向中国扶贫基金会捐赠3000万设立“健康帮扶基金”