during cancer immunotherapy 2018.4.12 목요세미나 Liver injury during cancer immunotherapy 분당서울대병원 소화기내과 장은선

Case 1. F/61 NSCLC M/adrenal gl, LN on Nivolumab+Ipilimumab #30 TTF1+, ALK IHC2+, EGFR ; wt, ALK FISH (-) PD-L1 90% s/p Unilateral adrenalectomy on Nivolumab+Ipilimumab #30

Liver, needle biopsy : Lobular hepatitis with Nivolumab 시작 Nivolumab 중단 Liver, needle biopsy : Lobular hepatitis with 1) perivenular zone cell loss 2) milder degree of portal tract changes 3) no evident fibrosis 4) iron deposition in hepatocytes and Kupffer cells (1+) Steroid Q1. Is this ‘Immune-related’ hepatitis?

Pathologic features of Autoimmune hepatitis

Checkpoint inhibitor related liver injury vs. AIH vs. DILI Histopathological features Checkpoint inhibitor related liver injury, Autoimmune hepatitis, DILI 모두 lobular injury, portal inflammation 정도에서는 차이가 없었으나 Checkpoint inhibitor로 인한 liver injury는 다른 두가지 원인보다 confluent necrosis가 유의미하게 적었고 Autoimmune hepatitis보다 plasmacytosis가 적고 DILI보다 eosinophilic infiltration이나 bile plug가 유의미하게 적게 관찰되었습니다. ------------------------------------ 또 AIH(8)나 DILI(4)에서 보이는 Hepatocellular rosettes나 emperipolesis는 checkpoint inhibitor related liver injury에서는 관찰되지 않았습니다.

Anti-CTLA4 induced hepatitis in malignant melanoma patients So far, specific feature of ‘immune-mediated hepatitis’ during immunotherapy is not determined.

Nivolumab induced AE in phase 3 trial for HCC patients

Anti-CTLA4 induced hepatitis in HCV related HCC patients A pilot study with tremelizumab for HCV related advanced HCC patients (n=21) LFT abnormality AST elevation : n=14 (70%) >gr 3, 9 (45%) ALT elevation : n=11 (55%) >gr 3, 5 (25%)

Case 2. F/45 Rectal cancer, M/LNs, liver, lung, bone (T3) MSS, KRAS WT, NRAS MT, BRAF WT on pall FOLFOX#6+avastin : PR on NK Cell therapy & Nivolumab #3

Q2. Is steroid treatment mandatory? Nivolumab 시작 Nivolumab #3 FOLFOX 중단 FOLFOX 다시 시작 FOLFOX Dose reduction FOLFOX 시작 Liver, needle biopsy : Predominantly perivenular confluent hepatocyte necrosis with 1) milder degree of portal inflammation (mixed infiltrates) 2) no evident fibrosis 3) no steatosis Q2. Is steroid treatment mandatory?

ESMO Clinical Practice Guidelines: Management of ICPi-related hepatitis

Concerns over treatment for immune-related hepatitis patients with cancer Re-administration of immunotherapy Antitumor effect Degree of immunosuppression Possible reactivation of viral hepatitis

38% were recovered without any corticosteroid therapy 3 were rechallenged with anti-PD1 mAb 1 died of tumor progression 1 experienced gr 1 liver enzyme elevation 1 had no recurrence of hepatitis High dose steroid therapy might be not mandatory in most ICPi related hepatitis patients.

Summary & Conclusion Immune related hepatitis will be not rare complication during immune checkpoint inhibitor (ICPi) therapy in cancer patients, especially with HCC. Treatment strategy for ICPi related hepatitis is still not established and needed more clinical experiences.