SCI

26 August 2024

Efficacy and safety of KRAS G12C inhibitor IBI351 monotherapy in patients with advanced non-small cell lung cancer: results from a phase 2 pivotal study

（Journal of thoracic oncology; if = 21）

  • Zhou Q, Meng X, Sun L, Huang D, Yang N, Yu Y, Zhao M, Zhuang W, Guo R, Hu Y, Pan Y, Shan J, Sun M, Yuan Y, Fan Y, Huang J, Liu L, Chu Q, Wang X, Xu C, Lin J, Huang J, Huang M, Sun J, Zhang S, Zhou H, Wu YL.

  • Correspondence: syylwu@live.cn

Introduction 引言

KRAS G12C mutation is a well-recognized and increasingly promising therapeutic target with significant unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study.

KRAS G12C突变是一个公认的、越来越有前景的治疗靶点，但在非小细胞肺癌患者中，临床需求尚未得到满足。IBI351是强效的KRAS G12C共价不可逆抑制剂。在这里，我们从一项开放标签、单臂、2期关键研究中介绍了IBI351的疗效和安全性。

 

Methods 方法

Eligible NSCLC patients with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. Primary endpoint was confirmed objective response rate (ORR) assessed by independent radiological review committee (IRRC) as per RECIST v1.1. Other endpoints were safety, IRRC-confirmed disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS).

纳入符合条件的KRAS G12C标准治疗失败的非小细胞肺癌患者。IBI351口服给药，剂量为600mg，每日两次。主要终点是由独立放射学审查委员会（IRRC）根据RECIST v1.1评估的确认客观反应率（ORR）。其他终点包括安全性、IRRC确认的疾病控制率（DCR）、反应持续时间（DoR）、无进展生存期（PFS）和总生存期（OS）。

 

Results 结果

As of December 13, 2023, 116 pts were enrolled (ECOG PS 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1/PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per IRRC assessment, confirmed ORR was 49.1% (95% CI: 39.7-58.6), and DCR was 90.5% (95% CI: 83.7-95.2). The median DoR was not reached while disease progression or death events occurred in 22 (38.6%) pts, and the median PFS was 9.7 months (95% CI: 5.6-11.0). OS data was immature. Treatment-related adverse events (TRAEs) occurred in 107 (92.2%) pts while 48 (41.4%) pts had grade≥3 TRAEs. Common TRAEs were anemia (44.8%), alanine aminotransferase increased (28.4%), aspartate aminotransferase increased (27.6%), asthenia (26.7%) and protein urine present (25.0%). TRAEs leading to treatment discontinuation occurred in 9 (7.8%) pts. In biomarker evaluable pts (n=95), all pts had positive KRAS G12C in tissue while 72 pts were blood positive and 23 pts were blood negative for KRAS G12C. Pts with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p <0.05) and worse PFS (p <0.05). Tumor mutation profiling identified TP53 (45.3%), STK11 (30.5%) and KEAP1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency ≥5%, mutations of 6 genes (STK11, KEAP1, PIK3CG, POLE, SMAD4, and BRINP3) were significantly associated with worse PFS (p <0.05). Mutation in STK11 also showed significant association with higher tumor burden at baseline and lower response rate (p <0.05).

截至2023年12月13日，共有116名患者入组（ECOG PS 1:91.4%；脑转移：30.2%；既往接受过抗PD-1/PD-L1抑制剂和铂类化疗的患者：84.5%）。根据IRRC评估，确认的ORR为49.1%（95%CI:39.7-58.6），DCR为90.5%（95%CI:83.7-95.2）。22名患者（38.6%）出现疾病进展或死亡事件，但未达到中位DoR，中位PFS为9.7个月（95%CI:5.6-11.0）。OS数据不成熟。107名（92.2%）患者发生了治疗相关不良事件（TRAE），48名（41.4%）患者的TRAE等级≥3级。常见的TRAE为贫血（44.8%）、丙氨酸氨基转移酶升高（28.4%）、天冬氨酸氨基转移酶增加（27.6%）、乏力（26.7%）和蛋白尿（25.0%）。9名患者（7.8%）发生了导致治疗中断的不良反应。在可评估生物标志物的患者中（n=95），所有患者的组织中KRAS G12C均为阳性，72例患者的KRAS G12C血液呈阳性，23例患者的血液呈阴性。血液和组织中KRAS G12C的Pts在基线时肿瘤负荷较高（p<0.05），PFS较差（p<0.05）。肿瘤突变分析确定TP53（45.3%）、STK11（30.5%）和KEAP1（21.1%）是与KRAS G12C共突变的最常见基因。在13个突变频率≥5%的基因中，6个基因（STK11、KEAP1、PIK3CG、POLE、SMAD4和BRINP3）的突变与较差的PFS显著相关（p<0.05）。STK11突变也与基线时较高的肿瘤负荷和较低的反应率显著相关（p<0.05）。

 

Conclusions 结论

IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

IBI351单药治疗显示出有希望和持续的疗效，安全性可控，支持其作为KRAS G12C突变型NSCLC新治疗选择的潜力。