作者: Petronini, P G ; Bordi, P ; Alfieri, R ; Ferracin, M ; La Monica, S ; Roncarati, R ; Minari, R ; Agustoni, F ; Galetti, M ; Cavazzoni, A ; Mazzaschi, G ; Palladini, A ; Pagano Mariano, M ; Lagrasta, C A ; Bonelli, M ; Aretini, P ; Pace, I ; Pluchino, M ; Angelicola, S ; Treccani, M ; Giovannetti, E ; Tiseo, M ; Digiacomo, G ; Gelsomino, F

BACKGROUND:

Resistance to KRAS^G12C inhibitors sotorasib and adagrasib, approved for KRAS^G12C-mutant advanced Non-Small Cell Lung Cancer (NSCLC), involves multiple subclonal events, raising significant concerns about overcoming the resistant phenotype. Cytokines, chemokines, and growth factors are key mediators of drug resistance and targeting their signaling pathways is an emerging strategy in cancer therapy.

METHODS:

We generated cell clones from KRAS^G12C-mutated NSCLC cells treated with KRAS inhibitors and cell cultures from a sotorasib-resistant patient-derived xenograft (PDX). Gene mutations and changes in gene expression were evaluated using NGS, RNAseq. The mRNA and protein levels encoded by the Hepatocyte Growth Factor (HGF) and CXCL1 genes were quantified using RT-PCR and ELISA assay. The effect of drug combination was obtained by the Sulforhodamine-B assay and analyzed by Combenefit Software. Cell death was detected by Annexin-V assay. Cell signaling and epithelial-to-mesenchymal transition were evaluated by Western blotting.

RESULTS:

NSCLC cell clones and PDX cell cultures with acquired and intrinsic resistance to KRAS^G12C inhibitors exhibited elevated levels of CXCL1 and HGF expression and secretion, with activation of CXCR2 and c-MET signalling pathways. The combination of CXCR2 and c-MET inhibitors led to synergistic inhibition of cell growth and reduced cell viability by inhibiting the ERK1/2 and AKT signalling pathways. This combination also reversed EMT and induced apoptosis in sotorasib- and adagrasib-resistant clones, regardless of the genetic alterations responsible for resistance.

CONCLUSIONS:

CXCL1/CXCR2 and HGF/c-MET may represent compensatory pathways that sustain proliferation and survival in resistance to KRAS^G12C inhibitors. The simultaneous blockade of these signals may offer a novel strategy for bypassing resistance.

2026-02-01·Lancet Respiratory Medicine

Glecirasib plus sitneprotafib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial

Article

作者: Yu, Yan ; Duan, Jianchun ; Xing, Ligang ; Ye, Feng ; Li, Xiaoyan ; Wang-Gillam, Andrea ; Liu, Zhe ; Cao, Baoshan ; Zhao, Yanqiu ; Xu, Jiachen ; Tang, Kejing ; Bi, Chao ; Zhong, Jia ; Wu, Lin ; Jin, Bo ; Liu, Lian ; Wan, Rui ; Fang, Xuefeng ; Song, Qibin ; Zhao, Jun ; Dong, Xiaorong ; Chen, Jiayan ; Li, Xingya ; Pang, Jiaohui ; Wang, Zhijie ; Chang, Jianhua ; Shi, Jianhua ; Wang, Jie ; Zhuang, Wu ; Fei, Kailun ; Pan, Yueyin ; Fang, Jian ; Sun, Boyang ; Chu, Qian ; Zhang, Li ; Pan, Pinhua ; Bai, Chunmei ; Ding, Yuli ; Shao, Yang

BACKGROUND:

Monotherapy with KRAS^G12C (ie, KRAS Gly12Cys) inhibitors has emerged as a mainstream treatment for patients with KRAS^G12C -mutated non-small-cell lung cancer (NSCLC). Synergistic effects have been observed with the combination of a KRAS^G12C inhibitor and a SHP2 inhibitor in multiple xenograft models. We aimed to evaluate the safety and efficacy of the KRAS^G12C inhibitor glecirasib combined with the SHP2 inhibitor sitneprotafib (JAB-3312; Jacobio Pharmaceuticals, Beijing, China) in patients with KRAS^G12C -mutated solid tumours.

METHODS:

We conducted an open-label, multicentre, single-arm, phase 1/2a trial at 26 hospitals across China. Patients (aged ≥18 years) with locally advanced or metastatic solid tumours harbouring a KRAS^G12C mutation, an Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1) were eligible for inclusion in both phases. Patients received oral glecirasib (400 mg or 800 mg once daily) in combination with oral sitneprotafib (2 mg or 3 mg once daily) in seven cohorts evaluating various dose levels and schedules of the two drugs. In phase 1, the primary endpoint was safety assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) from first treatment dose to 30 days after the last dose of both agents. In phase 2a, the primary endpoint was objective response rate (ORR) between baseline and disease progression or initiation of anticancer therapy, whichever occurred first, based on the comprehensive assessment of all tumour evaluations by investigators following RECIST (version 1.1). All patients who received at least one dose of combination therapy were included in the safety and efficacy analyses. This trial is registered with ClinicalTrials.gov (NCT05288205) and is currently recruiting.

FINDINGS:

Between May 7, 2022, and Aug 20, 2024, a total of 194 patients with advanced solid tumours were enrolled, of whom 171 (88%) had NSCLC (50 [29%] in phase 1 and 121 [71%] in phase 2a). Median participant age was 65 years (IQR 59-70); 140 (82%) were men and 31 (18%) were women. At data cutoff on Aug 20, 2024, the median follow-up duration was 14·5 months (IQR 11·9-17·1), and 106 (62%) patients had discontinued treatment. Phase 1 concluded with one dose-limiting toxicity (DLT; grade 3 pneumonitis) at the highest dose level (glecirasib 800 mg plus sitneprotafib 3 mg once daily, 1 week on and 1 week off); no DLTs were observed at other dose levels. Across phase 1 and 2a, 167 patients (98%) had at least one treatment-related adverse event, which were grade 3-4 in 78 (46%) patients. The most common treatment-related adverse events (occurring in ≥20% of all 171 patients) were anaemia (105 [61%]), hypertriglyceridaemia (103 [60%]), increased aspartate aminotransferase (95 [56%]), increased alanine aminotransferase (83 [49%]), increased blood bilirubin (78 [46%]), oedema (62 [36%]), increased blood creatine phosphokinase (60 [35%]), neutropenia (54 [32%]), decreased white blood cell count (50 [29%]), and increased bodyweight (44 [26%]). Three (2%) patients discontinued glecirasib and sitneprotafib due to treatment-related adverse events. No grade 5 treatment-related adverse event was reported. The ORR was 71% (72 patients [95% CI 61-79]) in the subgroup of 102 patients with previously untreated NSCLC; 49% (19 patients [32-65]) in the 39 patients previously treated with systemic therapy but naive to KRAS^G12C inhibitors; and 10% (three patients [2-27]) in the 30 patients previously treated with KRAS^G12C inhibitor therapy.

INTERPRETATION:

Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRAS^G12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group.

FUNDING:

Jacobio Pharmaceuticals.

TRANSLATION:

For the Chinese translation of the abstract see Supplementary Materials section.

2026-02-01·Journal of Thoracic Oncology

TTF-1 expression in lung adenocarcinoma: clinicopathologic, genomic, and immunophenotypic correlates and outcomes to immunotherapy-based treatments and KRASG12C inhibitors

Article

作者: Marinelli, Daniele ; Rodig, Scott J ; Ardizzoni, Andrea ; Heymach, John V ; Luo, Jia ; Johnson, Bruce E ; Nishino, Mizuki ; Arbour, Kathryn C ; Wang, Xinan ; Maugeri-Saccà, Marcello ; Gandhi, Malini M ; Hambelton, Grace M ; Makarem, Maisam ; De Giglio, Andrea ; Gibbons, Don L ; Sperandi, Francesca ; Cipriani, Laura ; Ricciuti, Biagio ; Gelsomino, Francesco ; Hong, Lingzhi ; Lamberti, Giuseppe ; Gainor, Justin F ; Haradon, Jessica ; Gogia, Pooja ; Gagliano, Ambrogio ; Zhang, Jianjun ; Scalera, Stefano ; Sholl, Lynette M ; Pecci, Federica ; Elkrief, Arielle ; Alessi, Joao V ; Garbo, Edoardo ; Thummalapalli, Rohit ; Voligny, Emma ; Ladanyi, Marc ; Cooper, Alissa J ; Vokes, Natalie I ; Heist, Rebecca S ; Shaverdian, Narek ; Arvind, Ravi ; Awad, Mark M ; Schoenfeld, Adam J ; Di Federico, Alessandro ; Nguyen, Tom ; Digumarthy, Subba ; Rekhtman, Natasha ; Janne, Pasi A ; Pfaff, Kathleen

BACKGROUND:

Thyroid transcription factor-1 (TTF-1) expression, routinely assessed through immunohistochemistry (IHC) in the diagnostic evaluation of lung adenocarcinomas (LUAD), is negative (TTF-1^Neg) in ∼15-20% of cases. While worse outcomes have been reported for these tumors compared to TTF-1 positive (TTF-1^Pos) LUAD, a comprehensive characterization of TTF-1 negativity is currently lacking.

METHODS:

Patients with LUAD and available TTF-1 IHC from five institutions, The Cancer Genome Atlas, the Stand Up To Cancer-Mark Foundation, and the POPLAR/OAK datasets were included. Features and outcomes were analyzed according to TTF-1 expression.

RESULTS:

Among 3,297 patients, TTF-1^Neg (15%, N=496), compared to TTF-1^Pos (85%, N=2,801), was associated with a more frequent tobacco use history and lower PD-L1 expression. TTF-1^Neg LUAD was enriched for STK11, KEAP1, SMARCA4, NKX2-1, CDKN2A, and KRAS mutations (q<0.05). Patients with metastatic TTF-1^Neg LUAD treated with immune checkpoint inhibitors (N=233), compared to TTF-1^Pos cases (N=1,179), had worse objective response rates (ORR, 17% vs 28%, P=0.001), median progression-free survival (mPFS, 2.5 vs 4.4 months, P<0.0001) and median overall survival (mOS, 9.6 vs 20.2 months, P<0.0001). Similarly, TTF-1^Neg cases had worse outcomes to chemo-immunotherapy (ORR 26% vs 41%, P<0.0001; mPFS 4.6 vs 8.2 months, P<0.0001; mOS 11.2 vs 23.4 months, P<0.0001), durvalumab after chemoradiation for unresectable stage III disease (mPFS 8.0 vs 24.8 months, P=0.016; mOS 20.0 months vs not reached, P=0.004), and KRAS^G12C inhibitors in KRAS^G12C-mutant LUAD (ORR 13% vs 36%, P=0.03; mPFS 2.7 vs 5.9 months, P<0.0001; mOS 4.4 vs 12.1 months, P<0.0001).

CONCLUSIONS:

TTF-1 negativity identifies a subset of LUAD with worse outcomes to immunotherapy, chemo-immunotherapy, and KRAS^G12C inhibitors.

项与 KRAS G12C inhibitors (Shenzhen Forward Pharmaceuticals) 相关的新闻（医药）

2026-03-03

·中国生物器材网

KRAS G12C突变非小细胞肺癌的核心诊疗痛点及靶向药物临床应用进展

一、引言 KRAS G12C突变是非小细胞肺癌（NSCLC）中重要的驱动基因变异之一，在亚洲NSCLC患者中约占4%。由于其独特的分子结构特征，KRAS G12C长期以来被视为“不可成药”靶点，给临床治疗带来诸多挑战。近年来，随着靶向药物研发的突破，KRAS G12C抑制剂相继问世，显著改善了该类患者的预后。随着医保政策的覆盖，药物可及性进一步提升，推动KRAS G12C突变肺癌的诊疗格局发生深刻变革。本文系统梳理KRAS G12C突变晚期NSCLC的核心诊疗痛点、靶向药物的临床应用进展、医保政策带来的影响、一线联合治疗的探索前景，以及未来面临的挑战与突破方向，以期为临床精准诊疗提供参考。二、KRAS G12C突变晚期NSCLC的临床挑战 KRAS G12C靶点因其独特的结构特征，长期面临药物研发困境。KRAS蛋白表面光滑且存在动态构象变化，缺乏明显的结合位点；同时KRAS与内源性配体GDP/GTP亲和力极强，小分子药物难以竞争结合，进一步增加了研发难度。在KRAS G12C靶向药物问世前，此类患者多参照驱动基因阴性人群的治疗策略，以化疗和免疫治疗为主，但整体疗效欠佳。化疗方案的客观缓解率（ORR）普遍低于20%，中位无进展生存期（PFS）仅为4~6个月；免疫联合化疗的获益亦有限，难以满足临床需求。此外，KRAS G12C突变晚期NSCLC患者中肝转移、脑转移及STK11/KEAP1共突变发生率较高，这类人群治疗难度大且缺乏针对性干预措施。肝转移病灶血供丰富、微环境复杂，常规治疗难以有效控制；脑转移患者受血脑屏障限制，多数药物穿透性不足；STK11/KEAP1共突变患者肿瘤异质性强、预后差，化疗联合免疫治疗的有效性进一步降低。尽管KRAS G12C抑制剂的问世显著改善了患者预后，但相较于EGFR、ALK等其他驱动基因阳性肺癌的靶向治疗，KRAS G12C抑制剂单药的疗效仍存在明显差距，需探索更多联合策略以提升治疗效果。三、KRAS G12C抑制剂的分子机制与临床优势新型KRAS G12C抑制剂（如索托拉西布、阿达格拉西布）通过选择性靶向KRAS G12C突变蛋白的SWITCH II口袋，将蛋白稳定锁定于GDP结合的失活状态，阻断其向GTP结合的活性构象转化，进而抑制下游信号通路的异常激活。其分子结构设计中的双甲基取代哌嗪结构，不仅增强了与突变蛋白的结合亲和力，还形成低能量稳定构象，延长药物作用时间并提升结合稳定性。临床研究数据显示，在既往经治的KRAS G12C突变晚期NSCLC患者中，该抑制剂治疗的ORR达52%，中位PFS提升至9个月以上，中位总生存期（OS）达14.1个月。对于肝转移和脑转移患者，ORR分别达65.2%和61.1%，填补了这类难治性人群的精准治疗空白。在安全性方面，该药物对野生型KRAS蛋白结合力低，减少了正常细胞损伤，血液学毒性较低，不良反应多控制在1-2级，未观察到因不良反应导致永久停药的案例。值得注意的是，该抑制剂的II期注册研究前瞻性纳入化疗、免疫治疗失败的患者，其中近20%为既往接受过三线及以上治疗的人群，基线特征更贴合真实世界中多线治疗的困境。即使在此背景下，药物仍实现52%的ORR及14.1个月的中位OS。此外，各亚组均能获得一致性疗效获益，STK11共突变亚组ORR达43.8%，KEAP1共突变亚组ORR为40%，打破了同类药物在共突变人群中治疗受限的瓶颈。四、KRAS G12C & CRBN Binding 试剂盒在耐药机制研究中的应用随着KRAS G12C抑制剂临床应用的拓展，耐药问题逐渐显现。获得性耐药机制包括继发性KRAS突变（如G12D、G12V、G13D等）、旁路信号激活（如MET扩增、EGFR激活）及组织学转化等。在针对耐药机制的研究中，准确评估KRAS G12C蛋白与E3泛素连接酶的相互作用对于理解降解途径介导的耐药逆转具有重要意义。人KRAS G12C & CRBN Binding 试剂盒(GTP load)为这一研究提供了标准化检测工具。该试剂盒基于KRAS G12C蛋白在GTP结合状态下的构象特征，模拟靶向降解剂或内源性降解途径中靶蛋白被招募至CRBN连接酶的过程。通过时间分辨荧光共振能量转移（TR-FRET）技术，可定量检测KRAS G12C与CRBN的结合活性，用于评估候选化合物是否通过泛素-蛋白酶体途径诱导KRAS降解。在耐药机制研究中，该试剂盒可用于验证耐药后出现的KRAS二次突变是否影响与E3连接酶的相互作用，或用于筛选能够克服耐药的新型降解分子。五、结语 KRAS G12C突变曾长期面临“不可成药”困境，近年来随着靶向药物的研发突破，已逐步实现从后线向前线的治疗前移。医保政策的全面覆盖显著提升了药物可及性，使更多患者获益。未来需进一步开展基于生物标志物的分层研究，完善全程化管理模式，探索联合治疗策略（如联合SHP2抑制剂、PD-1抑制剂、化疗等）以克服耐药，最终实现KRAS G12C突变肺癌患者的精准治疗与长期生存获益。声明：本篇文章在创作中部分采用了人工智能辅助。如有任何内容涉及版权或知识产权问题，敬请告知，我们承诺将在第一时间核实并撤下。 KRAS G12C突变非小细胞肺癌靶向治疗进展与展望-南京优爱(UA BIO), 重组蛋白专家

2026-03-03

·今日头条

KRAS G12C突变非小细胞肺癌靶向治疗进展与展望

一、引言 KRAS G12C突变是非小细胞肺癌（NSCLC）中重要的驱动基因变异之一，在亚洲NSCLC患者中约占4%。由于其独特的分子结构特征，KRAS G12C长期以来被视为“不可成药”靶点，给临床治疗带来诸多挑战。近年来，随着靶向药物研发的突破，KRAS G12C抑制剂相继问世，显著改善了该类患者的预后。随着医保政策的覆盖，药物可及性进一步提升，推动KRAS G12C突变肺癌的诊疗格局发生深刻变革。本文系统梳理KRAS G12C突变晚期NSCLC的核心诊疗痛点、靶向药物的临床应用进展、医保政策带来的影响、一线联合治疗的探索前景，以及未来面临的挑战与突破方向，以期为临床精准诊疗提供参考。二、KRAS G12C突变晚期NSCLC的临床挑战 KRAS G12C靶点因其独特的结构特征，长期面临药物研发困境。KRAS蛋白表面光滑且存在动态构象变化，缺乏明显的结合位点；同时KRAS与内源性配体GDP/GTP亲和力极强，小分子药物难以竞争结合，进一步增加了研发难度。在KRAS G12C靶向药物问世前，此类患者多参照驱动基因阴性人群的治疗策略，以化疗和免疫治疗为主，但整体疗效欠佳。化疗方案的客观缓解率（ORR）普遍低于20%，中位无进展生存期（PFS）仅为4~6个月；免疫联合化疗的获益亦有限，难以满足临床需求。此外，KRAS G12C突变晚期NSCLC患者中肝转移、脑转移及STK11/KEAP1共突变发生率较高，这类人群治疗难度大且缺乏针对性干预措施。肝转移病灶血供丰富、微环境复杂，常规治疗难以有效控制；脑转移患者受血脑屏障限制，多数药物穿透性不足；STK11/KEAP1共突变患者肿瘤异质性强、预后差，化疗联合免疫治疗的有效性进一步降低。尽管KRAS G12C抑制剂的问世显著改善了患者预后，但相较于EGFR、ALK等其他驱动基因阳性肺癌的靶向治疗，KRAS G12C抑制剂单药的疗效仍存在明显差距，需探索更多联合策略以提升治疗效果。三、KRAS G12C抑制剂的分子机制与临床优势新型KRAS G12C抑制剂（如索托拉西布、阿达格拉西布）通过选择性靶向KRAS G12C突变蛋白的SWITCH II口袋，将蛋白稳定锁定于GDP结合的失活状态，阻断其向GTP结合的活性构象转化，进而抑制下游信号通路的异常激活。其分子结构设计中的双甲基取代哌嗪结构，不仅增强了与突变蛋白的结合亲和力，还形成低能量稳定构象，延长药物作用时间并提升结合稳定性。临床研究数据显示，在既往经治的KRAS G12C突变晚期NSCLC患者中，该抑制剂治疗的ORR达52%，中位PFS提升至9个月以上，中位总生存期（OS）达14.1个月。对于肝转移和脑转移患者，ORR分别达65.2%和61.1%，填补了这类难治性人群的精准治疗空白。在安全性方面，该药物对野生型KRAS蛋白结合力低，减少了正常细胞损伤，血液学毒性较低，不良反应多控制在1-2级，未观察到因不良反应导致永久停药的案例。值得注意的是，该抑制剂的II期注册研究前瞻性纳入化疗、免疫治疗失败的患者，其中近20%为既往接受过三线及以上治疗的人群，基线特征更贴合真实世界中多线治疗的困境。即使在此背景下，药物仍实现52%的ORR及14.1个月的中位OS。此外，各亚组均能获得一致性疗效获益，STK11共突变亚组ORR达43.8%，KEAP1共突变亚组ORR为40%，打破了同类药物在共突变人群中治疗受限的瓶颈。四、KRAS G12C & CRBN Binding 试剂盒在耐药机制研究中的应用随着KRAS G12C抑制剂临床应用的拓展，耐药问题逐渐显现。获得性耐药机制包括继发性KRAS突变（如G12D、G12V、G13D等）、旁路信号激活（如MET扩增、EGFR激活）及组织学转化等。在针对耐药机制的研究中，准确评估KRAS G12C蛋白与E3泛素连接酶的相互作用对于理解降解途径介导的耐药逆转具有重要意义。五、结语 KRAS G12C突变曾长期面临“不可成药”困境，近年来随着靶向药物的研发突破，已逐步实现从后线向前线的治疗前移。医保政策的全面覆盖显著提升了药物可及性，使更多患者获益。未来需进一步开展基于生物标志物的分层研究，完善全程化管理模式，探索联合治疗策略（如联合SHP2抑制剂、PD-1抑制剂、化疗等）以克服耐药，最终实现KRAS G12C突变肺癌患者的精准治疗与长期生存获益。声明：本篇文章在创作中部分采用了人工智能辅助。如有任何内容涉及版权或知识产权问题，敬请告知，我们承诺将在第一时间核实并撤下。 KRAS G12C突变非小细胞肺癌靶向治疗进展与展望-南京优爱(UA BIO), 重组蛋白专家

2026-03-03

·SM4Life

国产KRas G12C四强争霸？从药物设计到临床疗效，一文读懂四款新药的前世今生！

随着济民可信子公司浙江杭煜制药申报的1类创新药硫酸索西美雷塞片（商品名：济乐美）于2026年2月28日获国家药监局附条件批准上市，国内KRAS G12C抑制剂市场正式形成"四强争霸"的格局：信达生物/劲方医药的氟泽雷塞（达伯特）、益方生物/正大天晴的格索雷塞（安方宁）、加科思/艾力斯的戈来雷塞（艾瑞凯）以及最新获批的济民可信/杭煜制药的索西美雷塞（济乐美）。本文将从四款药物的专利布局、药物设计和临床疗效三个方面进行全面分析，期望能让读者一文读懂这四款药物的前世今生。 1、专利布局四家药企在KRAS G12C抑制剂的核心化合物结构改造和专利布局策略上各有千秋，反映了不同的技术路线和保护策略。 2、药物设计 KRAS G12C抑制剂的核心机制是通过与KRAS G12C突变蛋白的Switch II口袋结合，不可逆地共价靶向突变半胱氨酸残基（Cys12），将KRAS锁定在失活状态（GDP结合状态）。四款国产新药均在ＡＭＧ５１０的结构基础上改造而成，均为共价、不可逆、靶向ＫＲａｓ　Ｇ１２Ｃ（ｏｆｆ）的小分子药物。氟泽雷塞专利突破策略，借鉴了AZ的四环母核结构，将AMG510进行环化而成。格索雷塞基本上是在AMG５１０专利的母核上，钻了个空子，采用环丙基替代链状烷基取代基，巧妙地避开了安进的专利保护。戈来雷塞采用吡啶并吡啶酮结构，替换AMG５１０的吡啶并嘧啶酮母核，以及多卤素取代苯胺替换苯酚结构，非常巧妙地突破了安进的专利。索西美雷塞的策略跟劲方非常类似，也是结合了AZ的四环母核，将AMG５１０环化所得，两家公司专利申请的时间也非常接近，济煜的优先权为２０１９年９月２０日，劲方的优先权为２０１９年１０月３０日，所以不存在像有些文章写的那样是谁根据谁的结构去改造的，应该都是独立研发的。附：氟泽雷塞（GFH925）的临床前数据３、关键临床数据四款药物的注册性临床II期单臂试验数据显示疗效相近，索西美雷塞的缓解率略高，氟泽雷塞的无进展生存期最高；整体安全性可控，常见不良反应主要为肝酶升高、贫血等，格索雷塞的3级及以上不良反应发生率最高。药物名称氟泽雷塞 (GFH925) 格索雷塞 (D-1553) 戈来雷塞 (JAB-21822) 索西美雷塞 (JMKX1899)IRC确认ORR 49.0% ４９.６% 47.9% ５２.４%疾病控制率DCR 90.8% 88.6% 86.3% 87.6%中位PFS 9.7 个月 9.1 个月 8.２个月 7.2 个月≥3级AE发生率４１.４% ５０.０% ３８.７% ４２.０%常见AE 贫血、肝酶升高、乏力、蛋白尿肝损伤、贫血、呕吐、恶心贫血、肝功能异常、高甘油三酯血症、白细胞降低贫血、肝酶升高总结与展望随着四款国产KRAS G12C抑制剂先后获批，二线非小细胞肺癌治疗的竞争将从"有无"转向"优劣"，未来竞争将主要体现在以下三个方面：一线联合治疗的突破、脑转移疗效的优化以及耐药机制的克服。目前，四款药物已获批适应症均为二线及后线治疗，但前沿已明确指向一线联合治疗，如信达生物探索氟泽雷塞联合西妥昔单抗一线治疗KRAS G12C突变NSCLC的KROCUS研究已显示优异疗效（ORR达80%），加科思的戈来雷赛与SHP２抑制剂JAB３３１２的联合治疗等。国产KRAS G12C抑制剂的发展历程，是中国医药创新实力提升的缩影，短短两年不到的时间完成了从“无药可用”到“四强争霸”的跨越，为晚期非小细胞肺癌患者提供了更多治疗选择。往期精选：１、道高一尺、魔高一丈，全球首个p53 Y220C靶向新药Rezatapopt尚在路上，临床耐药已然发生！２、从IK-930、VT-3989与IAG933的核心数据分析，看TEAD-YAP抑制剂三足鼎立，鹿死谁手？３、口服ACH治疗药物迎来重大进展！FGFR抑制剂Infigratinib三期数据顶线读出，FGFR1抑制或许是把双刃剑？４、2026，FDA获批新药预测TOP10：基于最新三期临床数据，这些药物将改写临床治疗格局！５、从自研小分子靶点布局，看再鼎医药内部创新成色到底如何？

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