Randomized Phase III Study of Second-Line Chemotherapy With or Without Panitumumab for KRAS Wild Type, Locally Advanced or Metastatic Pancreatic Adenocarcinoma

This phase III trial compares the effect of adding panitumumab to standard chemotherapy (with nanoliposomal Irinotecan, leucovorin, and 5-fluorouracil [5-FU] or irinotecan, leucovorin, and 5-FU or nab-paclitaxel and gemcitabine) versus standard chemotherapy alone in treating patients with KRAS wild type (WT) pancreatic ductal adenocarcinoma that cannot be removed by sugery (unresectable) or that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Panitumumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Chemotherapy drugs, such as nanoliposomal irinotecan, leucovorin, 5-FU, irinotecan, nab-paclitaxel and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding panitumumab to standard chemotherapy may be effective in treating patients with unresectable, locally advanced, or metastatic KRAS WT pancreatic ductal adenocarcinoma.

开始日期2026-01-06

申办/合作机构

SWOG

[+1]

NCT07124884

/ Not yet recruiting临床2期IIT

COLOSOTO: Single-arm Phase II Study Evaluating 5-fluorouracil Plus Panitumumab (Anti-EGFR) and Sotorasib (KRAS G12C Inhibitor) in First-line Treatment of Patients Non-eligible for a Doublet/Triplet Chemotherapy With Advanced Unresectab

5-fluorouracil (5-FU) is a standard of care in frail/elderly patients with an unresectable colorectal adenocarcinoma (CRC) in first-line setting. Panitumumab plus Sotorasib are promising in advanced line in KRAS G12C mutated CRC. In this study, We assess the safety and efficacy of 5FU combination with Panitumumab and Sotorasib as first-line treatment in frail/elderly patients with unresectable KRAS G12C mutated CRC

开始日期2025-08-31

申办/合作机构

Fédération Francophone de la Cancérologie Digestive

[+1]

NCT07094113

/ Not yet recruiting临床1期

A Phase 1/1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors

The purpose of this first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 410 when administered alone or in combination with other agents in participants with advanced or metastatic solid tumors harboring KRAS alterations.
This is a dose-escalation study in which participants will be assigned to multiple dose levels (DLs) of AMG 410, either as monotherapy or in combination with other agents, followed by expansion cohorts. The goal is to determine the Maximum Tolerated Dose (MTD)-the highest dose with acceptable safety and manageable side effects-or the Recommended Phase 2 Dose (RP2D) of AMG 410 in adult participants with KRAS-altered advanced or metastatic solid tumors.

开始日期2025-08-04

申办/合作机构

Amgen, Inc.

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100 项与帕尼单抗相关的专利（医药）

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2,479

项与帕尼单抗相关的文献（医药）

2025-12-01·Journal of Gastrointestinal Cancer

Anti-EGFR Rechallenge in Metastatic Colorectal Cancer and the Role of ctDNA: A Systematic Review and Meta-analysis

Review

作者: da Silva, Luís Felipe Leite ; Peixoto, Renata D 'Alpino ; Saldanha, Erick Figueiredo ; da Conceição, Lucas Diniz ; Noronha, Mariana Macambira ; da Silva, Marcos Vinícius Martins Grangeiro

BACKGROUND:

Metastatic colorectal cancer (mCRC) remains a significant clinical challenge. While anti-EGFR inhibitors have improved survival rates, their long-term efficacy is limited by disease progression, which is often associated with the development of acquired resistance mutations. However, some patients may regain sensitivity to anti-EGFR agents after alternative therapies, suggesting a potential benefit for rechallenge strategies. Our study aims to conduct a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of EGFR rechallenge in patients with mCRC.

METHODS:

A systematic search of the MEDLINE, EMBASE, and Cochrane databases was conducted between October 28 and December 24, 2023, to identify clinical trials investigating treatment regimens incorporating panitumumab or cetuximab as a rechallenge strategy. Pooled proportions or hazard ratios (HR) were calculated using a random effects model. Inter-study heterogeneity was assessed using the I².

RESULTS:

Among the 2105 articles identified through the search, 13 met the predetermined inclusion criteria. Of these, 12 were phase II studies, encompassing 92.3% of the patient population. Cetuximab was administered to 302 patients (75.1%), whereas panitumumab was utilized in 100 patients (24.9%).A pooled analysis of eight studies demonstrated an objective response rate of 20.50% (95% CI 7.94 to 33.07) and a disease control rate of 67.35% (95% CI 58.60 to 76.09). The median progression-free survival was estimated at 3.5 months (95% CI 2.68-6.69), with a median OS of 9.8 months (95% CI 6.71-12.89). Patients exhibiting RAS wild-type status in circulating tumor DNA (ctDNA) analysis derived enhanced benefits from anti-EGFR rechallenge (HR: 0.41; 95% CI 0.28-0.60, I² = 60%). Common grade 3 or higher treatment-related adverse events included neutropenia (22.8%) and rash (14.9%).

CONCLUSION:

This meta-analysis underscores the efficacy and safety of anti-EGFR rechallenge as a promising therapeutic approach for a subset of patients afflicted with mCRC. The observed correlation between wild-type RAS status, as determined through ctDNA analysis, and improved OS signals the prospect of precision oncology in guiding treatment decisions.

2025-12-01·Journal of Gastrointestinal Cancer

Efficacy and Safety of Anti-EGFR Therapy Rechallenge in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis

Review

作者: Burbano, Rommel Mario Rodríguez ; de Oliveira Rodrigues, Anna Luíza Soares ; de Moraes, Francisco Cezar Aquino ; Limachi-Choque, Jhonny ; Priantti, Jonathan N

BACKGROUND:

Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments.

METHODS:

A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I² statistics. R, version 4.2.3, was used for statistical analyses.

RESULTS:

Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63 years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9 months, while the median overall survival (mOS) ranged from 5 to 17.8 months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I², 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%).

CONCLUSIONS:

Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.

2025-12-01·Journal of Gastrointestinal Cancer

Final Results of ERBIMOX: A Randomized Phase II Study of Modified FOLFOX7 With or Without Cetuximab as First-Line Treatment for KRAS Wild-type Metastatic Colorectal Cancer

Article

作者: Zirrgiebel, Ute ; Müller, Lothar ; Depenbusch, Reinhard ; Lerchenmüller, Christian ; Boller, Emil ; Niemeier, Beate ; Marschner, Norbert ; Sahm, Stephan ; Tesch, Hans ; Potthoff, Karin

BACKGROUND:

The combination of FOLFOX/FOLFIRI with an EGFR-antibody (cetuximab/panitumumab) is a first-line standard for RAS wild-type metastatic colorectal cancer (mCRC). The OPTIMOX stop-and-go regimen, which reduces oxaliplatin-induced neuropathy, and fluorouracil/folinic acid (FU/FA) were standard maintenance-therapies in the pre-antibody era. Whether an EGFR-antibody adds value to the OPTIMOX strategy in the RAS wild-type setting remains unknown.

METHODS:

In the open-label, randomized, multicenter phase II ERBIMOX trial, patients with KRAS wild-type mCRC received either first-line induction-therapy with 8 cycles of mFOLFOX7 followed by maintenance-therapy with FU/FA (OPTIMOX arm) or mFOLFOX7 + cetuximab followed by FU/FA + cetuximab (ERBIMOX arm). Primary objective was to demonstrate superiority of additional cetuximab to mFOLFOX7 during induction/maintenance-therapy. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The trial is registered at EudraCT (No.2006-002744-28).

RESULTS:

From 2006-2011, 138 patients with KRAS wild-type mCRC from 23 German sites were randomly assigned to either OPTIMOX (N = 63) or ERBIMOX (N = 75). ORR numerically favored the ERBIMOX arm (64.0% vs. 54.0%, P = 0.3071). Median PFS (ERBIMOX vs. OPTIMOX) was 9.6 vs. 8.8 months (P = 0.7612), median OS 25.6 vs. 30.9 months (P = 0.5821). Most common grade 3/4 adverse events (AEs) were skin reactions (21.9% vs. 2.1%) and gastrointestinal disorders (13.5% vs. 9.5%). No cetuximab-related deaths occurred.

CONCLUSION:

In treatment-naïve KRAS wild-type mCRC, adding cetuximab to mFOLFOX7 resulted in numerically higher ORR than mFOLFOX alone, but no statistically significant differences in ORR, PFS or OS; probably because of the premature stop due to poor recruitment. The safety profile was as expected, with few discontinuations.

239

项与帕尼单抗相关的新闻（医药）

2025-08-22

·靶点圈

耐药不可怕？一文读懂 EGFR-TKIs 耐药机制及四代药最新临床进展，EGFR 突变者必看！

Vol.01 -EGFR的结构基础与功能- EGFR家族成员 ErbB受体家族是一类跨膜酪氨酸激酶受体，包括EGFR(ErbB1)、HER2(ErbB2)、HER3(ErbB3)和HER4(ErbB4)，通过与EGF等配体结合或形成异源二聚体激活下游信号通路，调控细胞增殖、分化与存活。图1 ErbB受体家族的排列和同源配体 EGFR的分子结构组成 EGFR是由1210个氨基酸组成的单通道跨膜酪氨酸激酶受体，分子量约170kDa。其结构可分为以下几个功能域： ● 胞外配体结合域：负责结合表皮生长因子(EGF)、转化生长因子α(TGF-α)等配体，触发受体激活。 ● 跨膜α-螺旋结构域：连接胞外与胞内区域，参与受体二聚化或寡聚化过程。 ● 胞内近膜结构域：调控激酶活性的开关。 ● 酪氨酸激酶结构域：包含N端和C端，中间形成ATP结合裂隙，是EGFR-TKIs的主要作用靶点。 ● C端尾部(非结构化区域)：含多个酪氨酸残基，磷酸化后招募下游信号分子(如Ras、PI3K)。图2 EGFR的结构、活化和突变的示意图 EGFR的激活机制 EGFR与配体结合后，通过胞外域构象变化促进二聚化(同源或异源二聚体)，进而引发胞内激酶结构域的不对称激活： ● 活性/非活性构象转变：激活环(A-loop)和αC-螺旋从“失活构象(αC-out)”转变为“激活构象(αC-in)”，形成稳定的盐桥(如Lys745-Glu762)，暴露ATP结合位点并增强催化活性。图3 EGFR在活性/非活性构象中的激酶结构域示意图 ● 相关信号通路：二聚体间相互磷酸化C端酪氨酸残基，启动Ras/MAPK、PI3K/Akt/mTOR、JAK/STAT等信号通路，调控细胞增殖、存活和分化。图4 EGFR介导的信号通路调节正常细胞和癌细胞中的关键过程 ● 异常激活：EGFR的异常激活会驱动细胞无限增殖，促进肿瘤侵袭，还可重塑肿瘤微环境，如促进血管内皮生长因子(VEGF)分泌，或通过PD-L1表达逃避免疫监视。 Vol.02 -EGFR突变的分布与类型- EGFR突变的分布特征 ● 人群差异：亚洲人群突变率高达30%-50%，显著高于高加索人群(10%-20%)。 ● 吸烟状态：从未吸烟者中EGFR突变率(58.7%)远高于吸烟者(18.4%)。 ● 组织学差异：腺癌突变率最高(52.9%)，鳞状细胞癌仅14.5%，可能与腺癌的上皮起源和信号通路依赖性相关。 ● 年龄与性别：年轻患者(<80岁)突变率49.6%，高于老年患者(24.1%)；女性突变率显著高于男性，可能与雌激素受体交叉信号有关。表1 EGFR突变分布 EGFR突变的主要类型 EGFR突变主要集中在激酶结构域的外显子18-21，占NSCLC患者的10%-35%，其中常见突变(19del、L858R)占90%，对TKIs敏感；罕见突变(如外显子20插入)占5%-10%，TKIs的疗效较差。图5 EGER激酶结构域的突变类型 ● 激活突变(驱动肿瘤生长的核心突变)：通过降低ATP结合亲和力，增强EGFR-TKIs的竞争性结合。 ①外显子19缺失(19del)：约占EGFR突变的45%-47%，常见为ΔE746-A750，破坏β3-αC环结构，降低激酶激活能垒，促进αC-in构象，增强信号传导。对TKIs敏感性高，患者接受一线治疗的中位无进展生存期(mPFS)显著长于其他突变类型。 ②外显子21点突变(L858R)：占比约40%-41%，位于激酶结构域A-loop的L858被精氨酸取代后破坏疏水簇，稳定激活构象(αC-in)，持续驱动细胞增殖。对TKIs敏感性略低于19del，且更易伴随T790M耐药突变。 ③外显子18突变(G719X)：如G719S/A/C，占3%-5%，位于P-loop，通过逆转失活构象增强激酶活性，对第二代TKIs(如阿法替尼)响应更好。 ④外显子20突变(S768I)：占1%-2%，激活PI3K/AKT通路，常与其他突变(如G719X)形成复合突变，联合用药效果更佳。 ● 耐药突变(导致TKIs治疗失败的关键突变)：通过增加ATP结合亲和力或空间位阻，削弱药物结合。 ①外显子20突变(T790M)：约50%-60%的第一代/二代TKIs耐药患者携带该突变，苏氨酸被甲硫氨酸取代后增加ATP结合亲和力，阻碍药物结合。此外，L858R突变患者更易出现该突变(较19del患者高30%)。 ②外显子20突变(C797S)：第三代TKIs(如奥希替尼)的特征性耐药突变，占比约20%，半胱氨酸被丝氨酸取代，消除药物共价结合位点，导致耐药。多与T790M共存，形成“三重突变”(如L858R/T790M/C797S)，导致治疗失败。 ③L718Q突变：与C797S共存时进一步增强耐药性。 ④EGFR基因扩增：野生型或突变型EGFR拷贝数增加，通过信号通路冗余导致耐药。 ⑤外显子20插入突变(ex20ins)：占EGFR突变的4%-10%，如D770-N771insNPG，在αC-螺旋附近插入氨基酸，形成空间位阻，对传统TKIs敏感性低，需特异性抑制剂(如莫博赛替尼)治疗。图6 EGFR激酶突变的频率 EGFR突变的致癌机制 EGFR 突变通过 “分子激活-信号传导-表型改变-微环境重塑” 的级联效应驱动癌变，其机制涉及多通路交叉调控及肿瘤异质性。 ● EGFR 突变的分子激活机制 ①激酶域突变驱动持续活化：EGFR突变导致激酶结构域构象改变，使EGFR摆脱配体依赖而持续激活。 ②配体结合域突变增强信号：部分EGFR突变通过改变胞外域结构，提高与EGF等配体的亲和力，延长信号传导时间。 ● EGFR下游信号通路的异常激活 ①PI3K/AKT/mTOR通路失控：EGFR突变激活 PI3K，促进PIP2转化为PIP3，招募AKT至细胞膜并磷酸化激活，进而抑制凋亡蛋白BAD、激活mTOR，驱动细胞周期进程(如G1/S期转换)和蛋白质合成。 ②RAS/RAF/MEK/ERK通路过度活化：突变型EGFR 通过GRB2-SOS复合体激活RAS，依次磷酸化RAF、MEK、ERK，诱导c-Fos、c-Jun等转录因子，促进细胞增殖、分化与迁移。 ③JAK/STAT通路异常激活：EGFR突变可直接或间接激活JAK2，磷酸化STAT3/5，诱导VEGF、IL-6等促炎因子表达，促进血管生成与免疫逃逸。 ● 细胞生物学行为的恶性转化 ①增殖与凋亡失衡：持续激活的EGFR信号抑制 p53、Bax等凋亡因子，同时上调Cyclin D1、c-Myc等增殖相关基因，使细胞突破接触抑制，无限增殖。 ②代谢重编程：通过mTOR调控葡萄糖转运蛋白(GLUT1)和己糖激酶2(HK2)，促进糖酵解(Warburg效应)，为肿瘤细胞提供能量与生物合成前体。 ③侵袭与转移能力获得：激活基质金属蛋白酶(MMP-2、MMP-9)降解细胞外基质，同时上调E-钙黏蛋白抑制剂(如Snail、Twist)，促进上皮-间质转化(EMT)，增强细胞迁移能力。 ● 免疫抑制微环境形成图7 EGFR突变型对TME中关键成分的作用示意图 ①PD-L1表达上调：EGFR突变激活STAT3通路，促进肿瘤细胞PD-L1表达，抑制T细胞杀伤。 ②免疫抑制细胞招募：EGFR突变会促进TME中髓系抑制细胞(MDSCs)、调节性T细胞(Tregs)通过分泌TGF-β、IL-10等抑制免疫应答。 ③CD39/CD73-腺苷轴：EGFR突变激活HIF-1α，促进MDSCs和肿瘤细胞表达CD39/CD73，生成免疫抑制性腺苷，抑制NK细胞和T细胞功能。 ④MHC-I/II下调：EGFR突变通过PI3K/AKT和JAK/STAT3通路抑制MHC-I和MHC-II表达，削弱肿瘤抗原呈递能力。 ⑤促进血管生成：EGFR突变细胞分泌VEGF、FGF等因子，诱导肿瘤血管异常生成，提供营养供应并促进转移。表2 EGFR突变对TME的每个组成部分的影响 ● 肿瘤突变负荷(TMB)水平：EGFR突变的TMB显著低于野生型，可能导致新抗原生成不足，免疫原性低。 ● 致癌/抑癌基因表达改变：EGFR突变导致癌基因(如CCND1、BCL2)上调和抑癌基因(如BAX、CDH1)下调，同时激活负反馈调节因子(如DUSP6、SPRY2)。表3 EGFR相关基因表达变化 Vol.03 -四代EGFR-TKIs的结构与作用机制- 第一代EGFR-TKIs：可逆结合激活构象 ● 代表药物：吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)、埃克替尼(Icotinib)。 ● 结构特点：均为苯胺喹唑啉类化合物，通过可逆结合EGFR激酶结构域的ATP结合口袋，竞争性抑制ATP结合，阻断磷酸化信号传导。 ● 临床应用 ①Gefitinib：2003年获批用于携带外显子19缺失(ΔE746-A750)或外显子21(L858R)突变的NSCLC一线治疗，无进展生存期(PFS)较化疗显著延长。 ②Erlotinib：可同时结合激活构象(αC-in/DFG-in)和Src样失活构象(αC-out/DFG-in)，但疗效与Gefitinib相似。 ● 局限性：毒性较高且缺乏OS获益，约1年后因T790M突变(占50%)出现获得性耐药。第二代EGFR-TKIs：共价结合与泛HER抑制 ● 代表药物：阿法替尼(Afatinib)、达可替尼(Dacomitinib)、奈拉替尼(Neratinib)。 ● 结构特点：在苯胺喹唑啉核心上引入迈克尔受体基团，与激酶结构域的Cys797共价结合，不可逆抑制EGFR(及HER2、HER4)活性。 ● 临床应用 ①Afatinib：于2013年获批用于一线治疗，中位PFS较化疗延长，并对罕见突变(如G719X、S768I)有效。 ②Dacomitinib：于2018年获批，对野生型EGFR抑制更强，毒性更高(如腹泻、皮疹)。 ● 局限性：仍无法克服T790M耐药，且因泛HER抑制导致不良反应较第一代更严重。第三代EGFR-TKIs：突变选择性与耐药应对 ● 代表药物：奥希替尼(Osimertinib)、罗西替尼(Rociletinib)、阿美替尼(Almonertinib)、伏美替尼(Furmonertinib)。 ● 结构特点：以嘧啶为骨架，含共价结合基团(与Cys797结合)，对T790M突变型EGFR的亲和力较野生型高200倍。 ● 临床应用： ①Osimertinib：一线治疗PFS达18.9个月，且对脑转移患者有效。 ②Rociletinib：可通过结合T790M突变型EGFR的αC-in/DFG-in构象发挥作用，但因疗效不足和高血糖等不良反应未获批准。 ● 局限性：长期使用后约15%患者会出现C797S突变，导致药物与EGFR的共价结合失效，形成三重突变(如L858R/T790M/C797S)，成为当前治疗瓶颈。图8 第三代EGFR-TKIs一线治疗后获得性耐药突变的频率及潜在治疗策略第四代EGFR-TKIs：设计策略与代表药物 ● 基于现有药物的结构优化 ①奥希替尼衍生物：通过添加羟基烷基链(如化合物17)或引入环化结构(如化合物18)，增强与EGFR的氢键作用，提高对C797S突变的抑制活性。例如，化合物18在体内试验中抑制肿瘤生长的TGI达70.75%。 ②布加替尼衍生物：利用其双靶点(ALK/EGFR)特性，通过修饰膦氧化物基团(如化合物26)提升对EGFR三重突变的选择性。化合物26对EGFRDel19/T790M/C797S的IC₅₀达0.20nM，并在小鼠模型中显著抑制肿瘤生长。 ● 新型骨架化合物的开发 ①EAI045类变构抑制剂：通过结合EGFR的变构口袋(而非ATP结合位点)，如化合物40(EAI045)与西妥昔单抗联用，可抑制C797S突变肿瘤生长，但单药活性有限。 ②JND3229衍生物：通过高通量筛选获得的化合物51(JND3229)对C797S突变的IC₅₀为5.8nM，其衍生物52通过引入甲基提升选择性，对野生型EGFR的抑制作用显著降低。 ● 混合骨架与多靶点设计 ①奥希替尼与布加替尼杂合分子：如化合物38结合两者优势，对EGFR三重突变的抑制活性优于单药，且在PC9-OR细胞中诱导凋亡的能力显著增强。 ②嘌呤类衍生物：化合物56通过磺酰基杂环取代提升对C797S的亲和力，IC₅₀达18nM，并能诱导细胞周期阻滞和凋亡。 ● 进入临床试验的第四代EGFR-TKIs ①JIN-A02：Phase1/2试验显示其对EGFRDel19/T790M/C797S的IC₅₀为92.1nM，在PDC模型中TGI达95.7%，目前正在评估安全性和疗效。 ②BLU-945：早期试验中对三重突变患者的客观缓解率(ORR)达55%，但因高剂量组肝毒性问题已暂停试验。 ③BDTX-1535：具有良好的血脑屏障穿透能力，在Osimertinib耐药患者中ORR达55%，低剂量组安全性较好。 Vol.04 -EGFR-TKIs的耐药机制与新型药物开发- 细胞凋亡逃逸与应激适应网络 ● 肿瘤细胞的应激适应网络 ①凋亡逃逸：EGFR-TKIs通过激活p53、上调促凋亡蛋白(如BIM、PUMA)诱导细胞凋亡，但肿瘤细胞可通过抑制BIM表达或激活NF-κB通路抵抗凋亡。 ②自噬与免疫逃逸：自噬可保护肿瘤细胞免受药物损伤；肿瘤微环境中免疫抑制细胞(如调节性T细胞)和PD-L1表达上调，促进免疫逃逸。图9 EGFR-TKIs的耐药性的应激适应网络 ● 药物耐受性细胞(DTCs)：约0.3%-5%的肿瘤细胞在EGFR-TKIs压力下进入静息状态，通过表观遗传修饰存活。DTCs可激活IGF-1R、AXL、YAP-TEAD等通路，或通过上皮-间质转化(EMT)获得耐药性。图10 DTCs介导的对EGFR-TKIs的适应性耐药机制获得性耐药的分子机制 ● 旁路激活相关耐药： ①MET与HER2扩增：约1%-6%的患者通过MET扩增激活PI3K-Akt通路；HER2过表达(2%-30%)可通过异源二聚化绕过EGFR抑制。 ②下游信号通路激活：PI3K/AKT(如PIK3CA突变)、RAS/MAPK(如KRAS突变)、JAK/STAT通路异常等。 ③组织学转化：NSCLC向小细胞肺癌或鳞状细胞癌转化，与RB1、TP53共突变及神经内分泌通路激活相关，预后更差。 ④上皮-间质转化(EMT)：通过激活SNAIL、SLUG等蛋白，增强肿瘤侵袭性和耐药性。 ● CNS转移相关耐药： ①血脑屏障限制药物渗透，CNS转移患者耐药后治疗困难，脑脊液(CSF)中ctDNA检测敏感性(81.5%)高于血浆(62.5%)。 ②免疫抑制微环境(如HMGB1/CALR介导的T细胞抑制)和代谢重编程(如线粒体氧化磷酸化激活)参与耐药。表4 导致EGFR激活和耐药性的复杂分子相互作用耐药机制的检测方法 ● 液体活检的应用 ①ctDNA检测：敏感性69%，特异性99%，可动态监测耐药突变，但对CNS转移检测受限。 ②脑脊液分析：对CNS转移相关突变(如EGFR、TP53)检测更敏感，可指导鞘内治疗。 ③细胞外囊泡(EV)mRNA测序：可解析体细胞突变、耐药机制及肿瘤复发信号，弥补ctDNA丰度不足的局限。 ④可溶性生物标志物：如血清sCDH3水平升高与EGFR-TKI耐药及不良预后相关，可作为早期预警指标。 ● 组织活检与多组学整合 ①组织活检仍是确诊耐药机制的金标准，但受限于肿瘤异质性；结合单细胞测序和空间转录组学，可解析耐药克隆的时空演化。 ②表观遗传标志物(如HOX基因高甲基化)和代谢通路异常(如谷胱甘肽合成增强)可作为耐药预测靶点。针对耐药突变的其他新型药物 ● 外显子20插入突变特异性抑制剂 ①莫博赛替尼(Mobocertinib)：通过嘧啶环上的羧基异丙酯基团特异性结合外显子20插入突变型EGFR，中位缓解持续时间11.1个月。 ②CLN081(TAS6417)：独特的6-甲基-8,9-二氢嘧啶并[5,4-b]吲哚嗪结构，适配插入突变导致的ATP口袋构象变化。 ● PROTAC降解剂：如HJM-561可降解EGFRL858R/T790M/C797S突变蛋白，在PDX模型中使肿瘤体积减少82%，为克服耐药提供新途径。 ● ADC药物 ①HER3-DXd(U3-1402)：在经治患者中ORR29%，中位OS11.9个月，脑转移患者颅内ORR33%。 ②T-DXd：在HER2突变NSCLC中mPFS8.2个月，OS17.8个月，成为后线治疗新选择。 ● 抗EGFR抗体类药物 ①西妥昔单抗(Cetuximab)：可结合EGFR胞外域，阻断生长因子结合，抑制EGFR二聚化和下游信号传导，在NSCLC治疗中，联合铂类化疗用于晚期NSCLC且EGFR过表达患者，但因临床获益小未获监管批准。 ②其他：尼妥珠单抗(Nimotuzumab)、帕尼单抗(Panitumumab)等也用于治疗EGFR过表达的实体瘤。 ●双特异性抗体 ①Amivantamab：可同时靶向EGFR和MET，抑制二者磷酸化，获批用于治疗经化疗进展的EGFR外显子20插入突变的NSCLC患者，对存在MET突变的患者更有效。 ②Bafisontamab：也是一种EGFR/MET双特异性抗体，正处于测试阶段。 ●靶向EGFR蛋白互作(PPIs)：EGFR寡聚体内的PPIs(如Bb2Bb、S2S界面)是潜在靶点，变构抑制剂可通过破坏这些界面抑制激酶活性。如EAI001、EAI045等变构抑制剂，结合EGFR的别构位点，促进激酶处于非活性构象，抑制肿瘤生长，与Cetuximab联合使用效果更显著。 EGFR-TKIs的临床应用策略与联合治疗 ●疗效预测标志物 ①激活突变类型：外显子19缺失和L858R对第一代TKI敏感，外显子20插入突变对莫博赛替尼敏感。 ②ATP结合亲和力：突变导致ATP亲和力降低(如ΔE746-A750)可增强药物敏感性，而T790M突变增加ATP亲和力，导致耐药。 ●EGFR-TKI的临床应用场景 ①新辅助治疗(术前治疗)：术前用药缩小肿瘤体积、降低临床分期，提高手术切除率；清除微转移灶，改善患者生存。 ②辅助治疗(术后治疗)：降低术后复发风险，延长无病生存期(DFS)。 ③局部晚期或转移性治疗：针对不可手术或局部进展的患者，替代传统放化疗，提高疾病控制率。 ● 联合治疗策略 ①EGFR-TKI+化疗：通过化疗直接杀伤肿瘤细胞，清除耐药亚克隆并抑制血管生成，如吉非替尼联合卡铂/培美曲塞可提升客观缓解率至84%，延长无进展生存期至20.9个月。短期疗效明确，但长期OS获益不一致，且AEs(如中性粒细胞减少、肝毒性)显著，需优化化疗剂量或方案。 ②EGFR-TKI+抗血管生成药物：抑制VEGF介导的血管生成，改善药物渗透。但只能短期改善PFS，未转化为OS获益，且AEs(如高血压、蛋白尿)显著增加，长期安全性需关注。 ③EGFR-TKI+靶向耐药通路药物：针对MET扩增、HER2过表达等旁路激活，如奥希替尼联合赛沃替尼可使客观缓解率达64%，阻断PI3K-Akt通路。 ④EGFR-TKI+靶向药物耐受性细胞药物：通过表观遗传修饰剂或线粒体功能抑制剂清除静息状态细胞，如联合组蛋白去乙酰化酶抑制剂逆转表观沉默，恢复药物敏感性。 ⑤EGFR-TKI+免疫治疗：降低肿瘤细胞PD-L1表达，增强T细胞杀伤。但毒性显著，如吉非替尼联合帕博利珠单抗因71.4%的肝毒性停药，需优化剂量或采用序贯治疗(如先EGFR-TKI后ICIs)降低风险。 ⑥EGFR-TKI+靶向蛋白互作药物：通过双特异性抗体靶向EGFR与MET等，如Amivantamab阻断二聚化并增强ADCC效应，获批用于外显子20插入突变患者。 ●非靶向耐药的联合治疗 ①MET扩增的靶向干预：奥希替尼联合赛沃替尼在TATTON试验中ORR达33%-67%，mPFS5.5-11.1个月。双特异性抗体Amivantamab(EGFR/MET双抗)联合化疗，使CNS转移患者颅内PFS延长至12.5个月。 ②其他旁路信号抑制：RET融合患者使用奥希替尼联合Selpercatinib，ROS1融合患者联合克唑替尼，均显示临床获益。AXL抑制剂Bemcentinib联合奥希替尼，可逆转AXL介导的耐药，但需警惕FGFR1代偿激活。 ③下游通路与细胞周期干预：PI3K/mTOR抑制剂Dactolisib联合奥希替尼，在体外模型中克服PIK3CA突变介导的耐药。CDK4/6抑制剂Palbociclib联合奥希替尼，使CDK4扩增患者PR维持超10个月。新兴技术与未来方向表5 EGFR-TKIs治疗的挑战和方向抗体发现服务 & 产品 01 羊驼免疫&骆驼免疫—自建现代化养殖农场 02 万亿级天然抗体库产品—轻松DIY科研抗体 03 配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！ protocol 获取 / 产品咨询邮箱｜find@renyubio.com 电话｜19136178673 地址｜成都市经开区科技产业孵化园关注我们，小编将持续更新相关内容～参考文献 Zhang D, Zhao J, Yang Y, Dai Q, Zhang N, Mi Z, Hu Q, Liu X. Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future. J Enzyme Inhib Med Chem. 2025 Dec;40(1):2481392. Roberts SK, Galgadas I, Clarke DT, Zanetti-Domingues LC, Gervasio FL, Martin-Fernandez ML. Targeting mutant EGFR in non-small cell lung cancer in the context of cell adaptation and resistance. Drug Discov Today. 2025 Jun 18:104407. Wu Y, Li Y, Onzere LE, Quan W, Zhang X, Ma J. EGFR-TKI combination treatment for NSCLC with EGFR-sensitive mutation. Expert Rev Anticancer Ther. 2025 Jun 17. Tian Z, Cen L, Wei F, Dong J, Huang Y, Han Y, Wang Z, Deng J, Jiang Y. EGFR mutations in non-small cell lung cancer: Classification, characteristics and resistance to third-generation EGFR-tyrosine kinase inhibitors (Review). Oncol Lett. 2025 Jun 2;30(2):375. Li Y, Yu L, Zhou S, Zhou H, Wu Q. Multimodal omics analysis of the EGFR signaling pathway in non-small cell lung cancer and emerging therapeutic strategies. Oncol Res. 2025 May 29;33(6):1363-1376. Zhou X, Zeng L, Huang Z, Ruan Z, Yan H, Zou C, Xu S, Zhang Y. Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges. Cancer Med. 2025 May;14(9):e70921. Stanzione B, Del Conte A, Bertoli E, De Carlo E, Bortolot M, Torresan S, Spina M, Bearz A. Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Common Mutations: New Strategies. Cancers (Basel). 2025 Apr 30;17(9):1515. Feng S, Liu H, Yun C, Zhu W, Pan Y. Application of EGFR-TKIs in brain tumors, a breakthrough in future? J Transl Med. 2025 Apr 16;23(1):449. Zhu P, Li Z, Sun Y, Liu T, Yin R. Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC. Cancer Sci. 2025 Mar;116(3):581-591. Lim JU, Jung J, Kim YW, Kim CY, Lee SH, Park DW, Choi SI, Ji W, Yeo CD, Lee SH. Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges. Biomedicines. 2025 Feb 14;13(2):470. Guo X, Liu X, Guo C, Miao Q, Cheng X, Hong X, Li H, Qiu X, Xiang Y, Zheng D, Zhou J, Jiang L, Xu Y, Wang M. Perioperative Treatment in EGFR-Mutant Early-Stage Non-Small Cell Lung Cancer: Current Evidence and Future Perspectives. Thorac Cancer. 2025 Feb;16(4):e70018. Spada A, Gerber-Lemaire S. Surface Functionalization of Nanocarriers with Anti-EGFR Ligands for Cancer Active Targeting. Nanomaterials (Basel). 2025 Jan 21;15(3):158. Tian J, Shi Z, Zhao L, Liu P, Sun X, Long L, Zang J, Xiao J. Revolutionizing NSCLC Treatment: Immunotherapy Strategies for EGFR-TKIs Resistance. Clin Respir J. 2024 Dec;18(12):e70037. Sha C, Lee PC. EGFR-Targeted Therapies: A Literature Review. J Clin Med. 2024 Oct 25;13(21):6391. Tawengi M, Al-Dali Y, Tawengi A, Benter IF, Akhtar S. Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies. Front Pharmacol. 2024 Aug 21;15:1394997. Dong Y, Khan L, Yao Y. Immunological features of EGFR-mutant non-small cell lung cancer and clinical practice: a narrative review. J Natl Cancer Cent. 2024 Jun 21;4(4):289-298.

临床结果ASCO会议

2025-08-20

·GlobeNewswire-Health Care

Cytokinetics Names Jim Daly to Board of Directors

SOUTH SAN FRANCISCO, Calif., Aug. 20, 2025 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (Nasdaq: CYTK) today announced the appointment of James M. Daly to its Board of Directors effective August 19, 2025. Mr. Daly brings over 30 years of global biopharmaceutical leadership experience with particular expertise in commercialization to the Company’s Board of Directors. “Jim has longstanding expertise leading commercial launches of innovative therapies, coupled with extensive Board experience guiding later-stage, global biopharma companies,” said Robert I. Blum, Cytokinetics’ President and Chief Executive Officer. “We are pleased to welcome him to our Board and look forward to his contributions and oversight as our company advances toward becoming a fully integrated commercial organization.” Most recently, Mr. Daly served as the Chief Commercial Officer at Incyte Corporation where he led the launch of Jakafi® (ruxolitinib) and oversaw development of the company’s global commercial capabilities. Previously, he spent 10 years at Amgen where he held multiple senior leadership positions, including Senior Vice President of North America Commercial Operations, and launched several successful medicines including Neulasta®, Xgeva®, Nplate® and Vectibix®. He began his career at GlaxoSmithKline, serving in escalating positions of seniority over his 16-year tenure with the company. He earned a B.S. in Pharmacy and an M.B.A. from the University at Buffalo, SUNY. Mr. Daly currently serves on the Boards of Madrigal Pharmaceuticals, argenx SE, and Acadia Pharmaceuticals. About Cytokinetics Cytokinetics is a specialty cardiovascular biopharmaceutical company, building on its over 25 years of pioneering scientific innovations in muscle biology to advance a pipeline of potential new medicines for patients suffering from diseases of cardiac muscle dysfunction. Cytokinetics is readying for potential regulatory approvals and commercialization of aficamten, a cardiac myosin inhibitor following positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial in patients with obstructive hypertrophic cardiomyopathy (HCM). Aficamten is also being evaluated in additional clinical trials enrolling patients with obstructive and non-obstructive HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac myosin activator, in patients with heart failure with severely reduced ejection fraction (HFrEF), ulacamten, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten, for the potential treatment of heart failure with preserved ejection fraction (HFpEF) and CK-089, a fast skeletal muscle troponin activator with potential therapeutic application to a specific type of muscular dystrophy and other conditions of impaired skeletal muscle function. For additional information about Cytokinetics, visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube. Forward-Looking Statements This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements and claims the protection of the Act’s Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements relating to Cytokinetics’ and its partners’ research and development activities of Cytokinetics’ product candidates. Such statements are based on management’s current expectations, but actual results may differ materially due to various risks and uncertainties, including, but not limited to the risks related to Cytokinetics’ business outlines in Cytokinetics’ filings with the Securities and Exchange Commission. Forward-looking statements are not guarantees of future performance, and Cytokinetics’ actual results of operations, financial condition and liquidity, and the development of the industry in which it operates, may differ materially from the forward-looking statements contained in this press release. Any forward-looking statements that Cytokinetics makes in this press release speak only as of the date of this press release. Cytokinetics assumes no obligation to update its forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. CYTOKINETICS® and the CYTOKINETICS and C-shaped logo are registered trademarks of Cytokinetics in the U.S. and certain other countries. Contact:Cytokinetics Diane WeiserSenior Vice President, Corporate Affairs(415) 290-7757

临床3期高管变更

2025-08-19

·今日头条

近半患者肿瘤缩小，疾病控制率85%！氟泽雷塞让肠癌实现长生存

5年前，大量的kras肠癌患者因为无药可用在绝望的等待中离去，如今，大量的KRAS抑制剂研发成功，纷纷问世，给这些曾经预后极差的患者带来了新的希望！在结直肠癌中，大概有40％的患者会出现KRAS突变，当存在这种突变的时候，使用EGFR抑制剂会产生抗药性。在一些研究中， KRAS 突变患者的总生存期对比无突变的患者缩短了 6 个月之多！并且对标准一线化疗的反应降低，也不太可能接受二线或三线治疗，临床治疗非常困难，预后差。研究人员发现，KRAS G12C是一种特定的KRAS亚突变，是第12个密码子的甘氨酸被半胱氨酸取代，约占所有KRAS突变的44％，其中非小细胞肺癌腺癌中最常见，占14％，其次是大肠腺癌占5％，胰腺癌占2％。近期，一款由中国研发的名为氟泽雷塞的（IBI351；GFH925）的 KRAS G12C 抑制剂公布的汇总分析数据证实，其疗效显著，安全性可控，更成为结直肠癌治疗史上的重要里程碑。难治靶点迎突破！氟泽雷塞为 KRAS G12C 突变结直肠癌患者点亮长生存希望 IBI351 (GFH925) 是一款国研的新型、具有口服活性的强效 KRAS G12C 抑制剂，通过阻断KRAS依赖的信号转导，抑制肿瘤细胞的增殖，并诱导细胞凋亡。临床前研究显示 IBI351 对 KRAS G12C 具有高选择性，IBI351 有效抑制下游信号通路，诱导肿瘤细胞凋亡和细胞周期停滞。 2024年8月，中国首款针对KRAS的h革命性靶向药-- 氟泽雷塞片（GFH925/IBI351）正式上市，用于 KRAS G12C突变型晚期非小细胞肺癌（NSCLC）成人患者，具有里程碑式的意义！无数携带KRAS突变的癌症患者迎来生存新希望！值得肠癌病友们振奋的是，这款药物还获得突破性疗法认定，用于治疗既往接受过治疗的携带 KRAS G12C 突变的晚期结直肠癌患者。近期，氟泽雷塞发表在《信号转导与靶向治疗》上的一项 1 期研究（NCT05005234）和一项 1b 期研究（NCT05497336）的汇总分析数据显示，这款药物对于未经 KRAS G12C 抑制剂治疗的转移性结直肠癌（mCRC）患者表现出良好的活性和可控的安全性。该分析纳入 56 例未经 KRAS G12C 抑制剂治疗的 KRAS G12C 突变转移性结直肠癌患者，均接受富泽拉西单药治疗。关键数据亮点：客观缓解率（ORR）达 44.6% ：近半数患者（44.6%）在治疗后肿瘤明显缩小，其中部分患者的缓解持续时间长达 12.6 个月，意味着肿瘤控制效果持久稳定。疾病控制率（DCR）高达 87.5% ：87.5% 的患者病情得到有效控制，避免了快速进展，为后续治疗争取了宝贵时间。生存数据亮眼：中位无进展生存期（PFS）达 8.1 个月，中位总生存期（OS）延长至 17.0 个月，远超传统治疗方案的预期。值得一提的是，在接受推荐 II 期剂量（600mg，每日两次）的 48 例患者中，客观缓解率进一步提升至 45.8%，疾病控制率达 89.6%，中位无进展生存期和总生存期分别为 8.2 个月和 17.0 个月。此外，在至少接受过两线治疗的 27 例患者中：客观缓解率飙升至 63.0%，意味着超六成患者在多线治疗失败后仍能从氟泽雷塞中获益；疾病控制率保持 88.9%，中位无进展生存期 8.2 个月，为晚期难治患者点亮希望。注：做了基因检测的病友可以拿出报告看看一旦存在KRAS突变，可以马上提交病历至全球肿瘤医生网医学部看看是否有机会接受国内新药治疗，看不懂的病友也可以致电全球肿瘤医生网医学部解读报告，还没有进行基因检测的病友也要考虑出现这些新药靶点的可能，积极进行基因检测，获得更多的治疗机会！多箭齐发！史上最难治靶点KRAS已被成功攻破！ 1.客观缓解率30%！肠癌重磅KRAS抑制剂AMG510震撼上市 2025 年 1 月 16 日，针对KRAS G12C这一特定的突变亚型，sotorasib (Lumakras) 与帕尼单抗 (Vectibix) 联合方案获批，用于KRAS G12C 突变的转移性结直肠癌 (mCRC) 成年患者，这些患者之前接受过氟嘧啶、奥沙利铂和伊立替康为基础的化疗。这种治疗可能为患者提供更长的生存机会。 2.疾病控制率高达100%！全球第2款KRAS抑制剂MRTX-849强势突围！ MRTX-849（Adagrasib ，阿达格拉西布，Krazati)是全球第2款上市的针对KRAS G12C突变体的特异性优化口服抑制剂。近期，Mirati Therapeutics公司公布了MRTX849与EGFR抑制剂西妥昔单抗（cetuximab）联用，治疗携带KRAS G12C基因突变的晚期经治结直肠癌患者的最新临床试验结果，引起了巨大轰动。结果显示：在28名adagrasib+西妥昔单抗治疗的可评估患者中，客观缓解率（ORR）为 46% （13/28），疾病控制率（DCR）高达 100% （28/28）！这意味着没有一名患者出现进展，100%的患者病情稳定或肿瘤出现不同程度的缩小！这是非常了不起的。 KRAS肠癌患者迎来曙光！多款新药启动招募！此外，在肠癌患者中，除了KRAS G12C比较常见，KRAS G12D，G12V，G13D等也占了很大比例，目前还没有上市的药物。好消息是，多项靶向KRAS各类亚型的新药临床试验已获得批准正式开展人体临床试验。已经有大量患者通过全球肿瘤医生网医学部的评估申请成功入组并接受治疗。我们希望有更多的病友知道这个好消息，有更多的病友能够获益于这些新型的抗癌疗法，战胜癌症！ KRAS G12v TCR-T 1.经HLA分型确认含有HLA-A*11:01亚型且肿瘤KRAS G12V阳性； 2.依照RECIST 1.1标准，至少有一个可以进行影像学测量评估的肿瘤病灶。 PRAME+TCR-T 1.年龄在18岁至75周岁，晚期复发的经病理学或组织学证实的胰腺癌及结直肠癌； 2.经研究者判断无可适用的治疗方案，或无法耐受目前可用的治疗方案； 3.经HLA-A分型确认含有HLA-A*02:01亚型且肿瘤PRAME 表达经IHC检测阳性； KRAS G12D 1.肿瘤KRAS G12D阳性 2.既往不能用过RAF, RAS,MEK和VEGFR抑制剂想寻求TCR-T及其他国内外新抗癌治疗帮助，且经济条件允许的情况下，可以先将病历提交至全球肿瘤医生网医学部进行初步评估，一旦审核通过，有机会获得”天价“疗法免费治疗的机会。研究人员说，晚期结直肠癌患者的预后一直很差，传统的三线疗法瑞戈非尼 (Stivarga) 和TAS-102（Lonsurf) 历史数据的客观缓解率（ ORR）仅为 1% 。中位无进展生存期仅为2 个月左右，而携带KRAS 突变的结直肠癌患者的预后往往更差。这些新药将为KRAS突变的结直肠癌患者带来救赎。期待这些全新治疗方案为病友们带来更好的治疗选择！

突破性疗法临床1期临床结果

100 项与帕尼单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D05350	帕尼单抗	L01XC08	DB01269

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
KRAS G12C突变结直肠癌	美国	Amgen, Inc.	2025-01-16
KRAS 野生型结直肠癌	美国	Amgen, Inc.	2014-05-23
结直肠癌	日本	Takeda Pharmaceutical Co., Ltd.	2010-04-16
RAS 野生型结直肠癌	澳大利亚	Amgen Australia Pty Ltd.	2008-05-14
转移性结直肠癌	美国	Amgen, Inc.	2006-09-27

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
大肠腺癌	临床3期	美国	Amgen, Inc.	2018-02-27
遗传性非息肉病性结直肠癌1型	临床3期	美国	Amgen, Inc.	2018-02-27
NRAS 野生型结直肠癌	临床3期	日本	Takeda Pharmaceutical Co., Ltd.	2015-05-29
转移性食管鳞状细胞癌	临床3期	德国	Amgen, Inc.	2012-05-01
KRAS 突变结直肠癌	临床3期	美国	Amgen, Inc.	2010-02-02
KRAS 突变结直肠癌	临床3期	澳大利亚	Amgen, Inc.	2010-02-02
KRAS 突变结直肠癌	临床3期	比利时	Amgen, Inc.	2010-02-02
KRAS 突变结直肠癌	临床3期	加拿大	Amgen, Inc.	2010-02-02
KRAS 突变结直肠癌	临床3期	捷克	Amgen, Inc.	2010-02-02
KRAS 突变结直肠癌	临床3期	法国	Amgen, Inc.	2010-02-02

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临床结果

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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


EUCTR2016-001490-33-FR (PANIRINOX-UCGI28, ESMO_GI2025)	临床2期	RAS/BRAF wild-type \| circulating DNA (cirDNA)	-	Panitumumab + FOLFIRINOX	糧鹽衊選蓋窪淵蓋鬱糧(鹹範艱艱遞醖憲簾繭壓) = 糧遞淵齋簾膚齋淵簾鹹鑰鹹範願範構鑰艱鏇鹹 (糧遞廠鏇鬱窪製夢網製 ) 更多	不佳	2025-07-05
EUCTR2016-001490-33-FR (PANIRINOX-UCGI28, ESMO_GI2025)	临床2期	RAS/BRAF wild-type \| circulating DNA (cirDNA)	-	Panitumumab + mFOLFOX6	糧鹽衊選蓋窪淵蓋鬱糧(鹹範艱艱遞醖憲簾繭壓) = 夢襯艱觸願築選醖餘鬱鑰鹹範願範構鑰艱鏇鹹 (糧遞廠鏇鬱窪製夢網製 ) 更多	不佳	2025-07-05
BEACON and BREAKWATER (ESMO_GI2025)	N/A	BRAF V600E突变结直肠癌二线 \| 三线 BRAF V600E	43	Panitumumab plus Encorafenib	壓廠糧淵餘積襯艱蓋製(構範獵簾鏇範築醖齋淵) = 7% 糧壓構衊鹽鬱襯壓膚積 (願願選製鏇齋衊願餘顧 ) 更多	积极	2025-07-03
AGEO group (ESMO_GI2025)	N/A	BRAF V600E突变结直肠癌	20	Cetuximab (CET)	餘積齋選衊繭製願窪鹽(範憲鑰鏇網壓窪餘範鑰) = 5% 範衊鏇蓋醖顧範網積蓋 (壓簾願夢遞獵獵選鹽膚 ) 更多	积极	2025-07-03
NCT05198934 (CodeBreaK 300 \| CodeBreak300, NEWS \| Pubmed) 人工标引	临床3期	KRAS G12C突变结直肠癌 KRAS G12C	160	960 mg索托拉西布联合帕尼单抗	遞願鹹窪範繭淵製憲網(齋選簾醖簾遞鏇壓鬱鹹) = 窪鹽醖顧簾糧構獵艱築襯蓋窪艱網構範簾鏇窪 (齋憲齋獵艱觸遞鹹壓衊 ) 更多	积极	2025-05-07
	临床3期	KRAS G12C突变结直肠癌 KRAS G12C	160	240 mg索托拉西布联合帕尼单抗	遞願鹹窪範繭淵製憲網(齋選簾醖簾遞鏇壓鬱鹹) = 遞構窪衊鏇襯製衊構網襯蓋窪艱網構範簾鏇窪 (齋憲齋獵艱觸遞鹹壓衊 ) 更多	积极	2025-05-07
NCT01814501 (CTgov)	临床2期	印戒细胞癌 \| 粘液腺癌 \| 复发性结肠癌 ... 更多	16	Leucovorin Calcium+irinotecan hydrochloride+fluorouracil+panitumumab	鹹憲窪鏇網窪獵糧膚鹽(築積淵壓選顧顧鬱襯壓) = 遞鏇簾鬱衊簾顧積襯醖壓簾淵簾衊鹹鹹製糧齋 (齋艱壓蓋鏇壓膚鑰衊製, 獵齋構願壓鑰範鬱衊廠 ~ 蓋繭積鬱築鬱醖淵觸壓) 更多	-	2025-02-05
NCT02593175 (Pubmed)	临床2期	三阴性乳腺癌新辅助	43	紫杉醇+卡铂+帕尼单抗	構餘憲襯繭夢積鏇糧餘(廠襯憲遞鹹窪艱願夢鏇) = 繭願鏇鹽鑰窪憲繭鑰淵衊構鬱鏇鏇齋衊製範製 (獵鹽夢衊鑰繭淵遞選範 )	积极	2024-10-02
NCT04117945 (CTgov)	临床2期	遗传性非息肉病性结直肠癌1型 \| 转移性结直肠癌	22	Regorafenib (Arm A (Regorafenib))	觸獵窪膚構構繭繭蓋鏇(繭構鏇網網餘簾製積蓋) = 繭襯蓋顧構獵獵觸艱憲願鏇製鏇繭蓋範蓋網獵 (襯築積構繭選齋觸壓範, 積觸遞鹽衊鏇襯範膚襯 ~ 窪鑰觸鹹蓋願蓋觸簾鹹) 更多	-	2024-09-27
NCT04117945 (CTgov)	临床2期	遗传性非息肉病性结直肠癌1型 \| 转移性结直肠癌	22	Cetuximab+Irinotecan+Panitumumab (Arm B (Cetuximab, Panitumumab, Irinotecan))	觸獵窪膚構構繭繭蓋鏇(繭構鏇網網餘簾製積蓋) = 夢觸夢憲窪鬱網願獵鏇願鏇製鏇繭蓋範蓋網獵 (襯築積構繭選齋觸壓範, 淵膚衊顧憲構觸醖膚顧 ~ 積製鏇製築鹹獵網糧構) 更多	-	2024-09-27
NCT03043950 (VALIDATE, ESMO2024) 人工标引	N/A	RAS 野生型结直肠癌一线	611	Panitumumab plus FOLFIRI/FOLFOX	蓋製餘夢憲簾餘淵衊夢(齋製餘膚憲廠齋製蓋鬱) = 膚築憲繭製範網鬱壓觸願艱顧廠壓構鹹憲鹹構 (蓋糧醖獵襯鹹衊築範壓, 24.8 ~ 29.2) 更多	积极	2024-09-16
NCT04185883 (CodeBreaK 101, ESMO2024) 人工标引	临床1期	KRAS G12C突变结直肠癌一线 KRAS G12C–mutated	40	Sotorasib (soto) + Panitumumab (pani) + FOLFIRI	願築蓋鬱蓋憲範鏇獵範(鹽獵遞構簾鹽壓夢觸鹹) = 憲鹹餘遞積窪鹽觸鹹夢壓製膚積夢簾繭繭醖蓋 (顧糧齋艱餘鹽觸憲網廠 ) 更多	积极	2024-09-15
NCT01581840 (FFCD 0904, CTgov)	临床1/2期	肛门鳞状细胞癌 \| 肛门上皮内瘤变	45	radiochemotherapy+Panitumumab	遞構鏇憲壓獵觸願築憲 = 窪餘鏇窪衊餘蓋範蓋壓衊網顧遞鹽構選積鑰獵 (淵衊憲選鹹憲願遞選餘, 糧範觸網蓋鹹觸鏇糧艱 ~ 構蓋積夢窪廠憲衊製網) 更多	-	2024-07-01