Severe Liver Injury Triggered by Sequential Use of Immune Checkpoint Blockers and Tyrosine Kinase Inhibitors: An Emerging Clinical Issue

We read with interest the article by Chour et al.1Chour A. Denis J. Mascaux C. et al.Brief report: severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-programmed cell death (ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar published in the Journal of Thoracic Oncology. The authors reported the results of a retrospective study that included 102 patients with advanced KRASG12C-mutated NSCLC who had received sotorasib and found a higher rate of severe adverse events in patients who received immune checkpoint inhibitor (ICPI) as last therapy (sequence group) as compared with patients who did not receive ICPI as last treatment before sotorasib (control group) (50% versus 13%, p < 0.001). Severe liver toxicities were threefold more frequent in the sequence group (33% versus 11%, p = 0.007), and also nonliver adverse events (27% versus 4%, p <0.001). According to the time interval from the last ICPI administration and sotorasib initiation, the authors observed a higher incidence of severe sotorasib-related hepatotoxicity among patients receiving the last infusion of ICPI within 30 days (58%) compared with 31 to 60 days (27%) and longer than 60 days (11%). Overall, the management of the 22 patients (21%) who experienced severe hepatotoxicity was very heterogeneous. The definitive sotorasib discontinuation rate was 81% among these patients. Notably, only seven patients (32%) received steroids and sotorasib was discontinued in all cases. Although all reported liver toxicities were likely to be related to sotorasib, potential alternative causes of liver injury were not ruled out; tests for viral and autoimmune hepatitis were performed in 18% to 59% and 27% of cases, respectively, and liver biopsy in only one patient. According to presence of bile duct injury, the histologic pattern, in this case, was suggestive of mixed liver damage rather than a classic (lobular) ICPI-induced hepatitis, although a typical picture of ICPI-related hepatitis has not yet been defined.2De Martin E. Michot J.M. Papouin B. et al.Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.J Hepatol. 2018; 68: 1181-1190Google Scholar We concur with the authors about the role of sotorasib as a potential trigger for ICPI-mediated hepatotoxicity, probably through an immune-mediated mechanism, potentially resulting in a synergistic pharmacodynamic interaction, and regarding the need to avoid starting sotorasib within 30 days from the last ICPI infusion. The implications of programmed death-ligand 1 expression on hepatocytes, not evaluated in liver biopsy samples, has not yet been defined, although it could be increased in the presence of concomitant liver disease or occult metastases. This condition could promote the synthesis of liver self-antigens and proinflammatory cytokines, activating T cells involved in ICPI-related liver injury.3Suzman D.L. Pelosof L. Rosenberg A. Avigan M.I. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents.Liver Int. 2018; 38: 976-987Google Scholar We think that the results of this work highlight the relevant issue on therapeutic sequences in patients previously exposed to ICPI, and receiving different small molecules,1Chour A. Denis J. Mascaux C. et al.Brief report: severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-programmed cell death (ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer.J Thorac Oncol. 2023; 18: 1408-1415Google Scholar also including MET inhibitors.4Vansteenkiste J.F. Smit E.F. Groen H.J.M. et al.Capmatinib in patients with METex14-mutated advanced nonsmall cell lung cancer who received prior immunotherapy: the phase II GEOMETRY mono-1 study.Ann Oncol. 2020; 31: S830Google Scholar,5Wolf J. Heist R. Kim T.M. et al.Efficacy and safety of capmatinib plus spartalizumab in treatmentnaïve patients with advanced NSCLC harboring MET exon 14 skipping mutation.Ann Oncol. 2022; 33: S1007-S1008Google Scholar On the basis of evidence of a higher risk of toxicity, starting at reduced doses is the recommended strategy in a trial (NCT03175224), which tested new selective MET inhibitors for those patients who had received ICPI within 90 days. In the presence of moderate-severe hepatotoxicity, we strongly recommend liver biopsy as it can provide useful information to better characterize liver damage to implement proper management (steroids versus no steroids) and identify candidates to rechallenge. Finally, identifying noninvasive diagnostic tools could help to recognize those patients at lower risk of hepatotoxicity, thus, avoiding delaying the beginning of a potentially effective drug. Francesco Gelsomino: Conceptualization, Writing-original draft, Writing-review draft. Giovanni Vitale: Conceptualization, Writing-review draft. Emanuel Raschi: Conceptualization, Writing-review draft. Andrea Ardizzoni: Conceptualization, Writing-review draft. Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti–Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung CancerJournal of Thoracic OncologyVol. 18Issue 10PreviewSequential anti–programmed cell death protein 1 (PD-1) or anti–programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti–PD-(L)1. This study was designed to address whether sequential anti–PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. Full-Text PDF