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Antithetical impacts of deleterious LRP1B mutations in non-squamous and squamous NSCLCs on predicting benefits from immune checkpoint inhibitor alone or with chemotherapy over chemotherapy alone: retrospective analyses of the POPLAR/OAK and CHOICE-01 trial

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Science China Life Sciences 2024年

作者： Jinliang Wang Wenyong Zhou Yu Xu jianchun duan Qiaoxia Zhou Guoqiang Wang Leo Li Chunwei Xu Wenxian Wang Shangli Cai Zhijie Wang Jie Wang Department of Oncology The Fifth Medical Center of Chinese PLA General Hospital Department of Thoracic Surgery Shanghai Chest Hospital School of Medicine Shanghai Jiao Tong University Burning Rock Biotech CAMS Key Laboratory of Translational Research on Lung Cancer State Key Laboratory of Molecular Oncology Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medicine and Cancer (IBMC) Chinese Academy of Sciences Department of Clinical Trial The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)

In non-small cell lung cancers, the non-squamous and squamous subtypes （nsqNSCLC and sqNSCLC） exhibit disparities in pathophysiology,tumor immunology, and potential genomic correlates affecting responses to immune checkpoint inhibitor （ICI）-based treatments. In our inhouse training cohort （n=85）, the presence of the LRP1B deleterious mutation （LRP1B-del） was associated with longer and shorter progression-free survival （PFS） on ICIs alone in nsqNSCLCs and sqNSCLCs, respectively (Pinteraction=0.008). These results were validated using a larger public ICI cohort (n=208, Pinteraction<0.001). Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs （P=0.040） and sqNSCLCs （P=0.014）, respectively. In the POPLAR/OAK cohort, nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel (hazard ratio （HR）=0.70, P=0.046), whereas this benefit was negligible in those without LRP1B-del （HR=1.05, P=0.64）. Conversely, sqNSCLCs without LRP1Bdel benefited more from atezolizumab （HR=0.60, P=0.002） than those with LRP1B-del （HR=1.30, P=0.31）. Consistent results were observed in the in-house CHOICE-01 cohort, in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone (Pinteraction=0.008). This multi-cohort study delineates the antithetical impacts of LRP1Bdel in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone. Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs, emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.

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Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated,EGFR-mutated,advanced non-small cell lung cancer:data froma randomized phase III trial(AENEAS)

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Cancer Communications 2024年第9期44卷 1005-1017页

作者： Shun Lu Xiaorong Dong Hong Jian Jianhua Chen Gongyan Chen Yuping Sun Yinghua Ji ZipingWang Jianhua Shi Junguo Lu Shaoshui Chen Dongqing Lv Guojun Zhang Chunling Liu Juan Li Xinmin Yu Zhong Lin Zhuang Yu ZhehaiWang Jiuwei Cui Xingxiang Xu Jian Fang Jifeng Feng Zhi Xu RuiMa Jie Hu Nong Yang Xiangdong Zhou XiaohongWu Chengping Hu Zhihong Zhang You Lu Yanping Hu Liyan Jiang Qiming wang Renhua Guo Jianying Zhou Baolan Li Chunhong Hu Wancheng Tong Helong Zhang LinMa Yuan Chen Zhijun Jie Yu Yao Longzhen Zhang JieWeng Weidong Li Jianping Xiong Xianwei Ye jianchun duan Haihua Yang Meili Sun HongyingWei JiaweiWei Zheyu Zhang QiongWu Department of Medical Oncology Shanghai Chest Hospital Shanghai JiaoTong UniversityShanghaiP.R.China Cancer Center Union Hospital Tongji Medical College Huazhong University of Science and TechnologyWuhanHubeiP.R.China Department of Medical Oncology-Chest Hunan Cancer Hospital&The Affiliated Cancer Hospital of Central South University Xiangya School of MedicineChangshaHunanP.R.China Thoracic OncologyMedicine HarbinMedical University Cancer HospitalHarbinHeilongjiangP.R.China Department of Oncology Jinan Central HospitalJinanShandongP.R.China Department of Oncology First Affiliated Hospital of Xinxiang Medical UniversityXinxiangHenanP.R.China Department of Chest Medicine Beijing Cancer HospitalBeijingP.R.China Department of Internal Medicine Linyi Cancer HospitalLinyiShandongP.R.China Department of Respiratory Medicine Nantong Tumor HospitalNantongJiangsuP.R.China Department of Oncology Binzhou Medical University HospitalBinzhouShandongP.R.China Breath Internal Medicine Taizhou Hospital of Zhejiang ProvinceLinhaiZhejiangP.R.China Department of Respiration The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanP.R.China Department of Lung Internal Medicine Affiliated Tumor Hospital of Xinjiang Medical UniversityUrumqiXinjiangP.R.China Department of Thoracic Oncology Sichuan Cancer HospitalChengduSichuanP.R.China Thoracic Medical Oncology Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital)HangzhouZhejiangP.R.China Department of Thoracic Oncology The Fifth Subsidiary Sun Yat-sen University HospitalZhuhaiGuangdongP.R.China Department of Oncology The Affiliated Hospital of QingdaoUniversityQingdaoShandongP.R.China Department of Oncology Shandong Cancer HospitalJinanShandongP.R.China Department of Oncology The First BethuneHospital of Jilin UniversityChangchunJilinP.R.China Department of Respiration Northern Jiangsu People’s Hospital Affiliated to Yangzhou UniversityYangzhouJiangsuP.R.China Department of Internal

Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of *** study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS ***:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded *** with asymptomatic,stable CNS metastases were ***-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every *** responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,*** risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at *** new safety findings were ***:The

关键词： aumolertinib brain metastasis non-small cell lung cancer third-generation EGFR-TKI

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First-line pemetrexed-platinum doublet chemotherapy with or without bevacizumab in non-squamous non-small cell lung cancer: A real-world propensity score-matched study in China

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Chinese Journal of Cancer Research 2019年第5期31卷 749-758页

作者： Fei Qi Xingsheng Hu Yutao Liu Zhijie Wang jianchun duan Jie Wang Mei Dong Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College

Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were ***: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance ***: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.

关键词： Bevacizumab pemetrexed non-squamous non-small cell lung cancer maintenance treatment propensity score matching

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Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions

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Frontiers of Medicine 2023年第1期17卷 18-42页

作者： Jia Zhong Hua Bai Zhijie Wang jianchun duan Wei Zhuang Di Wang Rui Wan Jiachen Xu Kailun Fei Zixiao Ma Xue Zhang Jie Wang State Key Laboratory of Molecular Oncology Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

关键词： non-small cell lung cancer driver mutations treatment strategy resistant mechanism immune-checkpoint inhibitors

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远程BOPPPS教学模式在胸部肿瘤教学中的应用探讨

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中国继续医学教育 2024年第17期16卷 29-33页

作者：费凯伦王志杰张永明万蕊徐佳晨马子骁孙博洋段建春国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院肿瘤内科北京100021

住院医师规范化培训系统已在我国广泛开展,并切实起到了提高医务人员医疗水平的积极作用。在此基础上,更有针对性的培训体系,如肿瘤内科专科医师一体化培训模式也在不断探索中。学生在既往住培医师培训过程中,暴露出对肿瘤内科知识体系... 详细信息

住院医师规范化培训系统已在我国广泛开展,并切实起到了提高医务人员医疗水平的积极作用。在此基础上,更有针对性的培训体系,如肿瘤内科专科医师一体化培训模式也在不断探索中。学生在既往住培医师培训过程中,暴露出对肿瘤内科知识体系缺乏系统化思考,临床思维模式转化较为困难等问题。基于此,设计了以胸部肿瘤为试点的衔接课程,围绕肿瘤学基础、胸部肿瘤病理特征、胸部肿瘤影像学特征、胸部肿瘤常见诊疗思路等进行线上教学,以期帮助学生了解肿瘤学基本概念并规范常规诊疗流程。并引入桥接-目标-准备-呈现-练习-自我评估(bridge-in,objective/outcome,pre-assessment,participatory learning,post-assessment,summary,BOPPPS)教学模式,以期利用内科培训之余的时间让一体化培训学员更好地适应肿瘤内科的教学体系,增强培训效果。从而实现为我国培养高质量医学人才的目标,为推进新医科方面建设而努力。

关键词：住院医师规范化培训肿瘤内科专科医师一体化培训创新改革医药类专业人才培养

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A phase I study of nimotuzumab plus docetaxel in chemotherapy- refractory/resistant patients with advanced non-small-cell lung cancer

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Chinese Journal of Cancer Research 2016年第1期28卷 12-18页

作者： Jun Zhao Minglei Zhuo Zhijie Wang jianchun duan Yuyan Wang Shuhang Wang Tongtong An Meina Wu Jie Wang Departments of Thoracic Medical Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Peking University Cancer Hospital and Institute Beijing 100142 China

Background： To determine the safety and therapeutic efficacy of nimotuzumab （h-R3） combined with docetaxel in advanced non-small-cell lung cancer （NSCLC） patients who have failed to respond to prior first-line chemotherapy. Methods： In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor （EGFR）-expressing stage IV NSCLC were treated with nimotuzumab plus doeetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and ***： There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade Ⅲ-Ⅳ toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients （66.7%）. The median progression-free survival （PFS） was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR （EGFR WT）. The median survival time （MST） was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT. Conclusions： Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients.

关键词： Nimotuzumab docetaxel non-small-cell lung cancer (NSCLC)

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伴远处孤立转移的非小细胞肺癌治疗进展

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中国肿瘤临床 2009年第20期36卷 1197-1200页

作者：段建春王洁北京大学临床肿瘤学院恶性肿瘤发病机制及转化机制教育部重点实验室北京肿瘤医院暨北京市肿瘤防治研究所胸部肿瘤内科北京市100142

肺癌是严重威胁人类健康及生命的恶性肿瘤之一,发病率逐年上升,非小细胞肺癌(NSCLC)中Ⅳ期患者可达40%左右。而其中一小部分Ⅳ期NSCLC者呈单脏器孤立转移,且原发灶亦为早期。对此部分患者,其治疗方式同初治时即有多部位远处转移者有所不... 详细信息

肺癌是严重威胁人类健康及生命的恶性肿瘤之一,发病率逐年上升,非小细胞肺癌(NSCLC)中Ⅳ期患者可达40%左右。而其中一小部分Ⅳ期NSCLC者呈单脏器孤立转移,且原发灶亦为早期。对此部分患者,其治疗方式同初治时即有多部位远处转移者有所不同;同样,其预后同初治时即有多部位远处转移者亦不相同。对于孤立脑转移患者,在原发NSCLC能够完全切除或已经得到良好控制的情况下,切除同时性或异时性孤立脑转移的5年生存率高达10%～30%,目前的标准治疗推荐手术切除原发灶及孤立脑转移灶或立体定向放疗联合全脑放疗。而孤立肾上腺转移发生率大约在1.62%～3.5%。通过积极的外科切除及联合化疗,NSCLC同时或异时性孤立肾上腺转移患者能延长生存并可获长期生存,5年生存率可达25%～40%。查阅大量相关文献,得出结论认为:对于伴有不同部位的远处孤立转移非小细胞肺癌患者,在原发灶完全切除基础上,进行积极的转移灶局部手术治疗,生存期明显优于其它Ⅳ期患者。

关键词：非小细胞肺癌孤立转移根治性切除术

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PIK3CA mutation in Chinese patients with lung squamous cell carcinoma

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Chinese Journal of Cancer Research 2013年第4期25卷 416-422页

作者： Jinglin Yu Hua Bai Zhijie Wang Zhigang Wei Xiaosheng Ding jianchun duan Lu Yang Meina Wu Yuyan Wang Jie Wang Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Thoracic Medical OncologyPeking University Cancer Hospital&Institute

Objective： To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma （LSCC） and explore their relationship with clinicopathological profiles. Methods： Tumor samples from 123 cases of LSCC were included in this study. PIK3CA mutations in exon 9 and 20 were screened by pyrosequencing and confirmed by clone sequencing or amplification refractory mutation system （ARMS）. Denaturing performance liquid chromatography （DHPLC） was employed for evaluation of EGFR mutation in exon 19, 21 and KRAS mutation. Results： PIK3CA mutations were found in 3 （2.4%） patients. The mutation type included E545K, E452Q and H1047R. Of these three patients, one coupled with EGFR mutation, and the other two coupled with PIK3CA amplification. All the three patients shared the same clinicopathologic characteristics： male, less than 60 years old, had smoke history, stage III and carried wild-type KRAS. Conclusions： The frequency of PIK3CA mutation is low in Chinese patients with LSCC. The mutational status of PIK3CA is not mutually exclusive to EGFR mutation.

关键词： Lung squamous cell carcinoma (LSCC) PIK3CA mutation EGFR mutation KRAS mutation

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Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer

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Signal Transduction and Targeted Therapy 2022年第11期7卷 4174-4189页

作者： Yanhua Tian Qingqing Li Zhenlin Yang Shu Zhang Jiachen Xu Zhijie Wang Hua Bai jianchun duan Bo Zheng Wen Li Yueli Cui Xin Wang Rui Wan Kailun Fei Jia Zhong Shugeng Gao Jie He Carl MGay Jianjun Zhang Jie Wang Fuchou Tang State Key Laboratory of Molecular Oncology Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijingChina Beijing Advanced Innovation Center for Genomics&Ministry of Education Key Laboratory of Cell Proliferation and Differentiation BeijingChina Department of Throacic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Academy for Advanced Interdisciplinary Studies Peking UniversityBeijingChina Department of Thoracic/Head&Neck Medical Oncology UT MD Anderson Cancer CenterHoustonTX77030USA Peking-Tsinghua Center for Life Sciences Peking UniversityBeijingChina

Small-cell lung cancer(SCLC)is the most aggressive and lethal subtype of lung cancer,for which,better understandings of its biology are urgently ***-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment(TME)and investigate their roles in tumorigenic ***,we performed high-precision single-cell transcriptomic analysis of~5000 individual cells from primary tumors(PTs)and matched normal adjacent tissues(NATs)from 11 SCLC patients,including one patient with both PT and relapsed tumor(RT).The comparison revealed an immunosuppressive landscape of human *** cells in SCLC tumors exhibited diverse states mainly related to the cell cycle,immune,and hypoxic *** data also revealed the intratumor heterogeneity(ITH)of key transcription factors(TFs)in SCLC and related gene expression patterns and *** non-neuroendocrine(non-NE)tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC,which contributed to better responses to immune checkpoint *** findings indicate a significant heterogeneity of human SCLC,and intensive crosstalk between cancer cells and the TME at single-cell resolution,and thus,set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.

关键词： cancer lung matched

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铂类抗肿瘤药物相关肾损伤作用机制的研究进展

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中国肺癌杂志 2015年第9期18卷 580-586页

作者：闫菲菲段建春王洁北京大学肿瘤医院(北京大学临床肿瘤学院)胸部肿瘤内一科北京100142

铂类药物是目前应用最广泛的抗肿瘤药物之一,广泛应用于卵巢癌、睾丸肿瘤、头颈部肿瘤、肺癌和结直肠癌等恶性实体瘤中,然而,其严重的不良反应以及耐药问题限制了其临床应用。同时该类药物可引起较严重的不良反应,从而限制了铂类药物的... 详细信息

铂类药物是目前应用最广泛的抗肿瘤药物之一,广泛应用于卵巢癌、睾丸肿瘤、头颈部肿瘤、肺癌和结直肠癌等恶性实体瘤中,然而,其严重的不良反应以及耐药问题限制了其临床应用。同时该类药物可引起较严重的不良反应,从而限制了铂类药物的临床应用范围。其中,限制顺铂使用的最主要因素是肾脏毒性。本文就不同铂类药物引起肾损伤的作用机制进行综述。

关键词：铂类药物肾损伤作用机制

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