索托拉西布治疗后既往免疫治疗的非小细胞肺癌患者的肝毒性：全面的临床和药代动力学分析。
Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysis.
机构信息
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands.
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands.
出版信息
EBioMedicine. 2024 Apr;102:105074. doi: 10.1016/j.ebiom.2024.105074. Epub 2024 Mar 19.
BACKGROUND
Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib.
METHODS
Patients with KRAS-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase.
FINDINGS
Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p = 0.016 and 75% versus 31%, p = 0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n = 18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n = 24) and ≥12 week (n = 38) interval (83% versus 33% versus 13%, respectively, p < 0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126 ng/mL, p = 0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1 μg/mL, p < 0.0001).
INTERPRETATION
In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity.
FUNDING
None.
背景
索托拉西布联合免疫治疗可能会增加患者发生肝毒性的风险。因此，需要深入了解抗 PD-(L)1 治疗、抗 PD-(L)1 浓度、索托拉西布浓度与索托拉西布治疗期间肝毒性发生率之间的潜在相关性。
方法
本研究前瞻性纳入了接受索托拉西布治疗的 KRAS 突变型 NSCLC 患者（NCT05221372），纳入了我们的生物标志物队列研究。在接受索托拉西布治疗前和治疗期间采集了血浆样本，用于检测抗 PD-1 和索托拉西布的浓度。前瞻性收集 ALT/AST/ALP/GGT 升高情况，并根据 CTCAEv5.0 进行分级。严重肝毒性定义为 ALT/AST/ALP/GGT 升高≥3 级。
结果
在 91 例纳入患者中，80 例（88%）接受了抗 PD-(L)1 治疗。既往接受抗 PD-(L)1 治疗和既往免疫相关性肝毒性与严重肝毒性的发生率较高相关（35%与 0%，p=0.016 和 75%与 31%，p=0.019）。在接受抗 PD-(L)1 治疗与索托拉西布治疗之间间隔≤6 周的患者（n=18）与间隔 6-12 周（n=24）和≥12 周（n=38）的患者相比，严重肝毒性发生率显著更高（83%与 33%与 13%，p<0.0001）。严重肝毒性患者与无严重肝毒性患者的索托拉西布谷浓度无显著差异（106 与 126ng/mL，p=0.16）。与无严重肝毒性患者相比，严重肝毒性患者的帕博利珠单抗浓度更高（25.6 与 6.1μg/mL，p<0.0001）。
结论
在这项初步的前瞻性研究中，PD-(L)1 阻断后接受索托拉西布治疗与严重肝毒性相关，尤其是在治疗间隔较短、既往存在免疫相关性肝炎和抗 PD-1 血浆浓度较高的患者中。我们的结果提示抗 PD-(L)1 和索托拉西布之间的最小间隔时间为 6 周，以最大程度降低肝毒性风险。
无。
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