Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysisResearch in context
Sophie M. Ernst,
Maaike M. Hofman,
Tessa E. van der Horst,
Marthe S. Paats,
Frank W.J. Heijboer,
Joachim G.J.V. Aerts,
Daphne W. Dumoulin,
Robin Cornelissen,
Jan H. von der Thüsen,
Peter de Bruijn,
Esther Oomen-de Hoop,
Ron H.J. Mathijssen,
Stijn L.W. Koolen,
Anne-Marie C. Dingemans
Affiliations
Sophie M. Ernst
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Maaike M. Hofman
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
Tessa E. van der Horst
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Marthe S. Paats
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Frank W.J. Heijboer
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Joachim G.J.V. Aerts
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Daphne W. Dumoulin
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Robin Cornelissen
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Jan H. von der Thüsen
Department of Pathology, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Peter de Bruijn
Department of Medical Oncology, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Esther Oomen-de Hoop
Department of Medical Oncology, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Ron H.J. Mathijssen
Department of Medical Oncology, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Stijn L.W. Koolen
Department of Medical Oncology, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands; Department of Pharmacy, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands
Anne-Marie C. Dingemans
Department of Respiratory Medicine, Erasmus MC Cancer Institute University Medical Center, Doctor Molewaterplein 40, Rotterdam 3015 GD, the Netherlands; Corresponding author. Department of Respiratory Medicine, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, Rotterdam 3015 GD, the Netherlands.
Summary: 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. 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.
