An Integrated Phase II/III Randomized Study Comparing Durvalumab and Tremelimumab +/- Hepatic ArteriaL Infusion Chemotherapy With GEMOX in Hepatocellular Carcinoma With High Tumor burdEn

Liver cancer is a highly lethal malignancy and has become increasingly important in western countries. The management of liver cancer is complex. In advanced disease, two combinations of immunotherapies are recommanded as first line (atezolizumab-bevacizumab or durvalumab-tremelimumab). Results in patients with high tumor burden (Portal vein thrombosis Vp3 or Vp4, or tumoral liver involvement >50%) are less impressive. Innovative combinations are necessary to improve the outcome of patients.
Recently, control trials conducted in Asia highlighted the benefit of hepatic arterial infusion chemotherapy, especially in patients with high tumor burden. Studies including a limited number of patients shown that the combination seems feasible.
ALICE is a randomized multicentric Phase II/Phase III trial conducted in French medical centers, evaluating the efficacy and safety of durvalumab+tremelimumab with or without Hepatic Arterial Infusion Chemotherapy of the GEMOX regimen (gemcitabine + oxaliplatin), in patients with high tumor burden.
Oxaliplatin induce immunogenic cell death, and gemcitabin deplete regulatory immune cells. The GEMOX regimen thus has the potential for a synergic effect with immunotherapy in HCC.
The trial will provide an innovative treatment to patients with no alternative for locoregional treatment, and with limited results with actual systemic treatments. It will also be the first trial of Hepatic Arterial infusion for such patients in the western population.

开始日期2025-09-01

申办/合作机构

UNICANCER

[+1]

NCT06855225

/ Not yet recruiting临床2期IIT

A Phase II Study of Single Tremelimumab With Regular Interval Durvalumab (STRIDE) Plus Gemcitabine and Cisplatin (GEMCIS) in Locally Advanced Unresectable/Metastatic Combined Hepatocellular-cholangiocarcinoma (cHCC-CCA)

This is a single arm phase 2 study of Single Tremelimumab with Regular Interval Durvalumab (STRIDE) plus Gemcitabine and Cisplatin (GEMCIS) in locally advanced unresectable/metastatic combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Cycles 1 through 8 will be in 3 week intervals and Cycles 9+ will be in 4 week intervals. Tremelimumab is administered at 300mg intravenously once at Cycle 1. Durvalumab is administered at 1500mg intravenously every 3 weeks for Cycles 1-8, then every 4 weeks for Cycles 9+. Gemcitabine is administered at 1000mg/m^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. Cisplatin is administered at 25mg/m^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. Subjects will require a visit with appropriate laboratory work prior to the start of each cycle. Disease assessment will occur at screening and then every 9 weeks until the end of Cycle 9. Disease assessments will then occur every 8 weeks. Subjects will continue treatment until progression per RECIST 1.1, toxicity or subject/physician decision. A maximum of 24 months treatment from Cycle 1 Day 1 is allowed.

开始日期2025-06-01

申办/合作机构

Hoosier Cancer Research Network

[+2]

NCT06608940

/ Not yet recruiting临床1/2期IIT

A Phase Ib/II Study of BC3402, a Novel Anti-TIM3 Agent, in Combination With Tremelimumab Plus Durvalumab (STRIDE) in Advanced, Unresectable Hepatocellular Carcinoma

The purpose of this study is to test the safety and efficacy of an investigational (experimental) product called BC3402. This product is considered experimental because it is not approved by the U.S. Food and Drug Administration (FDA).

开始日期2025-06-01

申办/合作机构

The Case Comprehensive Cancer Center

100 项与曲美木单抗相关的临床结果

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100 项与曲美木单抗相关的转化医学

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100 项与曲美木单抗相关的专利（医药）

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606

项与曲美木单抗相关的文献（医药）

2025-12-31·mAbs

Engineered ipilimumab variants that bind human and mouse CTLA-4

Article

作者: Barman, Ishita ; Lee, Peter S. ; Diong, SJ ; Bee, Christine ; Rajpal, Arvind ; Kumar, Anusha ; West, Sean M. ; Chau, Bryant ; Strop, Pavel ; Robison, Brett ; Chang, Olin ; Korman, Alan J. ; Moon, Thomas M.

Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used. The antibody 9D9, which binds mouse CTLA-4, is a commonly used surrogate for CTLA-4 checkpoint blockade studies in mouse cancer models. In this work, we reveal that 9D9 has significant biophysical dissimilarities to therapeutic CTLA-4 antibodies. The 9D9-mCTLA4 complex crystal structure was determined and shows that the surrogate antibody binds an epitope distinct from ipilimumab and tremelimumab. In addition, while ipilimumab has pH-independent binding to hCTLA-4, 9D9 loses binding to mCTLA-4 at physiologically relevant acidic pH ranges. We used phage and yeast display to engineer ipilimumab to bind mouse CTLA-4 with single-digit nM affinity from an initial state with no apparent binding. The engineered variants showed pH-independent and cross-reactive binding to both mouse and human CTLA-4. Crystal structures of a variant in complex with both mouse and human CTLA-4 confirmed that it targets an equivalent epitope as ipilimumab. These cross-reactive ipilimumab variants may facilitate improved translatability and future mechanism-of-action studies for anti-CTLA-4 targeting in murine models.

2025-12-01·Journal of Gastrointestinal Cancer

The Efficacy and Safety of Durvalumab and Tremelimumab with Concomitant Treatment for MSS/pMMR Metastatic Colorectal Cancer: A Single Arm Meta-Analysis

Article

作者: Zhang, Danning ; Chen, Tianyu

OBJECTIVES:

To address the issue that most microsatellite-stable (MSS) and proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) patients have minimal response to immunotherapy, this meta-analysis evaluated the efficacy and safety of durvalumab and tremelimumab with concomitant treatment in treating MSS/pMMR metastatic colorectal cancer.

METHODS:

All included trials were prospective studies with a median patient age of 63 years, of which 94.2% were MSS/pMMR mCRC patients, with a male to female ratio of 1.5:1. Based on durvalumab and tremelimumab treatment, one study performed surgical resection on resectable cases, while the other four studies performed radiotherapy or chemotherapy on unresectable cases. Analyses include objective response rate (ORR).etc. for drug activity, overall survival (OS) and progression-free survival (PFS) for therapeutic efficacy, and adverse events (AEs) for safety. The risk of bias was assessed by sensitivity analysis.

RESULTS:

5 studies involving 228 patients were included in this meta-analysis. The pooled estimates showed a median OS of 9.26 months, median PFS of 2.53 months, partial response (PR) of 13.6%, stable disease (SD) of 32.8%, ORR of 12.5% and disease control rate (DCR) of 65.4%. AEs were generally low, with pruritus (27.5%), diarrhea (28.8%), and fatigue (53.9%) being the most common, while other AEs occurred at less frequencies.

CONCLUSIONS:

Durvalumab and tremelimumab with concomitant treatment for MSS/pMMR mCRC patients is relatively effective and safe, which is helpful in addressing the problem of mCRC with MSS/pMMR that has minimal response to immunotherapy.

2025-04-03·Expert Review of Gastroenterology & Hepatology

What can real-world data teach us about treating patients with unresectable hepatocellular carcinoma?

Review

作者: Dalbeni, A. ; Natola, L. A. ; Villani, R. ; Auriemma, A. ; Cattazzo, F. ; Stefanini, B. ; Ravaioli, F. ; Faccincani, D. ; Sacerdoti, D. ; Zoncapè, M.

INTRODUCTION:

Hepatocellular carcinoma (HCC) remains a major global health concern, as it is the most common primary liver cancer and the fourth leading cause of cancer-related mortality.

AREAS COVERED:

Immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm, offering promising survival outcomes. However, the controlled conditions of randomized clinical trials (RCTs) often fail to reflect real-world complexities, emphasizing the necessity for strong real-world evidence (RWE). RWE, in most cases derived from observational studies, provides critical insights into the effectiveness, safety, and tolerability of systemic therapies across diverse populations and settings. The authors searched MEDLINE, Ovid Embase, and Scopus for full-text published articles in any language from the inception to 30 June 2024.This review evaluates RWE on systemic therapies for advanced HCC, including tyrosine kinase inhibitors (TKIs) like sorafenib and lenvatinib, ICIs such as nivolumab and pembrolizumab, and combination therapies like atezolizumab/bevacizumab and durvalumab/tremelimumab.

EXPERT OPINION:

Studies reveal discrepancies in treatment efficacy and adverse event profiles between RCTs and routine clinical practice, underscoring the need for individualized treatment strategies. RWE highlights the influence of liver disease etiology, liver function, and tumor burden on treatment outcomes, guiding therapy selection.

457

项与曲美木单抗相关的新闻（医药）

2025-04-13

·药事纵横

‌FDA批准百时美施贵宝（BMS）肝癌一线免疫联合疗法

美国食品药品监督管理局（FDA）于2025年4月12日批准百时美施贵宝（Bristol Myers Squibb，BMS）的免疫联合疗法——Opdivo®（纳武利尤单抗）与Yervoy®（伊匹木单抗）用于新诊断的不可切除或转移性肝细胞癌（HCC）患者。‌BMS肝癌一线疗法获FDA完全批准，改写竞争格局‌FDA此次对Opdivo®（纳武利尤单抗）联合Yervoy®（伊匹木单抗）的批准具有双重意义：‌加速批准转确证性批准‌：将此前二线肝癌的加速批准升级为一线完全批准‌确立三足鼎立格局‌：直接对标罗氏"T+A"方案（Tecentriq®+Avastin®）和阿斯利康"双Im"组合（Imfinzi®+Imjudo®）‌循证优势凸显‌：基于CheckMate-9DW三期临床数据，Opdivo-Yervoy组合较对照组（拜耳Nexavar®或默沙东/卫材Lenvima®）实现：‌死亡风险降低21%‌（HR=0.79, p=0.0034）‌中位总生存期（mOS）提升3.1个月‌：试验组23.7个月 vs 对照组20.6个月‌对照组表现超预期‌：值得注意的是，对照组20.6个月的mOS显著优于历史数据：罗氏"T+A"方案2020年获批时，索拉非尼对照组mOS为13.2个月（IMbrave150研究）阿斯利康"双Im"组合2022年获批试验中，索拉非尼对照组mOS为10.6个月（HIMALAYA研究）‌差异化竞争优势‌：BMS方案的独特之处在于：‌对照组含更强TKI药物‌：采用Lenvima®（乐卫玛®，仑伐替尼）而非传统索拉非尼，该药物在肝癌一线治疗中客观缓解率（ORR）可达24.1%（REFLECT研究）‌双免疫机制协同‌：CTLA-4抑制剂（Yervoy）与PD-1抑制剂（Opdivo）联用，可能激活更广泛的抗肿瘤免疫应答此次批准标志着肝癌一线免疫治疗进入2.0时代，三款方案将在真实世界疗效、用药便利性（Opdivo-Yervoy每6周给药 vs 罗氏/阿斯利康每3周方案）及药物经济学层面展开全面竞争。。药事纵横投稿须知：稿费已上调，欢迎投稿

临床3期免疫疗法上市批准临床结果

2025-04-09

·VIP说

肿瘤免疫治疗策略2.0

# 本篇笔记仅基于公开资料和信息撰写、为个人观点、供学术交流所用、不构成任何建议 #我用了差不多一个月的时间，看了几十家代表公司的产品线、几千篇研报和点评、几万个注册临床试验，想要看清楚肿瘤免疫治疗棋局的现状和未来。这不符合我的本性，我是宁可去无人区探险，也不想投入毫厘铢锱不能差错的极致内卷中。但是，现实就是，现在和未来很长一段时间内，免疫检查点抑制剂都会是肿瘤治疗的基石，即使MNC们早就已经布局于免疫检查点抑制剂之外甚至肿瘤治疗之外，国内大多数药企还有一段国产替代的长路要走。既然不能提前退休，只能强忍着非常严重的内卷PTSD看棋局，这种不适感压制了我的段子手级别语言天赋，所以这篇笔记会写的非常......直白。我个人给免疫治疗策略1.0的定义，就是大家手里都有个PD-(L)1抑制剂产品。全球已经有32个/国内已经有24个PD-(L)1抑制剂产品上市。图片引用来自“IO笔记”。至于免疫治疗策略2.0，就是如何进一步迭代和升级。PD-(L)1抑制剂产品本身的迭代和升级，目前大家的策略非常一致，改良单抗本身没能创造出什么奇迹，就开发双抗/多抗和复方，以及皮下注射、口服小分子、ADC等新剂型。双抗/多抗和复方本质类似于联合给药方案，所以放到后面再说。开发皮下注射剂型看上去是个捷径，不过如果大家的目标是国际市场，可能会有专利侵权风险：阿斯利康7.5亿美元引进Alteogen透明质酸酶技术，后者深陷侵权风险口服小分子PD-(L)1抑制剂，我是没有“小药说药”那么关注，而且似乎已经冷却：靶向PD-1/PD-L1小分子药物的研究进展至于PD-(L)1 ADC，反正已经热闹起来：靶向PD-L1 ADC：辉瑞首次国内申报临床！复宏汉霖、映恩生物“勇攀高峰”此外，国内外很多家药企已经想开了，不搞什么伪创新药，帕博利珠单抗核心专利将于2028年到期，直接开发生物类似药。国内外我已经数出来10个帕博利珠单抗类似药在做注册临床试验了，还有3个纳武利尤单抗生物类似药。更广谱的迭代和升级策略，就是以PD-(L)1抑制剂产品为基石，开发各种联合给药方案。汇总信息还是医药魔方做得最漂亮（反正我下载了PPT）：PD-1/PD-L1抑制剂中美获批及全球注册性临床试验15年动态趋势医药魔方PPT中部分内容截图：类似的汇总信息报告和点评很多，都能让大家一眼看清楚肿瘤免疫治疗棋局已经内卷到什么地步，看完不但没有思路，反而更加焦虑了。所以我们还是采用最简单高效的fast follow的老办法，看看几十家代表公司的肿瘤免疫治疗产品线，看看follow谁家的具体策略最适合自家。1. 默沙东/默克帕博利珠单抗(PD-1单抗)，长期被群殴和围攻的药王，王冠太重。在肿瘤领域，默沙东/默克不断探索和拓展其各种联合给药方案，并且积极布局复方和皮下等新剂型，双抗等新产品，以求夯实其在肿瘤领域的领先地位。复方主要是MK-1308A(PD-1+CTLA-4，Pembrolizumab+Quavonlimab)，MK-7684A(PD-1+TIGHT，Pembrolizumab+Vibostolimab)，MK-4280A(PD-1+LAG-3，Pembrolizumab+favezelimab)，2024年12月宣布终止开发后两个，目前只有MK-1308A还在推进。皮下剂型MK-3475A的III期临床试验刚官宣成功。近年来，默沙东/默克的肿瘤产品线重点已经布局于免疫检查点抑制剂之外，但免疫检查点抑制剂还是肿瘤治疗的基石，肿瘤领域且没有禁忌症，什么新产品都尝试联联看，就像吃什么菜都要配一碗白米饭。看帕博利珠单抗适应症布局是一项极其艰巨的工作，我差不多用了半个月时间，剩下几十个产品用了剩下的半个月时间。太多了。不仅因为默沙东/默克财大气粗，有把握的III期试验开几百个，没把握的I-II期试验和IIT开几千个，更因为帕博利珠单抗是基石中的基石，米饭中的白米饭，其他药企开发联合给药方案也是首选帕博利珠单抗。即使默沙东/默克没有布局，其他药企也会填空，所有瘤种所有适应症，完全没有空缺。最后得去翻默沙东/默克官网的PPT，才能找出他家真正的主线。如果布局图里出现了个别空缺，那也是某些III期临床试验失败导致的，绝不是没人尝试过填空。比如大家都吃过瓜的LEAP系列。但是有三个瘤种，即著名的冷肿瘤们，卵巢癌、胰腺癌、前列腺癌，所有药企都是屡战屡败+屡败屡战。先驱栽坑里那是代价，后来者再盲目跳坑，我可能忍不住嘲笑了，如果不是颠覆性作用机制的新药，建议不要再尝试将免疫治疗用于这几个瘤种。2. BMS纳武利尤单抗(PD-1单抗)，没能问鼎药王，所以在此基础上早早开发出皮下注射剂型，与伊匹木单抗(Ipilimumab, CTLA-4)联合方案，与Relatlimab(LAG-3单抗)联合方案，甚至开发了复方OPDUALAG(Nivolumab+Relatlimab)，均已成功获批多个适应症。也曾在TIGHT、IDO等靶点药物联合方案上栽过跟头，最新产品是复方BMS-986489(PD-1+fucosyl-GM1, Nivolumab+BMS-986012)。近年来，BMS的肿瘤产品线重点也已经布局于免疫检查点抑制剂之外。但免疫检查点抑制剂还是肿瘤治疗的基石，主动或被动开发联合方案也非常多。3. 罗氏阿替利珠单抗(PD-L1单抗)，其实已经算差异化开发了，靶点从PD-1换成了PD-L1。阿替利珠单抗是早早成功开发了皮下注射剂型。之后开发双抗时换回PD-1单抗，包括Tobemstomig(RO7247669, PD-1/LAG-3)，Lomvastomig(PD-1/TIM-3, RO7121661)。罗氏在肿瘤免疫治疗方面不算成功，主要是因为阿替利珠单抗与Tiragolumab(TIGHT单抗)的联合方案投入太大，受伤太深。但是深挖一下新技术平台，还能翻出来PD1-IL2v，PDL1 LNA等产品。值得注意的是，阿替利珠单抗用于三阴性乳腺癌非常波折，各种姿势的III期临床试验失败和撤回适应症，鉴于特瑞普利单抗在同一适应症里取得过成功，咱们不能说三阴性乳腺癌不适合免疫治疗，但PD-1单抗似乎比PD-L1单抗强一些。肾癌、尿路上皮癌、头颈癌、宫颈癌里也有类似情况，建议谨慎选择PD-L1单抗。4. 阿斯利康度伐利尤单抗(PD-L1单抗)，早期策略和BMS类似，开发皮下注射剂型，还有和替西木单抗(Tremelimumab, CTLA-4)的联合给药方案。后来者的好处就是可以避开先驱们栽过的坑，适应症开发都比较顺利。现在已经不做复方了，直接换双抗，Volrustomig(PD-1/CTLA-4)，Sabestomig(PD-1/TIM-3)，Rilvegostomig (PD-1/TIGHT)。发起IO+ADC潮流的应该就是他家，而且他家明显艺高人胆大，最偏爱Rilvegostomig (PD-1/TIGHT)，这是要死磕TIGHT靶点的节奏。5. 辉瑞、吉列德、再生元、GSK、Incyte、BIOCAD可以说，辉瑞几乎错了肿瘤免疫治疗浪潮。Avelumab(PD-L1单抗)开发顺位非常靠后，所以从超级冷门小适应症下手—皮肤默克尔细胞癌，弯道超车获批上市后，目前仅在膀胱癌领域取得成功（联合阿昔替尼用于肾癌一线是基于PFS成功附条件获批，但是OS失败，现在很尴尬；用于非小细胞肺癌、头颈癌和胃癌都是全面失败）。后来一度想悄悄开发PD-1单抗皮下注射剂型Sasanlimab（未获批上市），最终还是抢跑PF-08046054(PD-1 ADC)。后来者后来到辉瑞这个地步，如果还不愿赌服输，就得这么另辟蹊径。但是Sasanlimab有点过，首个适应症居然选择联合BCG用于非肌层浸润性膀胱癌，之前帕博利珠单抗和纳武利尤单抗都挑战失败的适应症，全球均未有免疫检查点抑制剂类产品获批。吉列德也是后来者，但是通过收购Arcus获得了赛帕利单抗(Zimberelimab，PD-1单抗)，果然顺产没有顺手快。在国内，赛帕利单抗用于经典型霍奇金淋巴瘤和晚期宫颈癌已获批上市。但是他家的联合给药方案，目前以Domvanalimab(TIGHT单抗)为主，又是一个死磕TIGHT靶点的。再生元不算后来者，Cemiplimab(PD-1单抗)虽然不算先驱，但是通过小适应症—皮肤鳞状细胞癌和皮肤基底细胞癌，早早弯道超车获批上市。他家毕竟是资深肿瘤免疫疗法biotech，联合给药方案非常多，目前以联合Fianlimab(LAG-3单抗)为主。GSK不算后来者也不算先驱，多塔利单抗(Dostarlimab，PD-1单抗) 通过小适应症—dMMR/MSI-H子宫内膜癌，早早弯道超车获批上市，之后仅专注于子宫内膜癌、结直肠癌和头颈癌，坚定的反内卷思维，深得我心。Incyte真不容易，当初为了卡瑞利珠单抗和恒瑞分分合合，最后终于拥有了自己的Retifanlimab(PD-1单抗)。跟辉瑞类似，因为Retifanlimab开发顺位非常靠后，所以从超级冷门小适应症下手—皮肤默克尔细胞癌，弯道超车获批上市。后来居然又被再鼎引入中国继续开发，反正各种不容易。再看Incyte产品线，始终专注于肿瘤免疫疗法，口服PD-L1，PD-1/LAG-3双抗、PD-1/TGF-βRII双抗均有布局。Prolgolimab(PD-1单抗)由俄罗斯药企BIOCAD开发，获得俄罗斯卫生部批准上市，用于治疗转移性黑色素瘤。在两国总理的共同见证下，由上药集团引进入国内共同开发，上药集团不愧是一流国企，非常正确。值得一提的是，Prolgolimab都这么正确了也没有躺平，继续开发复方BCD-217(Prolgolimab+Nurulimab，PD-1+CTLA-4)，还开发了帕博利珠单抗生物类似药。6. 其他外企艾博维：Budigalimab(PD-1单抗)Budigalimab绝对算后来者，我个人高度怀疑艾博维是为了联合其他自家真爱的新产品才被迫开发了基石。到现在最高开发阶段II期临床试验。强生：Cetrelimab(PD-1单抗)也不知道这个产品是不是和辉瑞的Sasanlimab高度类似，首个适应症居然也选择非肌层浸润性膀胱癌，但联合了自家TAR-200，我个人觉得就是为了陪衬TAR-200。2025年1月15日，强生宣布递交TAR-200的上市申请，用于治疗卡介苗（BCG）不应答的高危非肌肉侵袭性膀胱癌（HR-NMIBC）伴原位癌（CIS）患者。此次递交通过实时肿瘤审评（RTOR）项目，允许FDA在完全申请正式递交之前就开始审评以加快进度。 TAR-200为一种膀胱内局部给药的新型递送系统，采用一种双重小片设计，材质为硅聚合物半透小管，吉西他滨在膀胱持续缓慢释放。BI：Ezabenlimab(PD-1单抗)反正我个人高度怀疑BI是为了联合其他自家真爱的新产品才被迫开发了基石。到现在最高开发阶段II期临床试验。安进：Zeluvalimab(PD-1单抗)在安进最新的产品线信息里已经找不到Zeluvalimab了，但是找到了纳武利尤单抗生物类似药，预期2025年获批上市。放弃死磕开发顺位过于滞后的伪创新药，拥抱生物类似药，拥抱效率和利润，毕竟肿瘤免疫治疗也不是安进公司的主线，顶多用来联合其他自家真爱的新产品。Agenus：Botensilimab(PD-1单抗)Agenus还算比较重视Botensilimab，但主要是为了配合新一代产品—Balstilimab(CTLA-4单抗)，声称可以将冷肿瘤转化为热肿瘤。首个适应症选择联合Balstilimab用于non-MSI-H结直肠癌。坚定的反内卷思维，深得我心。BioNTech：BNT327(PD-L1/VEGF双抗)等收购普米斯生物等biotechs，跳过肿瘤免疫治疗1.0时代，直接飞跃至2.0时代潮头，拥有各种最热门双抗和ADC，又是顺产哪有顺手快的成功案例和典型代表。不过最新的消息是BNT311(PD-L1/4-1BB双抗)退回Genmab，这不是一个好消息，真正成功的双抗也不多。BioNTech的策略虽然有抄袭AZ，但非常清晰明确，值得学习。先分析免疫检查点抑制剂单药或既往的联合给药方案，在全球范围内获批过哪些适应症，还有哪些细分人群中有未被满足的临床需求，既往放弃开发或开发失败适应症的困难在哪里。再分析或补充自家产品线里的产品，是否有新颖的作用机制可能攻克之前的困难。最后设计BNT327的临床开发计划：第一步，联合化疗去攻克确定性高、能快速实现高市场价值的适应症；第二步，联合各种新颖作用机制的新产品，填补之前未被满足的临床需求；第三步，探索更多、更新的联合给药方案和适应症。篇幅原因，写完外企部分已经快5000字了，改天再写国内企业部分。信息量过大，CPU干烧到头晕，所有重点点到即止，如有疏漏错误，请大家多包涵。# 本篇笔记仅基于公开资料和信息撰写、为个人观点、供学术交流所用、不构成任何建议 #

抗体药物偶联物免疫疗法生物类似药

2025-04-08

·ioncology

大咖辩论：双特异性抗体会取代PD-(L)1抑制剂吗？丨IASLC肺癌靶向治疗会议

点击蓝字关注我们自2015年FDA首次批准纳武利尤单抗治疗晚期非小细胞肺癌（NSCLC）以来，临床医生已见证了使用抗PD-(L)1药物在一线和二线治疗中抑制癌细胞使总生存（OS）有所提高。[1]这十年的统治地位是否即将结束？双特异性抗体是否会取代PD-(L)1药物成为肺癌免疫治疗的主力？在2月20日举行的国际肺癌研究协会（IASLC）肺癌靶向治疗会议上，来自加州大学戴维斯分校的Jonathan W. Riess教授与密歇根大学的Greg Kalemkerian教授就此展开精彩正反辩论。▲Jonathan Riess, MD▼Greg Kalemkerian, MD正方：双特异性抗体即将加冕免疫治疗王冠Dr. Riess阐述三个核心论点捍卫其立场：1.双特异性抗体可靶向癌症免疫循环（cancer immunity cycle）的多个组成部分（包括阻断PD-1/PD-L1）双特异性抗体具有独特的能力，可以对一系列刺激/抑制免疫信号进行组合攻击，包括阻断免疫检查点、共刺激激活免疫细胞以及与细胞因子和炎症因子结合。图1. 双特异性抗体的特点2.作用机制的优势增强，例如产生协同结合（cooperative binding）双特异性抗体已显示出机制优势，例如协同结合。PD-1/VEGF双抗依沃西单抗的研究中就观察到这种机制优势。依沃西单抗与VEGF的协同结合可使PD-1亲和力（PD-1 affinity）增加18倍以上，而依沃西单抗与PD-1的协同结合可使VEGF亲和力增加4倍以上。[2]图2. 依沃西单抗的协同结合活性3.试验初始数据有前景随机III期头对头研究HARMONi-2显示，在PD-L1阳性NSCLC患者中，依沃西单抗相比帕博利珠单抗可显著延长无进展生存期（PFS），差异具有统计学意义，且获益在PD-L1表达高和PD-L1表达低的患者中均可见。[3]在EGFR突变NSCLC患者中，双特异性抗体的初步研究“非常有希望”。双特异性抗体（如volrustomig）在较难治疗的PD-L1阴性人群中具有良好的PFS数据。[4]反方：双抗尚难撼动PD-(L)1基石地位Dr. Kalemkerian从不同的角度探讨了这个问题，反驳了一系列他认为“未经证实”的关于双特异性抗体的假设。有人提出“双特异性抗体比联合疗法更好，已有初步数据和生物学原理证实”。他认为这些论点需要澄清，这一问题的关键在于“双特异性免疫靶向治疗是否比免疫检查点抑制剂单药治疗更能改善生存。”Dr. Kalemkerian通过展示一系列不成功的研究（涉及7,000多名患者）反驳了Dr. Riess的演讲。这些研究并未证明在抗PD-1/PD-L1疗法中添加其他免疫检查点抑制剂或血管内皮生长因子（VEGF）靶向药物有益。1.抗PD-(L)1联合抗血管生成Dr. Kalemkerian回顾了联用血管生成靶向药物贝伐珠单抗或多靶点酪氨酸激酶抑制剂（包括仑伐替尼、卡博替尼和司曲替尼）的试验生存数据，以及对比PD-1/VEGF双特异性抗体依沃西单抗和PD-1抗体帕博利珠单抗的HARMONi-2试验数据。Lung-MAP S1800A：在既往接受过抗PD-1/PD-L1治疗的患者中，使用帕博利珠单抗（pembrolizumab）+雷莫芦单抗（ramucirumab）缺乏无进展生存期和缓解率获益，尽管该试验以总生存（OS）为主要终点，且OS获益具有统计学意义。[5]APPLE(WJOG)：该试验发现在化疗中添加抗血管生成贝伐珠单抗没有任何有意义的增益。[6]LEAP-007：结果显示帕博利珠单抗+乐伐替尼（抗血管生成）组合疗效反劣于单药帕博利珠单抗，且毒性更大。[7]SAPPHIRE：这项研究对比了司曲替尼（sitravatinib）+纳武利尤单抗（nivolumab）vs多西他赛单药用于二线治疗，结果显示免疫疗法联合抗血管生成疗法并不能改善结果。[8]HARMONi-2：PD-1/VEGF双特异性抗体依沃西单抗的结果似乎优于PD-1抗体帕博利珠单抗，但对比两个药物的HARMONi-2试验存在需要考量的重要因素，比如III期HARMONi-2缺乏OS数据；帕博利珠单抗单药并不是PD-L1表达1-49%患者真正的标准治疗方法；中位随访时间仍然很短；需等待HARMONi-2研究结果在来自更广泛的地理和种族的患者中得到确认。2.抗PD-(L)1联合抗CTLA-4Dr. Kalemkerian分析了PD-(L)1和抗CTLA-4药物组合的研究结果在非小细胞肺癌和小细胞肺癌中的研究结果。通过从2019~2023年的一系列研究，他发现联合治疗的结果为“无有意义的获益”或“毒性增加”，其中一些研究是双输（lose lose），比如ARCTIC研究。ARCTIC：III期ARCTIC评估了度伐利尤单抗±Tremelimumab对比标准治疗（SoC）三线及以上治疗晚期NSCLC的疗效，根据PD-L1表达情况分为PD-L1 TC≥25％亚组和PD-L1 TC<25％亚组。结果显示PD-L1抑制剂+CTLA-4抑制剂的毒性更大，相比单用度伐利尤单抗无OS获益。[9]CASPIAN：在广泛期小细胞肺癌治疗方面，度伐利尤单抗+Tremelimumab+化疗相比度伐利尤单抗+化疗使毒性发生率增加，OS反而缩短2.5个月（10.4 vs 12.9个月）。[10]目前还有很多失败的ICI联合方案（联合化疗以外的药物），未来还会有更多失败的联合策略出现。那么，双特异性抗体免疫治疗会取代PD-(L)1药物吗？Dr. Kalemkerian的答案是‘不会’，至少现在不会。Dr. Kalemkerian说“至少今天不会”，这与他的辩论对手提出的一个关键概念“时机”相呼应。展望未来我们是根据目前已有研究发现对双特异性抗体做出判断，还是根据未来可能的研究发现做出判断？在演讲中，Dr. Riess着眼于不久的将来，并援引冰球传奇人物Wayne Gretzky的智慧来处理这个问题——滑向冰球将要去的地方，而不是它曾经去过的地方。[11]与之相反，Dr. Kalemkerian秉持"紧盯当下冰球位置"的务实精神，要求业内同道以当前最有效治疗方法为基准来评估新研究数据，在冰球滑向可能错误的角落之前，目光所及之处是正确的冰球。参考文献（上下滑动可查看）1. Parvez A, Choudhary F, Mudgal P, Khan R, Qureshi KA, Farooqi H, Aspatwar A. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front Immunol. 2023 Dec 1;14:1296341. doi: 10.3389/fimmu.2023.1296341. PMID: 38106415; PMCID: PMC10722272.2. Zhong T, et al. AACR-NCI-EORTC International Conference 2023. Poster #B123, Abstract #35333, Boston, MA, USA3. Zhou C, Chen J, Wu L, et al: Phase 3 study of ivonescimab (AK112) vs pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC: Primary analysis of HARMONi-2. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024.4. Dovedi SJ, Elder MJ, Yang C, Sitnikova SI, Irving L, Hansen A, Hair J, Jones DC, Hasani S, Wang B, Im SA, Tran B, Subramaniam DS, Gainer SD, Vashisht K, Lewis A, Jin X, Kentner S, Mulgrew K, Wang Y, Overstreet MG, Dodgson J, Wu Y, Palazon A, Morrow M, Rainey GJ, Browne GJ, Neal F, Murray TV, Toloczko AD, Dall’Acqua W, Achour I, Freeman DJ, Wilkinson RW, Mazor Y. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+?Activated T Cells. Cancer Discov. 2021 May;11(5):1100-1117. doi: 10.1158/2159-8290.CD-20-1445. Epub 2021 Jan 8. PMID: 33419761.5. Reckamp KL, Redman MW, Dragnev KH, et al. Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A [published correction appears in J Clin Oncol. 2022 Sep 1;40(25):3002. doi: 10.1200/JCO.22.01464.].?J Clin Oncol. 2022;40(21):2295-2306. doi:10.1200/JCO.22.009126. Shiraishi Y, Kishimoto J, Tanaka K, Sugawara S, Daga H, Hirano K, Azuma K, Hataji O, Hayashi H, Tachihara M, Mitsudomi T, Seto T, Nakagawa K, Yamamoto N, Okamoto I. Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2020 Sep;21(5):472-476. doi: 10.1016/j.cllc.2020.03.010. Epub 2020 Apr 10. PMID: 32381420.7. Yang, James Chih-Hsin et al. Journal of Thoracic Oncology, Volume 19, Issue 6, 941 – 953 Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial8. Borghaei H, de Marinis F, Dumoulin D, Reynolds C, Theelen WSME, Percent I, Gutierrez Calderon V, Johnson ML, Madroszyk-Flandin A, Garon EB, He K, Planchard D, Reck M, Popat S, Herbst RS, Leal TA, Shazer RL, Yan X, Harrigan R, Peters S; SAPPHIRE Investigators. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2024 Jan;35(1):66-76. doi: 10.1016/j.annonc.2023.10.004. Epub 2023 Oct 20. PMID: 37866811.9. Planchard D，et al. ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol. 2020 May;31(5):609-618. doi: 10.1016/j.annonc.2020.02.006. Epub 2020 Feb 20. PMID: 32201234.10. Paz-Ares L, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022 Apr;7(2):100408. doi: 10.1016/j.esmoop.2022.100408. Epub 2022 Mar 10. PMID: 35279527; PMCID: PMC9161394.11. A common misattribution of a quote that may have come from Wayne Gretzky’s father（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

免疫疗法临床结果临床3期上市批准上市后研究

100 项与曲美木单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06657	曲美木单抗	-	DB11771

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
肝细胞癌	加拿大	AstraZeneca Canada, Inc.	2023-08-31
晚期肝细胞癌	欧盟	AstraZeneca AB	2023-02-20
晚期肝细胞癌	冰岛	AstraZeneca AB	2023-02-20
晚期肝细胞癌	列支敦士登	AstraZeneca AB	2023-02-20
晚期肝细胞癌	挪威	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	欧盟	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	冰岛	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	列支敦士登	AstraZeneca AB	2023-02-20
转移性非小细胞肺癌	挪威	AstraZeneca AB	2023-02-20
晚期非小细胞肺癌	日本	AstraZeneca KK	2022-12-23
非小细胞肺癌	美国	AstraZeneca AB	2022-11-10
不可切除的肝细胞癌	美国	AstraZeneca AB	2022-10-21

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非肌层浸润性膀胱肿瘤	临床3期	美国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	日本	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	阿根廷	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	奥地利	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	巴西	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	加拿大	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	智利	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	法国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	德国	AstraZeneca PLC	2021-08-05
非肌层浸润性膀胱肿瘤	临床3期	希腊	AstraZeneca PLC	2021-08-05

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03164616 (POSEIDON, ESMO_ELCC2025)	临床3期	转移性非小细胞肺癌一线 EGFR/ALK wild-type	175	Durvalumab + Tremelimumab + Chemotherapy	選餘憲鹹積築選積淵憲(廠廠顧膚鑰壓網鏇選醖) = D+T+CT demonstrated statistically significant improvements in both progression-free survival (PFS; HR 0.72; 95% CI 0.60-0.86; p = 0.0003) and overall survival (OS; HR 0.77; 95% CI 0.65-0.92; p = 0.0030) vs CT alone, leading to approvals for this regimen. D+CT significantly improved PFS vs CT (0.74; 95% CI 0.62-0.89; p = 0.0009), with a positive trend for OS improvement (HR 0.86; 95% CI 0.72-1.02; p = 0.0758) 簾夢衊鏇顧衊蓋壓繭齋 (齋選構願餘構醖鑰夢窪 ) 更多	积极	2025-03-26
NCT03164616 (POSEIDON, ESMO_ELCC2025)	临床3期	转移性非小细胞肺癌一线 EGFR/ALK wild-type	175	Durvalumab + Chemotherapy		积极	2025-03-26
NCT02879162 (CTgov)	临床2期	晚期癌症	140	Tremelimumab+Durvalumab	糧範顧膚窪範網繭鑰鏇(齋醖願網鬱築顧窪獵艱) = 顧淵獵淵構廠選築鑰憲鹹鹽顧遞繭齋夢簾網鹽 (簾齋醖艱願鑰憲夢選餘, 餘願願艱齋顧鬱獵獵鹹 ~ 壓窪鹽積選齋願夢顧衊) 更多	-	2025-02-17
NCT03638141 (ASCO_GI2025) 人工标引	临床2期	肝细胞癌	20	Durvalumab + tremelimumab + TACE	製製艱遞襯範醖襯獵憲(鑰醖鹽網壓積蓋顧鹽醖) = 衊鑰鹹鬱願繭構觸衊構鹹構壓鑰構鹹選壓窪積 (製齋糧蓋獵顧窪簾繭襯, 32 ~ 77) 达到更多	积极	2025-01-23
STRIDE (ASCO_GI2025)	N/A	不可切除的肝细胞癌	79	STRIDE regimen (Tremelimumab 300 mg + Durvalumab 1500 mg)	觸範積醖網艱願齋淵鹽(觸網衊憲襯憲積觸簾壓) = 膚簾積網築膚醖鹽憲蓋憲蓋壓鏇鏇衊蓋衊鏇餘 (選遞製鹹鏇齋構觸鏇衊 ) 更多	-	2025-01-23
NCT03702179 (IMMUNOPRESERVE-SOGUG \| IMMUNOPRESERVE, CTgov)	临床2期	浸润性膀胱癌 \| 肌层浸润性膀胱癌	32	Radiotherapy+Tremelimumab+Durvalumab	鏇築觸築鏇衊願顧繭淵 = 憲襯繭憲壓膚觸壓顧醖糧願範廠憲鏇窪製窪遞 (網鬱蓋遞餘鹹觸夢餘選, 選積廠衊艱鑰願願繭淵 ~ 膚製遞積齋壓鑰淵鏇鹽) 更多	-	2024-12-05
NCT04989218 (ICC, CTgov)	临床1/2期	肝内胆管癌	1	Tremelimumab+Gemcitabine+Cisplatin+Durvalumab	醖範簾製鬱糧夢網選壓 = 顧餘襯糧憲鬱顧壓繭築鬱鹽憲醖獵獵醖鏇築願 (範遞齋醖夢醖憲艱憲選, 窪範憲鏇獵窪餘構觸獵 ~ 築鹹網鹽鹽醖鬱艱餘遞) 更多	-	2024-11-05
NCT03116529 (NEXIS, Pubmed \| Cureus) 人工标引	临床1/2期	软组织肉瘤新辅助	23	Durvalumab + Tremelimumab	積餘窪艱鏇淵築繭餘繭(獵蓋鏇獵願窪鏇獵簾鹽) = 廠鏇選鏇鑰窪憲積衊鏇鹽鬱築顧鑰憲夢夢選遞 (壓繭餘築簾廠窪衊繭膚 ) 更多	积极	2024-10-22
NCT02754856 (CTgov)	临床1期	肝转移 \| 结直肠癌肝转移	24	Durvalumab	壓簾簾淵衊積製餘選鹹 = 顧鏇積憲獵蓋衊簾範淵壓製鑰窪簾觸窪製衊淵 (壓網齋襯鑰壓鹽憲積顧, 選齋蓋衊壓齋範築襯窪 ~ 衊製積觸鏇壓鹹鑰顧願) 更多	-	2024-10-09
NCT03298451 (HIMALAYA, ESMO2024) 人工标引	临床3期	不可切除的肝细胞癌	-	STRIDETremelimumabDurvalumab	蓋憲衊構鏇艱鹹齋蓋齋(蓋顧簾範襯觸淵選憲獵) = 襯願鑰鬱廠窪範窪網衊遞鏇築艱範築範顧願觸 (鑰鑰艱壓襯夢齋簾製鹹 ) 更多	积极	2024-09-16
NCT03298451 (HIMALAYA, ESMO2024) 人工标引	临床3期	不可切除的肝细胞癌	-	Durvalumab	蓋憲衊構鏇艱鹹齋蓋齋(蓋顧簾範襯觸淵選憲獵) = 襯夢繭觸觸獵夢廠鏇選遞鏇築艱範築範顧願觸 (鑰鑰艱壓襯夢齋簾製鹹 ) 更多	积极	2024-09-16
NCT03899610 (KGOG3046 \| TRU-D, ESMO2024) 人工标引	临床2期	卵巢癌新辅助	45	Neoadjuvant chemotherapy durvalumabltremelimumabtiple low dose of tremelimumab	簾鹽壓鬱積醖糧糧醖獵(獵膚遞艱築壓衊製廠壓) = 餘築製夢鏇觸構憲繭衊顧鏇鹹獵範齋鑰繭憲選 (襯糧範窪積餘艱淵願鹽 ) 更多	积极	2024-09-14
NCT03899610 (KGOG3046 \| TRU-D, ESMO2024) 人工标引	临床2期	卵巢癌新辅助	45	Neoadjuvant chemotherapy durvalumabltremelimumabgle high dose of tremelimumab	簾鹽壓鬱積醖糧糧醖獵(獵膚遞艱築壓衊製廠壓) = 選鑰鏇壓糧餘獵壓簾網顧鏇鹹獵範齋鑰繭憲選 (襯糧範窪積餘艱淵願鹽 ) 更多	积极	2024-09-14