Real-world experience of immune-mediated hepatitis in Danish lung cancer patient using PD1 inhibitors

Abstract

Abstract Background There is limited information about the response to steroids in treatment of immune-mediated hepatitis (IMH) in patients treated with immune checkpoint inhibitors (ICI). We investigated the incidents of IMH in 307 Danish lung cancer patients with advanced non-small cell lung cancer (NSCLC) and reviewed the efficacy of the IMH treatment. Methods Data from NSCLC patients medical records were retrospectively registered when treated with ICI between July 2016 and December 2018 at University Hospital Herlev and Rigshospitalet, Copenhagen, Denmark. Results In all 307 patients were treated with ICI – 85 patients received nivolumab and 222 pembrolizumab. Age ranged from 21 to 87 years, median 69. IMH was more common with pembrolizumab than with nivolumab (13% vs. 5%). There were 32 patients with grade 1-4 immune-related adverse events (irAEs) IMH (10 %), here off grade 1, 18 (56 %), grade 2, 6 (19 %), grade 3, 7 (22 %) and grade 4, 1 patient (3 %). Onset of raised transaminases ranged from 1-54 weeks, median 8. Time to normalization ranged from 2-464 days, median 24. In 24 patients with grade 1-2 the range was 2-256 days, median 24, until normalization; for grade 3-4 the range was 10-464, median 24. Half of the patients with grade 2 irAEs initiated treatment with steroids and 7 of 8 patients with grade 3-4 irAEs received immediately treatment with steroids. Steroid dose was on average 32 mg/day over a period of 1 year (range 1-32 months). The single patient with grade 4 irAEs also received treatment with mycophenolate mofetil however the transaminases never normalized. One patient with grad 3 irAEs received treatment with ursodeoxycholic acid and tacrolimus due to lack of improvement with steroids. Over a year passed before the transaminases normalized. This patient exclusively underwent liver biopsy which was diagnosed as autoimmune hepatitis. All patients with grade 3-4 had PD-L1 expression above 50% and all permanently discontinued ICI treatment. Conclusion Liver toxicity frequency correlates to findings in clinical trials (KEYNOTE-024 and KEYNOTE-042) and are mainly of grade 1. There was no correlation, in this dataset, between dose of steroids and time to normalizing of transaminases in patients treated with immunosuppressants. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.