Cobolimab

近日，葛兰素史克（GSK）在今年第二季度财报中披露，其TIM3抗体的COSTARLung的Ⅲ期试验未能达到总体生存（OS）主要终点，相比对照组，cobolimab+ dostarlimab+docetaxel未能提高非小细胞肺癌（NSCLC）患者的总生存期。cobolimab（TSR-022）是一款人源化抗TIM-3 IgG4抗体，最初由Tesaro公司研发，GSK于2019年通过收购Tesaro获得了该管线。GSK原本计划2025年上半年在美国和欧盟提交用于二线NSCLC患者的上市申请。基于这一临床结果，GSK将终止cobolimab在这一适应症中的进一步开发，但cobolimab另外两项临床试验仍将继续，即，针对肝细胞癌的II期临床，以及针对儿科及青少年实体瘤的I/II期临床。陷入僵局的TIM-3与LAG3、TIGIT一样，TIM-3同样也是免疫检查点的热门选手之一。TIM-3在T细胞、Treg细胞以及其他先天免疫细胞表面均有表达，其能够引起癌症与慢性病毒感染过程中T细胞的衰竭。除了TIM-3本身表现出的免疫抑制外，相关研究发现，共表达TIM-3/PD-1的Ｔ细胞表现出更严重的衰竭，并且对抗PD⁃1治疗无反应的患者往往与TIM-3的表达高度相关，而对PD⁃1治疗产生耐药的患者也是由于TIM-3被选择性的高表达，以致肿瘤免疫逃逸。在多种肿瘤中发现，TIM-3水平也与肿瘤预后不良有关。基于TIM3的应用前景，推动了针对该靶点的开发。但是与TIGIT相比的话，其实业内对TIM-3的开发声势不算浩大，参与开发的基本上还是最初那一批企业。而这几年来，参与布局开发的大药企们对TIM-3的态度也不愠不火，礼来、罗氏等较早就退出了TIM-3的研发，坚持推进到Ⅲ期也只有诺华和GSK，其他的TIM-3管线基本上少有临床进展或者临床数据的公布。诺华还是先倒下了。2024 EHA年会上，诺华公布了IIISTIMULUS-MDS2结果，试验未达到总生存期（OS）的主要终点，与阿扎胞苷单用相比，Sabatolimab+阿扎胞苷未显著延长高危MDS或CMML-2患者的总生存。随即，诺华便放弃了对Sabatolimab的开发，并将其从公司研发管线中将其剔除。诺华的退出仍一定程度上打击了TIM-3领域，随后，Incyte、BMS、阿斯利康也相继退出了TIM-3的开发，正大天晴则是终止了TQB2618食管癌中的临床。目前，国内还有百济神州的surzebiclimab以及恒瑞SHR-1702等还在推进，但没有相关的临床数据公布。TIM-3，陷入的是与TIGIT不同的另一种僵局。参考出处：https://www.gsk.com/media/zhfdbsly/q2-2025-results-announcement.pdfhttps://www.gsk.com/media/zhfdbsly/q2-2025-results-announcement.pdfhttps://www.oncologypipeline.com/apexonco/no-starring-role-gsks-tim-3#:~:text=Cobolimab%2C%20Tim-3%20MAb%2C%20GSK%2C%20Failed%20ph3%20Costar%20Lung%20study%20in%20post-PD-%28L%291%20NSCLC%20in%20Jul%202025.%20Surzebiclimab%2C%20Tim-3%20MAb%2C%20BeOne%20Medicines······

GSK may not have been surprised its anti-TIM-3 drug couldn’t secure a phase 3 win based on how its pharma peers have struggled.\n GSK’s cobolimab has become the latest anti-TIM-3 antibody to flunk a crucial oncology test, as the pharma absorbs a more than $600 million hit from its anti-TIGIT drug failure.The British Big Pharma had been evaluating cobolimab—which it acquired in the $5.1 billion Tesaro takeover in 2018—in various combinations with oncology med Jemperli and the chemotherapy docetaxel in a phase 3 study of 750 patients with non-small cell lung cancer (NSCLC).The company revealed in its second-quarter earnings this morning that the study didn’t reach its primary endpoint of improving overall survival in advanced NSCLC after prior immuno-oncology therapies.“All regimens were well-tolerated and toxicities were consistent with known safety profiles of docetaxel and immune checkpoint inhibitors,” GSK said in its July 30 earnings release (PDF). “This remains a challenging treatment setting where novel combinations have yet to improve outcomes for most patients.”The late-stage fail doesn\'t mark the end of GSK\'s hopes for cobolimab. The company is still evaluating the drug in a phase 1/2 trial in a range of pediatric cancer settings as well as in a midstage trial for advanced liver cancer.TIM-3 is expressed by immune effector cells, where it acts as an immune checkpoint, and leukemic stem cells, leading various Big Pharmas to identify the receptor as a way to simultaneously activate the immune system and suppress the proliferation of cancer cells.GSK may not have been surprised that cobolimab couldn’t secure a phase 3 win. The drug was the most advanced anti-TIM-3 antibody left standing after Novartis’ own candidate failed a late-stage study in patients with myelodysplastic syndrome or leukemia at the start of 2024.While Novartis focused on blood cancers, GSK and other big names with TIM-3 candidates had largely looked at solid tumors. Roche removed (PDF) a PD-1xTIM-3 bispecific from its pipeline in 2022, while Bristol Myers Squibb terminated a phase 1 trial of a TIM-3 candidate, BMS-986299, in 2022 because its “business objectives” had changed. Eli Lilly and Incyte have also axed their respective TIM-3 drugs. AstraZeneca appears to still have a foot in the anti-TIM-3 space, with a PD-1xTIM-3 bispecific that is due to complete a phase 1/2 study this year.TIM-3 wasn’t the only high-risk cancer target where GSK crashed and burned this quarter. The pharma revealed in the same earnings document that its decision to end development of the anti-TIGIT antibody belrestotug had resulted in a 471 million pound sterling ($629 million) impairment charge.GSK paid iTeos $625 million upfront for the rights to belrestotug four years ago. In the wake of belrestotug’s phase 2 failure, the biotech initially planned to wind down operations before accepting a buyout offer from Concentra Biosciences earlier this month.This morning’s release also revealed that GSK has discontinued a phase 2-stage adjuvanted recombinant protein vaccine for malaria dubbed GSK3437949. A spokesperson for the company put this move in the context of the pharma’s recently announced push into second-generation, multistage malaria vaccines.Meanwhile, sanfetrinem cilexetil—an oral prodrug of the antibiotic sanfetrinem—has been removed from the company’s phase 2 pipeline after having “not compared favourably in early studies to existing treatments and other tuberculosis-specific assets also in development at GSK,” the spokesperson said.