AACR 2024 | H药汉斯状国际多中心III期临床研究ASTRUM-005...

2024年4月10日，复宏汉霖（2696.HK）宣布，公司首个创新型单抗H药 汉斯状（斯鲁利单抗）一线治疗广泛期小细胞肺癌（ES-SCLC）的国际多中心III期临床试验ASTRUM-005的探索性生物标志物分析数据在2024年美国癌症协会年会（AACR 2024）上以壁报形式展示，该研究的主要研究者为吉林省肿瘤医院程颖教授。

H 药为复宏汉霖自主研发的重组人源化抗PD-1单抗注射液，也是全球首个且目前唯一获批一线治疗小细胞肺癌的抗PD-1单抗，已在中国和印尼获批上市，成为首个在东南亚国家成功获批上市的国产抗PD-1单抗。自2022年3月首次获批以来，H药已累计批准用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、ES-SCLC和食管鳞状细胞癌4项适应症，惠及患者超过6万人。此外，H药联合化疗一线治疗非鳞状非小细胞肺癌（nsNSCLC）和一线治疗广泛期小细胞肺癌（ES-SCLC）的上市申请也分别获得中国NMPA和欧盟EMA受理，同时，公司于泰国、新加坡、马来西亚等国家递交了H药的上市许可申请，进一步推动H药在东南亚地区的上市进程。公司亦稳步推进H药对比一线标准治疗阿替利珠单抗用于治疗ES-SCLC的头对头美国桥接试验，计划于2024年在美国递交上市许可申请（BLA)。

其中，H药ES-SCLC适应症的获批主要基于一项关键性临床研究ASTRUM-005（NCT04063163）。该研究为一项随机、双盲、国际多中心的III期临床试验，旨在研究斯鲁利单抗对比安慰剂分别联合化疗一线治疗广泛期小细胞肺癌（ES-SCLC）的疗效和安全性。该研究结果于2022年ASCO年会上由程颖教授首次报告，并于2022年9月登顶全球四大顶级医学期刊之一的《美国医学会杂志》（JAMA），随后，其数据更新于2022年欧洲肿瘤学会亚洲分会（ESMO Asia）年会上发布。ASTRUM-005研究结果表明，该研究中患者的PD-L1肿瘤阳性比例评分TPS≥1%与其能否从H药 斯鲁利单抗联合化疗中获益无直接关联。为进一步探究该研究中能够从H药获益的ES-SCLC患者的生物学特征，复宏汉霖进行了探索性生物标志物分析，回顾性地评估了H药的疗效与蛋白组特征、基因突变及血液学指标间的关系。

以下为此次大会公布的数据详情：

论文题目

Exploratory biomarker analysis of phase 3 ASTRUM-005 study: Serplulimab versus placebo plus chemotherapy for extensive-stage small cell lung cancer

国际多中心III期临床试验ASTRUM-005的探索性生物标志物分析：斯鲁利单抗联合化疗对比安慰剂用于广泛期小细胞肺癌（ES-SCLC）一线治疗

试验设计

ASTRUM-005研究的生物标志物分析

人群主要纳入标准包括：①≥18周岁，②经组织学/细胞学确诊的ES-SCLC患者，③之前没有接受过系统性治疗，④至少有一个可测量的病灶，⑤ECOG 活动状态（PS）评分为0或1分。患者按照2:1的比例随机分配至实验组和对照组，两组治疗方案分别为斯鲁利单抗或安慰剂（4.5mg/kg，D1）+ 卡铂（AUC 5，D1）+ 依托泊苷（100 mg/m2，D1-3），静脉输注，每 3 周一次，最多4个治疗周期，序贯斯鲁利单抗（4.5 mg/kg，D1，3周1次）维持治疗，直至疾病进展或不可耐受的毒性。

本研究对患者的蛋白组学、基因组学以及血液学指标与治疗疗效之间的相关性进行了分析。蛋白组学和基因组学检测在中心实验室进行，分别采集患者的血清样本，通过 Olink Explore 3072 平台进行蛋白组学检测，采集肿瘤组织样本提取DNA经 Med1CDx^TM panel进行高通量测序分析基因突变。血液学检测在研究中心进行，纳入分析的指标包括中性粒细胞与淋巴细胞比值（NLR）、血小板与淋巴细胞比值（PLR）和乳酸脱氢酶（LDH）水平等。

统计分析

客观缓解率（ORR）采用 Clopper-Pearson 法计算出95% 置信区间（CI），并用Cochran-Mantel-Haenszel 法计算OR值及其 95%置信区间（CI）。无进展生存期（PFS）和总生存期（OS）的中位值采用Kaplan-Meier法计算得出，n为每个亚组类别的患者人数。风险比及其95%置信区间采用未分层Cox 比例风险模型计算，并列值采用Efron 方法处理。

对于血清蛋白组学数据，首先采用t检验法确定治疗组中疾病缓解者（包括完全缓解和部分缓解）和未缓解者（包括疾病稳定和疾病进展）的差异表达蛋白（differential expression protein, DEP），然后进一步通过广义线性模型确认预测性/预后生物标志物，并进5倍交叉验证。

对于血液学指标，采用 X-tile法确定每个生物标志物对应的最佳临界值^[1]。并进一步采用多变量 Cox 回归模型确定独立的生物标志物。

临床疗效数据截止时间为2022年6月13日。

试验结果

血清蛋白组

蛋白组分析结果收集自168名患者，其中斯鲁利单抗给药组128人，安慰剂组40人。通过对斯鲁利单抗给药组中缓解者和未缓解者的蛋白组图谱进行比较，确定了181个DEP。为了进一步筛选生物标志物蛋白，研究者将患者分为训练集（斯鲁利单抗给药组80人）和验证集（斯鲁利单抗给药组48人，安慰剂组40人）。并用广义线性模型选择和 5 倍验证，筛选出一组基于15个蛋白表达的分子标签（15-蛋白标签）（表1），能够最大化预测斯鲁利单抗给药组中的缓解者和未缓解者。

根据15-蛋白标签建立的预测模型在训练集上的AUC为0.982，在验证集上斯鲁利单抗给药组和安慰剂组的AUC分别为0.918和0.545。在15-蛋白标签的验证集中，综合评分较高的患者使用斯鲁利单抗联合化疗相比于化疗单药，在PFS和OS方面获益更为显著（表2＆图2）。

基因组突变

共有 305 例患者基因突变数据，排除 3 例异常值后，有 302 例患者的数据被纳入分析。研究发现，RB1基因或NOTCH通路突变的患者相比较于没有对应突变的患者，对斯鲁利单抗联合化疗的应答率更高（表3），RB1基因突变的患者接受斯鲁利单抗联合化疗能获得更长的PFS和OS（图3）。

血液学参数

585名患者中，583名患者NLR 和 PLR检测结果有效，582名患者LDH检测结果有效。数据分析表明，无论治疗方式如何，较高的基线NLR、PLR、和 LDH水平都和较短的PFS和OS相关（图4），提示它们是小细胞肺癌的预后性生物标志物，和患者的不良预后相关。

在单变量Cox回归模型中，NLR、PLR和 LDH水平均和小细胞肺癌的治疗结局相关，多变量 Cox 回归模型显示，仅基线 NLR 和 LDH 水平是独立的预后性生物标志物（表4）。

结论

目前，已有数个ES-SCLC免疫联合化疗的研究药物获批，但尚无明确的预测性生物标志物，找到ES-SCLC患者对免疫联合化疗的生物标志物对于了解小细胞肺癌患者对免疫治疗的优势人群的生物学特征，从而进一步改善小细胞肺癌患者的生存十分重要。

我们的研究结果表明，上述15-蛋白分子标签可作为预测性生物标志物，提示患者接受斯鲁利单抗联合化疗的治疗效果。在基因突变层面，我们发现RB1基因突变或NOTCH通路突变患者可能从斯鲁利单抗联合化疗中获得更高的获益，由于样本量有限，以上结果还需临床研究的进一步验证。此外，和既往研究结果相似，我们发现NLR和LDH是ES-SCLC患者的独立的预后生物标志物，基线NLR或LDH水平高的患者的预后更差，有待进一步临床研究的探索。

关于H药 汉斯状

H药 汉斯状为重组人源化抗PD-1单抗注射液（通用名：斯鲁利单抗注射液），是全球首个获批一线治疗小细胞肺癌的抗PD-1单抗，已在中国和印度尼西亚获批上市。截至目前，H药已有4项适应症获批上市，2项适应症上市申请分别在中国和欧盟获受理，10余项临床试验同步在全球开展。

2022年3月，H药正式于中国获批上市，目前可用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌（sqNSCLC）、广泛期小细胞肺癌（ES-SCLC）及食管鳞状细胞癌（ESCC）。H药联合化疗一线治疗非鳞状非小细胞肺癌（nsNSCLC）和一线治疗广泛期小细胞肺癌（ES-SCLC）的上市申请也分别获得中国NMPA和欧盟EMA受理。聚焦肺癌和消化道肿瘤，复宏汉霖积极推进H药与公司其他产品的协同以及与创新疗法的联合，在全球同步开展10余项肿瘤免疫联合疗法临床试验，于中国、美国、土耳其、波兰、格鲁吉亚等国家和地区累计入组超3900人。H药的4项关键性临床研究结果分别发表于知名期刊《美国医学会杂志》（JAMA）、《自然-医学》（Nature Medicine）、Cancer Cell和British Journal of Cancer。此外，H药还荣获《CSCO 小细胞肺癌诊疗指南》、《CSCO非小细胞肺癌诊疗指南》、《CSCO 食管癌诊疗指南》、《CSCO结直肠癌诊疗指南》、《CSCO免疫检查点抑制剂临床应用指南》和《中国食管癌放射治疗指南》等多部权威指南推荐，为肿瘤临床诊疗提供重要参考。海外方面，H药治疗SCLC也已获得美国FDA和欧盟EC的孤儿药资格认定，并在美国启动了一项H药对比一线标准治疗阿替利珠单抗的头对头桥接试验。

关于复宏汉霖

复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市5款产品，在国际上市2款产品，19项适应症获批，7个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，上海徐汇基地和松江基地（一）均已获得中国和欧盟GMP认证。

复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状的肿瘤免疫联合疗法。继国内首个生物类似药汉利康（利妥昔单抗）、中国首个自主研发的中欧双批单抗药物汉曲优（曲妥珠单抗，欧洲商品名：Zercepac）、汉达远（阿达木单抗）和汉贝泰（贝伐珠单抗）相继获批上市，创新产品汉斯状（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。

Results of Exploratory Biomarker Analysis of Pivotal Clinical Trial ASTRUM-005 of Serplulimab Initially Released at AACR 2024

Shanghai, China, April 10^th, 2024 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the exploratory biomarker analysis of ASTRUM-005, Henlius’ phase 3 clinical study of its innovative anti-PD-1 monoclonal antibody(mAb) HANSIZHUANG (serplulimab) as first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC) was published as poster presentation at the American Association for Cancer Research 2024 meeting (AACR 2024), with Professor Ying Cheng from Jilin Province Cancer Hospital as the leading principal investigator of this study.

HANSIZHUANG (serplulimab) is the company’s first innovative product, as well as the world's first anti-PD-1 mAb for the first-line treatment of SCLC. As of now, HANSIZHUANG has been approved in China and Indonesia, making it also the first China anti-PD-1 mAb approved in Southeast Asia. Since its first approved in China in March 2022, HANSIZHUANG has been approved for 4 indications in China including MSI-H solid tumour, squamous non-small cell lung cancer (sqNSCLC), ES-SCLC, and esophageal squamous cell carcinoma (ESCC), benefiting more than 60,000 patients. The marketing applications of the first-line treatment for non-squamous non-small cell lung cancer (nsNSCLC) and ES-SCLC are under review by the NMPA and the European Medicines Agency (EMA), respectively. Furthermore, the company submitted marketing applications for HANSIZHUANG in Thailand, Singapore, Malaysia to further promote the product in Southeast Asia. Moreover, Henlius also launched a head-to-head bridging trial of HANSIZHUANG versus first-line standard-of-care atezolizumab for ES-SCLC in the U.S. and the company plans to submit a Biologics License Application (BLA) for HANSIZHUANG in the U.S. in 2024.

The approval of HANSIZHUANG for the treatment of ES-SCLC was primarily based on ASTRUM-005 (NCT04063163), a randomised, double-blind, international, multicentre, phase 3 study aimed to compare the efficacy and safety of serplulimab, versus placebo in combination with chemotherapy in previously untreated ES-SCLC patients. The results of ASTRUM-005 were first presented at 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, and published in the Journal of the American Medical Association (JAMA), one of the top four medical journals in the world in September 2022. Thereafter, the updated results of ASTRUM-005 were released at the 2022 European Society for Medical Oncology Asia (ESMO Asia) Congress. The results of ASTRUM-005 has showed that a PD-L1 tumor proportion score (TPS)≥ 1% did not appear to be associated with better response to serplulimab plus chemotherapy. To elaborate biological characteristics of the ES-SCLC patients who has benefited from serplulimab in this study, Henlius completed an exploratory biomarker analysis to retrospectively evaluate the association of proteome signature, genetic mutations, and hematological indices with the efficacy of serplulimab.

Details of the results presented at 2024 AACR Annual Meeting are as follows:

Title

Exploratory biomarker analysis of phase 3 ASTRUM-005 study: Serplulimab versus placebo plus chemotherapy for extensive-stage small cell lung cancer

Methods

Biomarker Analysis of the ASTRUM-005 Study

Study design of ASTRUM-005 is presented in Figure 1.

Correlation analysis between the proteomic, genomic and hematological parameters of the patients and the treatment efficacy were conducted in this study. Proteomic and genomic assays were performed in the central laboratory. Serum samples were collected from patients and serum proteomics data were generated via the Olink Explore 3072 platform. While tumour DNA was extracted from tumour samples and genomic mutations were assessed by a Med1CDx^TM panel. Hematology tests were performed at hospital sites, with hematologic parameters of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lactate dehydrogenase (LDH) levels were included in the analysis.

Statistical Analysis

For the analysis of objective response rate (ORR), 95% confidence interval (CI) of rate was calculated by the Clopper-Pearson method, and the odds ratio and its 95% CI were estimated by Cochran-Mantel-Haenszel statistics. And for progression-free survival (PFS) and OS, the median was calculated from product-limit (Kaplan-Meier) estimates, while n was the number of patients in each subgroup category. The hazard ratio and its 95% CI were estimated using an unstratified Cox proportional hazards model. Efron's method was used to handle ties. 

For serum proteomics, differentially expressed proteins (DEP) were identified using a t-test between responders (patients showing complete response or partial response) and non-responders (patients with stable disease or progressive disease) in the treatment group. Predictive/prognostic biomarkers are identified through generalized linear model selection with 5-fold cross validation. 

For hematological parameters, the optimal cutoffs to predict efficacy were determined using X-tile^[1]. And multivariate Cox regression was conducted to identify independent biomarkers. 

The clinical efficacy data cutoff date was June 13, 2022.

Results

Serum Proteomics

Proteomic profiling results were obtained from 168 patients (128 in the serplulimab group and 40 in the placebo group). The proteomic profiles were compared between responders and non-responders in the serplulimab group, and 181 DEP were identified. To further select the protein signature, investigators divided the patients into a training set (80 in the serplulimab group) and a validation set (48 in the serplulimab group and 40 in the placebo group). A generalized linear model selection with 5-fold validation was applied on the training set use 181 DEP and 15-protein signature was selected, which can sufficiently predict the responders from non-responders in the serplulimab group.

The predictive model based on the 15-protein signature showed an AUC of 0.982 in the training set, and 0.918 and 0.545 in the validation sets for the serplulimab and the placebo groups, respectively. Patients with high signature scores, which were generated from the protein set analysis of the 15-protein signature, derived benefits from adding serplulimab to chemotherapy in terms of PFS and OS (Table 2 and Figure 2), while those with low signature scores did not appear to derive benefits.

Genomic Mutations

Genetic mutation data were available for 305 patients. After excluding 3 outliers, 302 patients were included in the analysis.  Patients with mutations in the RB1 gene or the NOTCH pathway had higher response rates to serplulimab-chemotherapy compared with those without mutations (Table 3). While Patients with RB1 mutations and treated with serplulimab-chemotherapy had a tendency towards longer PFS and OS (Figure 3).

Hematological Parameters

Among all 585 patients, 583 had available test results for NLR and PLR, while 582 had available test results for LDH. The analysis results indicated that high levels of baseline NLR, PLR, and LDH level were correlated with shorter PFS and OS in both treatment groups (Figure 4), implicating these are potential prognostic biomarkers for SCLC and correlate with poor patient prognosis. 

In the univariate Cox regression model, NLR, PLR and LDH levels were associated with patient outcomes in SCLC, while the multivariate Cox regression model showed that baseline NLR and LDH level were independent prognostic biomarkers (Table 4).

Conclusion

Although several treatments of immunotherapy plus chemotherapy have been approved for the treatment of small cell lung cancer (SCLC), biomarkers to predict immunotherapy for SCLC are not well characterised. There is an urgent need to identify reliable biomarkers that can predict elaborate biological characteristics of the ES-SCLC patients who can benefit from the treatment, further improving survival in SCLC patients.  

Our results showed that a 15-protein signature score exhibited potential as a predictive biomarker for the efficacy of serplulimab plus chemotherapy. Additionally, mutations in the RB1 gene and the NOTCH pathway were associated with a more favorable treatment response to serplulimab plus chemotherapy (due to the limited sample size, the above results need further validation in clinical studies). Furthermore, high baseline NLR and LDH correlate with poor prognosis, suggesting that baseline NLR and LDH were independent prognostic biomarkers for ES-SCLC. These findings shed light on the potential of new biomarkers for immunotherapy plus chemotherapy in patients with ES-SCLC, which warrant further investigation.

参考文献

1. Camp R L, et al. Clin Cancer Res. 2004;10:7252–7259.

About HANSIZHUANG

HANSIZHUANG (recombinant humanized anti-PD-1 monoclonal antibody injection, generic name: serplulimab injection) is the first anti-PD-1 mAb for the first-line treatment of SCLC and has been approved in China and Indonesia. Up to date, 4 indications are approved for marketing, 2 marketing applications are under review in China and the EU, and more than 10 clinical trials are ongoing across the world.

HANSIZHUANG was approved in China in March 2022 and has been approved by the National Medicinal Products Administration (NMPA) for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC). The marketing applications of the first-line treatment for non-squamous non-small cell lung cancer (nsNSCLC) and ES-SCLC are under review by the NMPA and the European Medicines Agency (EMA), respectively. Focus on lung and gastrointestinal cancer, the synergy of HANSIZHUANG with in-house products of the company and innovative therapies are being actively promoted. The company has initiated more than 10 clinical trials on immuno-oncology combination therapies in a wide variety of indications with  more than 3,900 subjects enrolled in China, the U.S., Turkey, Poland, Georgia and other countries and regions. The results of 4 pivotal trials of HANSIZHUANG were published in the Journal of the American Medical Association (JAMA), Nature Medicine, Cancer Cell, and the British Journal of Cancer, respectively. Furthermore, HANSIZHUANG was respectively recommended by the CSCO Guidelines for Small Cell Lung Cancer, the CSCO Guidelines for Non-Small Cell Lung Cancer, the CSCO Guidelines for Esophageal Cancer, the CSCO Guidelines for Colorectal Cancer, the CSCO Clinical Practice Guidelines on Immune Checkpoint Inhibitor, the China Guidelines for Radiotherapy of Esophageal Cancer, and other definitive guides, providing valuable references for clinical diagnosis and treatment of tumours. On the other hand, serplulimab was granted orphan drug designations by the U.S. FDA and the EC for the treatment of SCLC, and its bridging head-to-head trial in the United States to compare HANSIZHUANG to standard of care atezolizumab (anti-PD-L1 mAb) for the first-line treatment of ES-SCLC is well under way.

About Henlius

Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 5 products have been launched in China, 2 have been approved for marketing in overseas markets, 19 indications are approved worldwide, and 7 marketing applications have been accepted for review in China, the U.S., and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Facility and Songjiang First Plant, both certificated by China and the EU GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab for injection, trade name in Europe: Zercepac), the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world's first anti-PD-1 mAb for the first-line treatment of SCLC. What's more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

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