美国丹娜-法伯癌症研究所Pasi A. Jänne团队研究了阿达格拉西布治疗携带KRAS^G12C突变的非小细胞肺癌的疗效和安全性。相关论文于2022年6月3日发表在《新英格兰医学杂志》上。

阿达格拉西布是一种KRAS^G12C抑制剂，能不可逆地选择性结合KRAS^G12C，将其锁定在非活性状态。阿达格拉西布在KRYSTAL-1的临床1-2期研究的1-1b期部分显示出临床活性，并具有可接受的不良事件特征。

在一个注册的2期队列研究中，研究组评估了阿达格拉西布（600 mg，每日两次口服）对先前接受过铂类化疗和抗程序性死亡1或程序性死亡配体1治疗的KRAS^G12C突变非小细胞肺癌（NSCLC）患者的疗效。主要终点是通过盲法独立中心审查评估的客观缓解。次要终点包括反应持续时间、无进展生存期、总生存期和安全性。

截至2021年10月15日，共有116例KRAS^G12C突变的非小细胞肺癌患者接受了治疗（中位随访12.9个月）；98.3%曾接受过化疗和免疫治疗。在基线检查时疾病可评估的112名患者中，48名（42.9%）有明确的客观缓解。中位缓解时间为8.5个月，中位无进展生存期为6.5个月。

截至2022年1月15日（中位随访15.6个月），中位总生存期为12.6个月。在33例先前接受过治疗的中枢神经系统转移稳定的患者中，颅内确认的客观缓解率为33.3%。97.4%的患者发生了与治疗相关的不良事件，1级或2级的患者占52.6%，3级及以上的患者占44.8%（包括两个5级事件），6.9%的患者因此停药。

研究结果表明，对于先前接受过治疗的KRAS^G12C突变NSCLC患者，阿达格拉西布显示出临床疗效，且没有新的安全信号。

附：英文原文

Title: Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation

Author: Pasi A. Jnne, M.D., Ph.D.,, Gregory J. Riely, M.D., Ph.D.,, Shirish M. Gadgeel, M.D.,, Rebecca S. Heist, M.D., M.P.H.,, Sai-Hong I. Ou, M.D., Ph.D.,, Jose M. Pacheco, M.D.,, Melissa L. Johnson, M.D.,, Joshua K. Sabari, M.D.,, Konstantinos Leventakos, M.D., Ph.D.,, Edwin Yau, M.D., Ph.D.,, Lyudmila Bazhenova, M.D.,, Marcelo V. Negrao, M.D.,, Nathan A. Pennell, M.D., Ph.D.,, Jun Zhang, M.D., Ph.D.,, Kenna Anderes, Ph.D.,, Hirak Der-Torossian, M.D.,, Thian Kheoh, Ph.D.,, Karen Velastegui, B.Sc.,, Xiaohong Yan, Ph.D.,, James G. Christensen, Ph.D.,, Richard C. Chao, M.D.,, and Alexander I. Spira, M.D., Ph.D.

Issue&Volume: 2022-06-03

Abstract:

Background

Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1–1b part of the KRYSTAL-1 phase 1–2 study.

Methods

In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.

Results

As of October 15, 2021, a total of 116 patients with KRASG12C-mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients — grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) — and resulted in drug discontinuation in 6.9% of patients.

Conclusions

In patients with previously treated KRASG12C-mutated NSCLC, adagrasib showed clinical efficacy without new safety signals.

DOI: 10.1056/NEJMoa2204619

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2204619