Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA.
Institut Gustave Roussy, Villejuif, France.
Oncologist. 2022 Jul 5;27(7):536-e553. doi: 10.1093/oncolo/oyab080.
Patients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation.
Eligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method.
Ten patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non-small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3-4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%).
Based on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development.
CLINICALTRIALS.GOV IDENTIFIER: NCT04006301.
KRAS 突变型癌症患者的治疗选择有限。本研究报告了 JNJ-74699157 的 I 期临床试验结果，这是一种口服、选择性、共价 KRAS G12C 同型抑制剂，用于治疗携带 KRAS G12C 突变的晚期癌症患者。
纳入标准为年龄≥18 岁、既往接受过治疗或不符合标准治疗条件的患者，接受 JNJ-74699157 每日一次、21 天为一个周期的治疗。剂量递增采用改良连续评估法指导。
共纳入 10 例患者（100mg 剂量组 9 例，200mg 剂量组 1 例），肿瘤类型包括非小细胞肺癌（n=5）、结直肠癌（n=4）和不明原发灶癌（n=1）。中位年龄为 65 岁（范围：36-74 岁），中位治疗持续时间为 2.91 个月（范围：0.5-7.5 个月）。在 100mg 和 200mg 剂量水平观察到 3-4 级血肌酸磷酸激酶（CPK）升高的剂量限制毒性。最常见的不良反应是血 CPK 升高（6 例）。未观察到明显的临床获益，4 例患者（40%）的最佳缓解为疾病稳定。
基于骨骼肌毒性的剂量限制和 100mg 剂量无疗效，停止进一步入组。JNJ-74699157 的安全性特征不适合进一步的临床开发。
NCT04006301。
