  Timeline illustrating the development of targeted therapies and immunotherapies for the treatment of NSCLC over two decades    Biology of lung cancer Lung cancer is composed of sub-populations of cells, or clones, with distinct molecular features, resulting in intratumoral heterogeneity. The identification of clonal targetable genetic alterations occurring early during cancer evolution has changed the paradigm of treatment for oncogene-addicted cancers Alterations in targetable oncogenic pathways in LUAD and LUSC  R S Herbst et al. Nature 553, 446–454 (2018)   Significantly mutated genes in lung SQCC  Alterations in targetable oncogenic pathways in lung SQCCs PS Hammerman et al. Nature 000, 1-7 (2012)  Mechanisms of TME-driven immune suppression. Johanna A. Joyce, and Douglas T. Fearon Science 2015;348:74-80 Diagnostic Algorithm for Non–Small-Cell Lung Cancer (NSCLC) Reck M, Rabe KF. N Engl J Med 2017;377:849-861 cancer biology profiling workstream (ideally) Current and investigative treatment options for advanced or metastatic NSCLC R S Herbst et al. Nature 553, 446–454 (2018) Gecitabine : 一个马鼻子的胜利 108例EGFR/ALK （靶向治疗失败）PFS HR为0.59，对比BCP，但benchmark是否应该为2nd G TKI？ Treatment value ：PFS HR 还是2年生存率 37% vs 18%？ KEYNOTE-189：峰回路转 2017年10月27宣布撤回欧洲适应症申请；2018年1月宣布达到co-primary终点（PFS&OS） cm227:IO/IO combo,prolonged PFS in TMB high(>10 mut/mb) Upcoming randomized immunotherapy trials in first-line NSCLC and projected read-out timelines Mok TS et al. N Engl J Med 2009;361:947-957. more critical than positive PFS: negative patient will not benefit from TKI J Soria et al. N Engl J Med 2018;378:113-125 “你被焦虑了吗？”：新药上市似乎总是会带来一种名为sequential的哲学思考，如果新药用在一线，耐药后怎么办？问题是，场景1 –用在一线，焦虑26个月后的“耐药策略”，场景2-新药用在二线，焦虑10.9 8=19个月后的“耐药策略”，你选择26个月后焦虑还是19个月后？ Next decade, let's start believing in a CURE 'Here's my sequence. Please give me my cocktail.””The New Yorker |
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