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Abstract：
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 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.
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.
摘要：
背景：Sotorasib在免疫治疗后给药可能增加患者肝毒性的风险。因此,需要深入了解抗PD-（L）1治疗之间的潜在相关性，抗PD-（L）1浓度，索托拉西浓度，以及索托拉西期间肝毒性的发生率。
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。
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。
