METHODS: Patients with KRASG12C-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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: None.
方法:在我们的生物标志物队列研究(NCT05221372)中,前瞻性地纳入了接受索托拉碱治疗的KRASG12C突变NSCLC患者。在索托拉西治疗之前和期间收集血浆样品用于抗PD-1和索托拉西浓度。前瞻性收集ALT/AST/ALP/GGT增加,并根据CTCAEv5.0分级。严重肝毒性定义为ALT/AST/ALP/GGT升高≥3级。
结果:在纳入的91名患者中,80(88%)接受了先前的抗PD-(L)1。先前的抗PD-(L)1和先前的免疫相关肝毒性与严重肝毒性的较高发生率相关(35%对0%,p=0.016和75%对31%,分别为p=0.019)。抗PD-(L)1和索托拉西(n=18)之间间隔≤6周的患者严重肝毒性的发生率明显高于6-12周(n=24)和≥12周(n=38)间隔(83%对33%对13%,分别,p<0.0001)。Sotorasib谷浓度在有或没有严重肝毒性的患者之间没有显着差异(106对126ng/mL,p=0.16)。Pembrolizumab在有严重肝毒性的患者中的浓度高于无(25.6对6.1μg/mL,p<0.0001)。
结论:在这项初步的前瞻性研究中,PD-(L)1阻断后的索托拉西与严重的肝毒性有关,特别是在治疗间隔时间短的患者中,先前的免疫相关肝炎和更高的抗PD-1血浆浓度。我们的结果表明,抗PD-(L)1和索托拉西之间的最小间隔为6周,以最大程度地减少肝毒性的风险。
背景:无。