Adgrasib (MRTX849)在晚期KRASG12C实体瘤(KRYSTAL-1)患者中的首次人体I/IB期剂量探索研究

13 March 2022

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)

（IF: JCO, 44.544）

• Ou SI, Jänne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova LA, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, Papadopoulos KP. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Feb 15:JCO2102752. 

• CORRESPONDING AUTHOR：Sai-Hong Ignatius Ou, MD, PhD, Chao Family Comprehensive Cancer，Center, University of California Irvine School of Medicine, 200 South，Manchester Ave, Suite 400, Orange, CA 92868; e-mail: siou@hs.uci.edu.

PURPOSE 目的

Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.

Adagrasib（MRTX849）是一种口服高选择性小分子KRASG12C的共价抑制剂。我们报告了Adagrasib在非小细胞肺癌、结直肠癌和其他携带KRASG12C突变的实体瘤中的I/IB期研究结果。

MATERIALS 材料与方法

AND METHODS Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.

晚期KRASG12C突变型实体瘤患者口服adagrasib，150mg每日一次，300mg每日一次，600mg每日一次，1200mg每日一次或600mg每日两次，采用加速滴定设计，当观察到预定的毒性程度或达到adagrasib的目标暴露时，转变为改进的毒性概率区间设计。评估了安全性、药代动力学和临床活性。

RESULTS 结果

Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non–small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).

25名患者被纳入研究，并接受了至少一剂adagrasib。基于安全性、耐受性和观察到的药代动力学特性，推荐的II期剂量（RP2D）为600毫克，每天两次。没有正式定义最大耐受剂量。在中位随访19.6个月后，15名RECIST可评估的KRASG12C突变非小细胞肺癌患者中有8名（53.3%；95% CI，26.6至78.7）在每天两次600毫克的剂量下获得了确认的部分缓解。中位缓解持续时间为16.4个月（95% CI，3.1至不可估计）。中位无进展生存期为11.1个月（95% CI，2.6至不可估计）。每天两次服用600毫克的KRASG12C突变型的两名结直肠癌患者中，有一名获得部分缓解（缓解持续时间为4.2个月）。在RP2D，最常见的治疗相关不良事件（任何级别）为恶心（80.0%）、腹泻（70.0%）、呕吐（50.0%）和疲劳（45.0%）。最常见的3-4级治疗相关不良事件是疲劳（15.0%）。

CONCLUSION 结论

Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

每天两次服用600毫克的Adagrasib耐受性良好，对携带KRASG12C突变的晚期实体瘤患者显示出抗肿瘤活性。