"人工智能分型指导CDK4/6抑制剂耐药HR+/HER2-晚期乳腺癌精准治疗-LINUX研究(多中心、开放标签、随机对照Ⅱ期平台试验)"方案解读
Interpretation of the protocol of"artificial intelligence-based subtyping to guide precision therapy for CDK4/6 inhibitor-resistant HR+/HER2-advanced breast cancer—the LINUX study(multicenter,open label,randomized controlled phase Ⅱ platform trial)"
摘要
Abstract
Background and purpose:The LINUX trial is a multicenter,open-label,randomized,controlled phase Ⅱ platform trial designed to continuously enroll patients with hormone receptor(HR)-positive/human epidermal growth factor receptor 2(HER2)-negative advanced breast cancer who have developed resistance to CDK4/6 inhibitors(CDK4/6i).This article analyzed its clinical trial protocol to provide a reference for clinicians conducting precision therapy platform trials.Methods:After enrollment,patients are subtyped using a previously constructed artificial intelligence model applied to HE-stained pathological slide images of metastatic lesion specimens(if metastatic biopsy specimens are unavailable,digital pathological subtyping is performed on primary tumor samples).Patients are classified into four subtypes(SNF1,SNF2,SNF3,and SNF4)and then randomized 2 to 1 to a precision therapy arm tailored to the molecular characteristics of each subtype or a control arm(investigator's choice of chemotherapy).The primary endpoint is objective response rate(ORR).Secondary endpoints include clinical benefit rate(CBR),investigator-assessed progression-free survival(PFS),and overall survival(OS).Safety assessment includes evaluation of the incidence and severity of treatment-related adverse events(TRAEs).Throughout the exploratory process,a Bayesian adaptive design is used to monitor the efficacy of different precision therapy arms within each SNF subtype to predict the likelihood of success in larger-scale phase Ⅲ clinical trials.Results:There are three core design features of the LINUX protocol.① A platform architecture supporting parallel evaluation of multiple subtypes and dynamic incorporation of new regimens.② Artificial intelligence(AI)-based digital pathology replacing multi-omics sequencing to reduce costs and improve accessibility.③ A Bayesian design enabling"stop for futility,advance for efficacy."Results from the first cohort of 105 patients showed that precision therapy in SNF2 and SNF4 met pre-specified success criteria,with ORRs of 65%vs 30%and 70%vs 20%,respectively,with significantly prolonged PFS and manageable safety;these arms have advanced to phase Ⅲ confirmatory studies.The protocol also specifies dose modification rules,concomitant therapy management,and stratified follow-up procedures.The LINUX protocol establishes a complete framework of"AI subtyping-precision therapy-Bayesian monitoring"with core innovations in achieving clinical translation of molecular subtyping through low-cost digital pathology,accommodating multi-regimen evaluation via platform design,and optimizing resource allocation through Bayesian statistics.Conclusion:This protocol suggests that when designing precision oncology trials,clinicians should emphasize the accessibility of subtyping tools,statistical flexibility,and comprehensiveness of the endpoint system,thereby providing methodological support for the translation from"omics discovery"to"clinical decision-making."关键词
精准治疗/人工智能/CDK4/6抑制剂耐药/HR+/HER2-晚期乳腺癌/平台研究/贝叶斯统计Key words
Precision therapy/Artificial intelligence/CDK4/6 inhibitor resistance/HR+/HER2-advanced breast cancer/Platform trial/Bayesian statistics分类
医药卫生引用本文复制引用
张文娟,赵珅,梁斐,范蕾.."人工智能分型指导CDK4/6抑制剂耐药HR+/HER2-晚期乳腺癌精准治疗-LINUX研究(多中心、开放标签、随机对照Ⅱ期平台试验)"方案解读[J].中国癌症杂志,2026,36(8):777-788,12.基金项目
中国国家重点研发计划(2023YFF1205004、2020YFA0112304)、国家自然科学基金(82473273、91959207、92159301和82472866)、上海市自然科学基金(20ZR1412400、22ZR1479200)、上海市科学技术委员会(22Y11912800)、上海市乳腺癌重点实验室(12DZ2260100)、上海市医院发展中心(SHDC)上海市医院发展前沿与新兴技术市级项目(SHDC12021103)、上海临床研究计划(SHDC2020CR5005)、上海抗癌协会SOAR项目(SACA-AX202208).本研究还得到江苏恒瑞医药的资助. National Key R&D Program of China(2023YFF1205004,2020YFA0112304),National Natural Science Foundation of China(82473273,91959207,92159301,and 82472866),the Shanghai Natural Science Foundation(20ZR1412400,22ZR1479200),the Shanghai Municipal Science and Technology Commission(22Y11912800),the Shanghai Breast Cancer Key Laboratory(12DZ2260100),the Shanghai Hospital Development Center(SHDC)Shanghai Hospital Development Frontline and Emerging Technology Municipal Project(SHDC12021103),the Shanghai Clinical Research Program(SHDC2020CR5005),and the Shanghai Anti-Cancer Association SOAR Project(SACA-AX202208).The LINUX study was also funded by Jiangsu Hengrui Medicine. （2023YFF1205004、2020YFA0112304）
