Andrew J Armstrong,Hilary Dietz,David Balli,William J Geese,Chunzhe Duan,Yu-Han Hung,Virginia Ip,Gerald Li,Ryon P Graf,Neal Ready
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We separately evaluated a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) for associations of LRP1b alterations and progression-free survival with anti-PD-1 immunotherapy.\r\n\r\nRESULTS\r\nIn the CGDB cohort of patients with NSCLC (N=18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n=1569, adjusted HR 0.86 p=0.014). In CM026, patients with LRP1b alterations had a statistically significant improvement in ORR to nivolumab vs. LRP1b wild-type (wt) patients (odds ratio 3.5; 95% CI 1.71-7.13; p=0.0006) but not with chemotherapy (odds ratio 0.63; 95% CI 0.32-1.26; p=0.19), adjusting for TMB, age, gender, histology, smoking and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR 0.66, p=0.04) but not chemotherapy (HR 1.26, p=0.25), also maintained in multivariate and TMB adjusted analysis.\r\n\r\nCONCLUSIONS\r\nLRP1b mutations are a candidate predictive biomarker for ICI vs. chemotherapy in NSCLC. Further mechanistic characterization of LRP1b and prospective validation are warranted, and might enable future clinical use.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"LRP1B loss predicts sensitivity to immunotherapy in patients with NSCLC: an analysis of the phase 3 Checkmate 026 randomized trial.\",\"authors\":\"Andrew J Armstrong,Hilary Dietz,David Balli,William J Geese,Chunzhe Duan,Yu-Han Hung,Virginia Ip,Gerald Li,Ryon P Graf,Neal Ready\",\"doi\":\"10.1158/1078-0432.ccr-25-0952\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"PURPOSE\\r\\nLow-density lipoprotein receptor-related protein 1b (LRP1b) is a cell surface receptor, commonly altered in many cancers and associated with improved responses, progression free survival (PFS) and overall survival (OS) with immune checkpoint inhibition (ICI).\\r\\n\\r\\nEXPERIMENTAL DESIGN\\r\\nLRP1b alterations were determined by whole exome sequencing (WES) and associated with PFS and objective response rates (ORR) in patients with non-small cell lung cancer (NSCLC) in post-hoc analysis of the randomized controlled phase 3 Checkmate-026 trial (CM026, NCT02041533) examining chemotherapy vs nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) for associations of LRP1b alterations and progression-free survival with anti-PD-1 immunotherapy.\\r\\n\\r\\nRESULTS\\r\\nIn the CGDB cohort of patients with NSCLC (N=18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n=1569, adjusted HR 0.86 p=0.014). In CM026, patients with LRP1b alterations had a statistically significant improvement in ORR to nivolumab vs. LRP1b wild-type (wt) patients (odds ratio 3.5; 95% CI 1.71-7.13; p=0.0006) but not with chemotherapy (odds ratio 0.63; 95% CI 0.32-1.26; p=0.19), adjusting for TMB, age, gender, histology, smoking and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR 0.66, p=0.04) but not chemotherapy (HR 1.26, p=0.25), also maintained in multivariate and TMB adjusted analysis.\\r\\n\\r\\nCONCLUSIONS\\r\\nLRP1b mutations are a candidate predictive biomarker for ICI vs. chemotherapy in NSCLC. 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引用次数: 0
摘要
低密度脂蛋白受体相关蛋白1b (LRP1b)是一种细胞表面受体,在许多癌症中通常发生改变,并与免疫检查点抑制(ICI)改善应答、无进展生存期(PFS)和总生存期(OS)相关。lrp1b的改变通过全外显子组测序(WES)确定,并与非小细胞肺癌(NSCLC)患者的PFS和客观缓解率(ORR)相关,在随机对照3期Checkmate-026试验(CM026, NCT02041533)的事后分析中,该试验检查了化疗与nivolumab,调整肿瘤突变负担(TMB)和临床特征。我们单独评估了一个去鉴定的全国性(美国)NSCLC临床基因组数据库(CGDB),以研究LRP1b改变和抗pd -1免疫治疗与无进展生存期的关系。结果在NSCLC患者的CGDB队列中(N= 18369), LRP1b突变与TP53/KRAS改变呈正相关,与EGFR/RET/MET/ERBB2改变呈负相关,显著改善PFS并抑制PD-1 (N= 1569,校正HR 0.86 p=0.014)。在CM026中,与LRP1b野生型(wt)患者相比,LRP1b改变患者对nivolumab的ORR有统计学意义上的改善(优势比3.5;95% CI 1.71-7.13; p=0.0006),但在调整TMB、年龄、性别、组织学、吸烟和运动状态后,化疗患者的ORR无统计学意义(优势比0.63;95% CI 0.32-1.26; p=0.19)。LRP1b突变与纳武单抗改善PFS相关(HR 0.66, p=0.04),但与化疗无关(HR 1.26, p=0.25),在多变量和TMB调整分析中也保持不变。结论slrp1b突变是非小细胞肺癌ICI与化疗的候选预测性生物标志物。进一步的LRP1b机制表征和前瞻性验证是必要的,并可能使未来的临床应用。
LRP1B loss predicts sensitivity to immunotherapy in patients with NSCLC: an analysis of the phase 3 Checkmate 026 randomized trial.
PURPOSE
Low-density lipoprotein receptor-related protein 1b (LRP1b) is a cell surface receptor, commonly altered in many cancers and associated with improved responses, progression free survival (PFS) and overall survival (OS) with immune checkpoint inhibition (ICI).
EXPERIMENTAL DESIGN
LRP1b alterations were determined by whole exome sequencing (WES) and associated with PFS and objective response rates (ORR) in patients with non-small cell lung cancer (NSCLC) in post-hoc analysis of the randomized controlled phase 3 Checkmate-026 trial (CM026, NCT02041533) examining chemotherapy vs nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) for associations of LRP1b alterations and progression-free survival with anti-PD-1 immunotherapy.
RESULTS
In the CGDB cohort of patients with NSCLC (N=18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n=1569, adjusted HR 0.86 p=0.014). In CM026, patients with LRP1b alterations had a statistically significant improvement in ORR to nivolumab vs. LRP1b wild-type (wt) patients (odds ratio 3.5; 95% CI 1.71-7.13; p=0.0006) but not with chemotherapy (odds ratio 0.63; 95% CI 0.32-1.26; p=0.19), adjusting for TMB, age, gender, histology, smoking and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR 0.66, p=0.04) but not chemotherapy (HR 1.26, p=0.25), also maintained in multivariate and TMB adjusted analysis.
CONCLUSIONS
LRP1b mutations are a candidate predictive biomarker for ICI vs. chemotherapy in NSCLC. Further mechanistic characterization of LRP1b and prospective validation are warranted, and might enable future clinical use.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.