OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Nivolumab – Opdivo®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 23 June 2022

Abbreviations used: CPI, checkpoint inhibitor; CTLA-4, cytotoxic T lymphocyte associated antigen 4; HCC, hepatocellular carcinoma; irAE, immune related adverse event; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand-1; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Danan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125554.

  (FDA website with current and previous product labels and the 2015 medical review of the new drug application for nivolumab).
• Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7. [PMC free article: PMC166236] [PubMed: 12826605]

  (Initial study of anti-CTLA-4 therapy in 14 patients with melanoma, 6 of whom developed clinically apparent immune adverse reactions including one with hepatitis arising after the third infusion [ALT 6820 U/L], resolving over the ensuing 4 months with corticosteroid therapy: Case 1).
• Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40. [PMC free article: PMC3792485] [PubMed: 22434096]

  (Clinical and histological features of 5 patients with liver injury due to ipilimumab; 3 men and 2 women, ages 43 to 76 years, arising after 2-4 courses, 39-71 days after initial dose [peak bilirubin 1.5-5.1 mg/dL, ALT 326-3070 U/L, Alk P 206-427 U/L], only one had autoantibodies, resolving with immunosuppressive therapy within 1-4 months; one had recurrence on rechallenge; liver biopsies showed acute hepatitis usually with prominent inflammation, interface hepatitis and confluent necrosis: Case 1).
• Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. [PMC free article: PMC3544539] [PubMed: 22658127]

  (Among 296 patients with advanced cancers [melanoma, NSCLC, renal, prostate and colorectal] treated with 1 of 5 doses of nivolumab every 2 weeks, response rates were highest with melanoma and renal cancer, and drug related adverse events were common, including immune related conditions such as pneumonitis [3 fatal], vitiligo, colitis, hepatitis [reversible in all cases], hypophysitis and thyroiditis; ALT elevations occurred in 11 patients [4%] and were greater than 5 times ULN in 2 [1%]).
• Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. [PMC free article: PMC3563263] [PubMed: 22658128]

  (Among 207 patients with various advanced solid tumors treated with nivolumab given daily for 14 days in 6 week cycles for an average of 12 weeks, durable tumor regression occurred in 6-17% of patients; serious adverse events considered related to therapy occurred in 5%, but no patient had ALT elevations above 5 times ULN).
• Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, et al. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One. 2013;8:e63818. [PMC free article: PMC3661719] [PubMed: 23717490]

  (Among 56 patients with chronic hepatitis C treated with a single injection of nivolumab or placebo, decreases in HCV RNA occurred in 11% of both groups, 12% had immune related adverse events and one a transient ALT elevation above 10 times ULN).
• Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33. [PMC free article: PMC5698004] [PubMed: 23724867]

  (Among 53 patients with advance melanoma treated with the combination of ipilimumab and nivolumab, the objective response rate was 53% to the optimal dose regimen, but adverse events were common [98%] as were serious adverse events [49%], any ALT elevations [23%] and elevations above 5 times ULN [13%]; lower response rates [20%] and ALT elevations [3%] occurred with sequential therapy).
• Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311–8. [PMC free article: PMC3837092] [PubMed: 24145345]

  (Among 90 patients with refractory or naïve melanoma treated with nivolumab in 1 of 3 doses every 2 weeks for 24 weeks, then every 12 weeks with or without a peptide vaccine, response rates were approximately 25% and adverse events were manageable; no mention of ALT elevations or hepatotoxicity).
• Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, Del Vecchio M, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J Transl Med. 2014;12:116. [PMC free article: PMC4030525] [PubMed: 24885479]

  (Among 855 patients with melanoma treated with ipilimumab in an expanded access program, 19 [2%] developed “liver toxicity”, which led to stopping therapy in 1 patient and death from hepatitis in another).
• Teply BA, Lipson EJ. Identification and management of toxicities from immune checkpoint-blocking drugs. Oncology (Williston Park). 2014 Nov;28 Suppl 3:30–8. [PubMed: 25384885]

  (Clinical review of the toxicities of immune checkpoint blocking drugs such as ipilimumab, pembrolizumab and nivolumab, mentions that elevations of serum aminotransferase elevations should lead to careful exclusion of other causes of liver injury and increased monitoring; that elevations above 3 times ULN should lead to withholding the drug and starting corticosteroids; and, that elevations above 5 times ULN should lead to hospital admission and immediate administration of high doses of corticosteroids).
• Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. [PMC free article: PMC4246418] [PubMed: 25428505]

  (Analysis of expression of PD-1 and its ligand on CD8+ T cells at the margins of melanoma tumors before and after treatment with pembrolizumab showed that high levels of PD-1 and its ligand are found in responders to therapy).
• Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311–9. [PMC free article: PMC4348009] [PubMed: 25482239]

  (Among 23 patients with refractory Hodgkin lymphoma treated with nivolumab [3 mg/kg every 2 weeks], objective responses occurred in 87% and 3 patients had drug related serious adverse events, but none were hepatic; no mention of ALT elevations).
• Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430–7. [PMC free article: PMC4806782] [PubMed: 25452452]

  (Among 168 patients with metastatic renal cell cancer treated with 1 of 3 doses of nivolumab every 3 weeks, objective response rates were 20-22% and ALT elevations occurred in 7 [4%] and were above 5 times ULN in 2 [1%]).
• Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320-30. 25399552. [PubMed: 25399552]

  (Among 418 patients with metastatic melanoma [BRAF-] treated with nivolumab or dacarbazine, one year survival was 73% vs 42%, and common side effects of nivolumab were fatigue [20%], pruritus [17%] and nausea [17%]; 2 patients [1%] had ALT elevations above 5 times ULN, 1 requiring corticosteroid therapy).
• Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257–65. [PMC free article: PMC5726228] [PubMed: 25704439]

  (Among 117 patients with advanced, refractor NSCLC treated with nivolumab [3 mg/kg every 2 weeks], the objective response rate was 15% and adverse events were common [74%]; no serious adverse events were liver related and ALT elevations [less than 5 times ULN] occurred in only 1 patient [1%]).
• Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84. [PubMed: 25795410]

  (Among 272 patients with refractory, advanced melanoma treated with nivolumab, the objective response rate was 32% and adverse events were common [68%] and 2 patients [1%] had ALT elevations above 5 times ULN, resolving with corticosteroid therapy).
• Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8. [PMC free article: PMC4993154] [PubMed: 25765070]

  (Exome sequencing from NSCLC tumors in patients treated with pembrolizumab showed that patients with a durable clinical benefit of therapy typically had higher numbers of nonsynonymous mutations, an association confirmed in a second cohort; mutations were not in the known PD-1 or checkpoint pathways, but likely represented genes that express neo-antigens).
• Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61. [PubMed: 25838373]

  (Commentary and review of the rationale, history, clinical efficacy and mechanism of action of immune checkpoint therapy).
• Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother. 2015;64:765–7. [PubMed: 25828465]

  (54 year old woman with melanoma who was treated unsuccessfully with nivolumab and ipilimumab, developed diabetic ketoacidosis after 3 doses of pembrolizumab [anti-GAD positive] having had normal glucose levels before treatment, but also having high risk HLA alleles for type 1 diabetes; no mention of ALT elevations).
• Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, Herold KC. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38:e55–7. [PMC free article: PMC4370325] [PubMed: 25805871]

  (Description of 5 patients with cancer who had new-onset of insulin dependent diabetes 1 week to 5 months after starting nivolumab [n=4] or pembrolizumab [n=1], 3 with anti-GAD, and all requiring insulin therapy chronically; 3% of patients treated with these agents at this cancer center).
• Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33:2004–12. [PMC free article: PMC4672027] [PubMed: 25897158]

  (Among 129 patients with advanced, refractory NSCLC treated with 1 of 3 doses of nivolumab every 2 weeks for up to 96 weeks, objective response rates at 1 year were 42%; serum enzyme elevations occurred in 6 patients [5%] and were above 5 times ULN in one; 2 patients died of suspected treatment-related, immune mediated pneumonitis).
• McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, Brahmer JR, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33:2013–20. [PMC free article: PMC4517051] [PubMed: 25800770]

  (Among 34 patients with advanced renal cell cancer treated with pembrolizumab [1 or 10 mg/kg every two weeks], objective responses occurred in 10 patients [29%], and immune mediated adverse events in 19 [56%], including ALT elevations in 4 patients [12%] which were above 5 times ULN in 1 [3%]).
• Nivolumab (Opdivo) for metastatic melanoma and metastatic NSCLC. Med Lett Drugs Ther. 2015;57(1470):85–7. [PubMed: 26035747]

  (Concise review of the mechanism of action, efficacy, safety and costs of nivolumab for metastatic melanoma shortly after its approval for this use in the US; mentions that side effects can include immune mediated reactions including hepatitis as well as transient, but marked serum ALT elevations).
• Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372:2509–20. [PMC free article: PMC4481136] [PubMed: 26028255]

  (Among 41 patients with advanced cancers with or without mismatch repair deficiency, response rates to pembrolizumab were higher in those with mismatch repair deficiency [53%] than in those without [0%]; adverse events occurred in 98% of patients; ALT elevations occurred in 3 [7%] patients and were greater than 5 times ULN in 2 [5%]).
• Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123–35. [PMC free article: PMC4681400] [PubMed: 26028407]

  (Among 272 patients with advanced NSCLC treated with nivolumab or docetaxel, overall one year survival rates were greater with nivolumab [42% vs 24%] and side effects were less, ALT elevations occurring in 2% vs 1%, but were mostly mild and self-limited).
• Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. [PMC free article: PMC5698905] [PubMed: 26027431]

  (Among 945 patients with advanced, untreated melanoma treated with checkpoint inhibitors, median progression-free survival was 3 months with ipilimumab, 7 months with nivolumab and 11.5 months with the combination of both, adverse events including ALT elevations also being more common with the combination [any ALT elevation 17.6%, ALT above 5 times ULN 8.3%] than either alone [3.8% and 1.3% for nivolumab vs 3.9% and 1.6% for ipilimumab], almost all resolving with immunosuppressive therapy).
• Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD-1-related pneumonitis during cancer immunotherapy. N Engl J Med. 2015;373:288–90. [PMC free article: PMC4539956] [PubMed: 26176400]

  (Summary of 3 patients with melanoma treated with nivolumab [2 also received ipilimumab] who developed severe immune mediated interstitial pneumonitis 7-24 months after starting therapy with diffuse pulmonary ground-glass and reticular opacities, 2 eventually recovering with corticosteroid therapy, one dying after 4 weeks).
• Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J, Wolchok JD. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: A pooled analysis of 4 clinical trials. JAMA Oncol. 2015;1:433–40. [PubMed: 26181250]

  (Pooled analysis of 4 clinical trials of 5 doses of nivolumab in 440 adults with advanced melanoma found similar efficacy and safety in tumors with mutant vs wild-type BRAF; no specific mention of ALT elevations or hepatotoxicity).
• Narita T, Oiso N, Taketomo Y, Okahashi K, Yamauchi K, Sato M, Uchida S, et al. Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab. J Dermatol. 2016;43(2):210–4. [PubMed: 26198822]

  (Two patients, 65 and 70 years old, one woman and one man developed thyroid test abnormalities soon after starting nivolumab therapy for metastatic melanoma, having subtle abnormalities before treatment; ALT values remained normal or minimally elevated).
• Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39. [PMC free article: PMC5705936] [PubMed: 26412456]

  (Among 582 patients with NSCLC treated with nivolumab or docetaxel, the one year overall survival rate was better with nivolumab [51% vs 39%] and overall adverse events were less, and ALT elevations above 5 times ULN occurred in none on nivolumab and 1 on docetaxel).
• Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, et al. CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. [PMC free article: PMC5719487] [PubMed: 26406148]

  (Among 831 patients with advanced renal cancer treated with nivolumab or everolimus, median overall survival was better with nivolumab [25 vs 19.6 months] and side effects were less [79% vs 88%]; no mention of ALT elevations or hepatotoxicity).
• Abdel-Rahman O, El Halawani H, Fouad M. Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Expert Opin Drug Saf. 2015;14:1507–18. [PubMed: 26394770]

  (Analysis of publications on checkpoint inhibitors including nivolumab and ipilimumab indicated that therapy was associated with higher rates of ALT elevations).
• Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33:4015–22. [PubMed: 26351349]

  (Among 20 patients with advanced, refractory ovarian cancer treated with 1 of 2 doses of nivolumab, adverse events were common [95%] and included ALT elevations in 5 patients [25%] which were above 5 times ULN in 1 [5%]).
• Davar D, Wilson M, Pruckner C, Kirkwood JM. PD-1 blockade in advanced melanoma in patients with hepatitis C and/or HIV. Case Rep Oncol Med. 2015;2015:737389. [PMC free article: PMC4581502] [PubMed: 26448890]

  (59 year old woman and 47 year old man with metastatic melanoma and combined HIV and hepatitis C infection were treated with pembrolizumab, tolerating therapy with no worsening of liver disease or HIV infection).
• Nivolumab (Opdivo) plus ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs Ther. 2015;57(1483):168. [PubMed: 26633687]

  (Concise review of the rationale, clinical efficacy, adverse effects and costs of nivolumab and ipilimumab for metastatic melanoma shortly after approval of this combination in the US; no mention of hepatotoxicity or ALT elevations).
• Kanameishi S, Otsuka A, Nonomura Y, Fujisawa A, Endo Y, Kabashima K. Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. Ann Oncol. 2016;27(3):546–7. [PubMed: 26602778]

  (79 year old woman with metastatic melanoma developed severe thrombocytopenia after 2 doses of nivolumab [platelet count 2000/µL], having been normal before therapy, ultimately responding to corticosteroids, IVIG and romiplostim; no information given on subsequent course).
• Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209. [PubMed: 27085692]

  (Among 496 patients with metastatic melanoma treated in 15 European centers with either nivolumab or pembrolizumab, 138 [28%] had at least one immune related adverse event including 11 [2%] with hepatitis arising after 1-4 infusions in all but 1, all treated with corticosteroids, 2 needing addition of mycophenolate, 9 resolving and 2 improving, none fatal).
• Gelsomino F, Vitale G, D'Errico A, Bertuzzi C, Andreone P, Ardizzoni A. Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury. Ann Oncol. 2017;28:671–672. [PubMed: 27993797]

  (79 year old man with NSCLC developed jaundice after 4 infusions of nivolumab [day 62] with bilirubin 10.5, ALT ~480 U/L, Alk P~950 U/L, jaundice resolving 14 weeks after stopping therapy and with corticosteroid treatment, but patient died of progressive cancer shortly thereafter and before Alk P and GGT were completely normal).
• Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27:271–273. [PubMed: 28146044]

  (46 year old man with melanoma developed fever, rash, eosinophilia with elevations in ALT [115 U/L] and creatinine [1.2 mg/dL] while being treated with ipilimumab and nivolumab, but also shortly after courses of doxycycline and levofloxacin, responding rapidly to corticosteroid therapy).
• Spänkuch I, Gassenmaier M, Tampouri I, Noor S, Forschner A, Garbe C, Amaral T. Severe hepatitis under combined immunotherapy: Resolution under corticosteroids plus anti-thymocyte immunoglobulins. Eur J Cancer. 2017;81:203–205. [PubMed: 28641200]

  (49 year old woman with metastatic melanoma developed hepatitis after 3 cycles of ipilimumab and nivolumab [bilirubin 5.8 mg/dL, ALT 772 U/L, Alk P 449 U/L], with inadequate response to corticosteroids but eventual response after starting antithymocyte globulin, later tolerating pembrolizumab without recurrence on low doses of prednisone).
• Kawakami H, Tanizaki J, Tanaka K, Haratani K, Hayashi H, Takeda M, Kamata K, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs. 2017;35:529–536. [PubMed: 28317087]

  (Among 91 Japanese patients with advanced NSCLC treated with nivolumab, 3 developed severe cholangitis arising after 6, 9 and 12 cycles in 2 women and 1 man, ages 64 to 82 years with marked elevations in Alk P (peak 1769, 1947 and 2996 U/L], modest ALT elevations [144, 101 and 70 U/L], no autoantibodies, and imaging showing localized common bile duct dilatation with distal breaking but no obstruction, hypertrophy of bile duct wall and no intrahepatic duct abnormalities, all with poor or only moderate response to corticosteroids).
• Doherty GJ, Duckworth AM, Davies SE, Mells GF, Brais R, Harden SV, Parkinson CA, et al. Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury. ESMO Open. 2017;2:e000268. [PMC free article: PMC5652580] [PubMed: 29081991]

  (Three cases of checkpoint inhibitor induced cholestatic liver injury in 2 women and 1 man, ages 47, 59 and 76 years, who developed liver injury after 1-3 cycles of pembrolizumab or nivolumab, one with severe ductopenia who died of liver failure, one with focal ductopenia who eventually recovered, and one with prolonged cholestasis who died of progressive cancer, all with poor or only moderate response to corticosteroids).
• Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients With advanced melanoma. J Clin Oncol. 2017;35:785–792. [PubMed: 28068177]

  (Among 576 patients with advanced melanoma treated with nivolumab [every two weeks] for an average of 6 months, 4.2% developed liver abnormalities, most commonly ALT elevations [1.9%] but few [0.7%] were above 5 times ULN).
• Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35:3807–3814. [PMC free article: PMC5791828] [PubMed: 28841387]

  (Among 407 patients with advanced melanoma treated with the combination of ipilimumab and nivolumab for 4 cycles and then nivolumab alone, 156 discontinued therapy because of adverse events, including 13 with liver toxicity, but progression-free survival was similar in those who continued and those who discontinued therapy, largely during the induction period).
• El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–2502. [PMC free article: PMC7539326] [PubMed: 28434648]

  (Among 262 patients with advanced hepatocellular carcinoma [HCC] treated with nivolumab in dose escalation and expansion studies, objective responses were achieved in 15-20% of patients and toxicity was “manageable” with ALT elevations in 15% that were above 5 times ULN in 6%; among 51 patients with HBV all were receiving antiviral prophylaxis and none had HBV reactivation).
• Lake AC. Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy. AIDS. 2017;31:2115–2118. [PubMed: 28906278]

  (72 year old man with HIV infection, recurrent metastatic lung cancer and anti-HBc without HBsAg was started on dolutegravir and abacavir and then on nivolumab and was found to have acute liver injury 1 month later [bilirubin 0.5 mg/dL, ALT 332 UL, Alk P 205 U/L, HBsAg positive and HBV DNA > 170 million IU/mL], started on tenofovir and later tolerated restarting nivolumab).
• Koksal AS, Toka B, Eminler AT, Hacibekiroglu I, Uslan MI, Parlak E. HBV-related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma. Ann Oncol. 2017;28:3103–3104. [PubMed: 28945827]

  (56 year old man with melanoma and HBsAg in serum developed liver injury 12 weeks after starting ipilimumab [bilirubin 0.7 rising to 1.9 mg/dL, ALT 246 rising to 888 U/L, HBV DNA 244,259 IU/mL], responding to tenofovir and was continued on nivolumab).
• Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, Ancell KK, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol. 2018;29:250–255. [PMC free article: PMC5834131] [PubMed: 29045547]

  (Among 80 patients treated with checkpoint inhibitors who developed immune related adverse events requiring discontinuation who were then restarted on therapy, 31 [39%] had recurrence or toxicities requiring discontinuation again, of the 29 who had hepatitis initially, 5 had recurrence on restarting).
• Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M, Wilkins O, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res. 2018;6:1093–1099. [PMC free article: PMC6125223] [PubMed: 29991499]

  (Among 482 patients with metastatic or advanced NSCLC treated with checkpoint inhibitors at a single US referral center between 2011 and 2016, 68 [14%] developed a serious immune related adverse event [irAE] that required discontinuation of whom 38 were retreated, of whom 18 had no recurrence, 10 had recurrence of the same irAE, 10 had a new irAE [2 of which were fatal]; restarting therapy appeared to be beneficial only in those who had no tumor response before onset of the first event).
• Zarrabi K, Wu S. Risk of liver toxicity with nivolumab immunotherapy in cancer patients. Oncology. 2018;94:259–273. [PubMed: 29539626]

  (Meta-analysis of 27 clinical trials of nivolumab cancer chemotherapy found incidence of any ALT elevation to be 5% and ALT elevation above 5 times ULN 1.7%, with higher rates of any ALT elevations in 3 trials of its combination with ipilimumab [24%] vs in 17 trials of nivolumab monotherapy [3.5%]).
• Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31:965–973. [PubMed: 29403081]

  (Liver histology from 7 patients with checkpoint inhibitor [CPI] induced hepatitis [4 nivolumab, 2 ipilimumab, arising after 1-6 doses] and classical autoimmune hepatitis showed similar rates of lobular hepatitis, but less confluent necrosis with CPIs and absence of autoantibodies and IgG elevations).
• Matsubara T, Nishida T, Higaki Y, Tomita R, Shimakoshi H, Shimoda A, Osugi N, et al. Nivolumab induces sustained liver injury in a patient with malignant melanoma. Intern Med. 2018;57:1789–1792. [PMC free article: PMC6047996] [PubMed: 29434164]

  (42 year old man with metastatic melanoma developed ALT elevations after 17 cycles [1 year] of nivolumab therapy [ALT initially 380 rising to 693 U/L, Alk P 373 U/L, bilirubin 0.6 mg/dL, ANA negative], with slow response to corticosteroid therapy, ALT falling to near normal by 4 months but remaining mildly elevated after stopping).
• Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2018;41:760–765. [PubMed: 28749795]

  (Among 281 patients with cancer treated with checkpoint inhibitors at the Mayo Clinic over a 5 year period, 17 [6%] developed liver injury within 16-151 [median=52] days of starting [ipilimumab alone in 12, with nivolumab in 2 and pembrolizumab alone in 3], all with ALT elevations [59 to 2355 U/L], often with Alk P elevations [up to 1728 U/L], 6 with jaundice [bilirubin 2.5 to 15.7 mg/dL], all but one treated with corticosteroids, responding in 6 to 56 [median 31] days, 2 requiring a second agent [azathioprine or cycloserine], none fatal).
• Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–168. [PubMed: 29320654]

  (Review of the clinical features, outcomes, pathogenesis and therapy of immune related adverse events of checkpoint inhibitor therapy).
• De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, Roche B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190. [PubMed: 29427729]

  (Among 536 patients treated with checkpoint inhibitors, 19 [3.5%] were referred to a liver service for high grade hepatitis and 16 underwent liver biopsy; ages 33 to 84 years, 56% female, injury arising after 1-36 [median=5] weeks and 1-36 [median=2] doses, presenting with fever in 38%, rash in 31%, ALT 266 to 3137 [460] U/L, Alk P 54 to 768 [309] U/L, bilirubin 0.4 to 19 [1.1] mg/dL, enzyme pattern most commonly being mixed, 10 patients treated with corticosteroids and 6 resolving spontaneously and no deaths).
• Kashima J, Okuma Y, Shimizuguchi R, Chiba K. Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report. Cancer Immunol Immunother. 2018;67:61–65. [PubMed: 28913619]

  (63 year old Japanese man with refractory lung adenocarcinoma was found to have a dilated gallbladder without gallstones on routine CT scan of the chest after 4 cycles of nivolumab, subsequently he developed abdominal discomfort and imaging suggesting obstruction of lower end of common bile duct but none found of endoscopic imaging [ALT 92 U/L, Alk P 1543 U/L], improving temporarily with stenting and then more completely with high dose prednisone).
• Kuraoka N, Hara K, Terai S, Yatabe Y, Horio Y. Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer. Endoscopy. 2018;50:E259–E261. [PubMed: 29969801]

  (69 year old man with advanced, refractory adenocarcinoma of the lung, developed rash after 3^rd course of nivolumab with elevations in ALT and Alk P not responsive to prednisolone, imaging showing hypertrophy and dilatation of extrahepatic bile ducts without obstruction, endoscopy demonstrating yellow plaques and inflammation of biliary duct epithelium resulting in progressive cholestasis and death 3 months later).
• Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol. 2018;71:665–671. [PubMed: 29703758]

  (Review of the gastrointestinal and hepatic pathology of checkpoint inhibitor induced immune adverse events with acute hepatitis and acute cholangitic patterns found on liver biopsy).
• Pandey A, Ezemenari S, Liaukovich M, Richard I, Boris A. A rare case of pembrolizumab-induced reactivation of hepatitis B. Case Rep Oncol Med. 2018;2018:5985131. [PMC free article: PMC6207901] [PubMed: 30416833]

  (51 year old man with metastatic lung cancer developed liver injury after 1^st dose of pembrolizumab and was found to have reactivation of HBV [bilirubin normal, ALT 528 rising to 994 U/L, Alk P normal, HBsAg positive, HBeAg negative, HBV DNA > 170 million IU/mL], responding to tenofovir therapy, and later restarted on checkpoint inhibitor therapy).
• Zhang X, Zhou Y, Chen C, Fang W, Cai X, Zhang X, Zhao M, et al. Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition. J Immunother Cancer. 2019;7:322. [PMC free article: PMC6873745] [PubMed: 31753012]

  (Among 114 HBsAg-positive Chinese patients undergoing checkpoint inhibitor therapy for advanced malignancies, 6 developed HBV reactivation [1 of 85 on prophylaxis vs 5 of 29 not] after 3-35 [median=18] weeks of therapy with peak ALT 28 to 465 U/L, HBV DNA 1,800 to 60 million IU/mL [all were undetectable at baseline], none with jaundice, 5 treated with rapid improvement, all 6 recovered).
• Abu-Sbeih H, Tran CN, Ge PS, Bhutani MS, Alasadi M, Naing A, Jazaeri AA, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J Immunother Cancer. 2019;7:118. [PMC free article: PMC6499962] [PubMed: 31053161]

  (Among 4253 patients treated with checkpoint inhibitors at the MD Anderson Cancer Center between 2010 and 2018, 25 [0.6%] developed acalculous cholecystitis attributed to the immunotherapy most frequently with anti-CTLA-4 agents alone [1.6%], than anti-PD-1/PD-L1 [0.4%] and combination [0.9%], mean age of patients was 60 years, 60% male, 64% white, median peak ALT 55 U/L, bilirubin 1.4 mg/dL, 20% underwent cholecystectomy, all recovered, 10 [40%] restarted therapy, all without recurrence).
• Fouchard M, Jantzem H, Quere G, Descourt R, Robinet G, Poureau PG. Three cases of immune cholangitis related to anti-programmed cell death and programmed cell death ligand agents for the treatment of non-small cell lung cancer. Eur J Cancer. 2019;115:107–110. [PubMed: 31132740]

  (3 patients with metastatic lung cancer developed cholangitis 2, 4 and 9 months after starting checkpoint inhibitor therapy [nivolumab, durvalumab/tremelimumab, pembrolizumab] presenting with abdominal pain and fever, modest ALT but marked Alk P elevations and minimal jaundice; imaging showing biliary dilation and thickening of the gallbladder wall, biopsies showing inflammation with CD8+ lymphocytes, and slow clinical response to corticosteroids but long-term remission in cancer).
• Oda H, Ishihara M, Miyahara Y, Nakamura J, Kozuka Y, Iwasa M, Tsunoda A, et al. First case of cytokine release syndrome after nivolumab for gastric cancer. Case Rep Oncol. 2019;12:147–156. [PMC free article: PMC6477485] [PubMed: 31043953]

  (43 year old man with advanced, refractory gastric cancer developed high fever, fatigue and jaundice 8 days after starting nivolumab [ALT 31 rising to ~160 U/L, Alk P 598 rising to 1400 U/L, bilirubin 3.7 rising to 8 mg/dL], with concurrent elevations in serum levels of interferon gamma, TNF alpha and ferritin, responding minimally to corticosteroid therapy and dying before recovery of progressive cancer).
• Zhang HC, Luo W, Wang Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J Immunother Cancer. 2019;7:47. [PMC free article: PMC6380028] [PubMed: 30777137]

  (79 year old man with metastatic prostate cancer treated 3 cycles of nivolumab and ipilimumab developed corticosteroid-refractory immune mediated enterocolitis and was treated with a single infusion of infliximab and one month later developed jaundice [bilirubin 7.5 mg/dL, ALT 291 U/L, Alk P 677 U/L, ANA negative], which was attributed to infliximab and eventually resolved without corticosteroid therapy).
• Kopecký J, Kubecek O, Geryk T, Podhola M, Ziaran M, Priester P, Hanisova M, et al. Hepatic injury induced by a single dose of nivolumab - a case report and literature review. Klin Onkol. 2019 ;32(:133-138. [PubMed: 30995854]

  (38 year old female with metastatic melanoma developed liver injury 14 days after an initial infusion of nivolumab [bilirubin 6.1 rising to 21 mg/dL, ALT 720 rising to 3012 U/L, GGT >2000 U/L], with only a partial response to corticosteroids and mycophenolate and death from progressive disease 2 months later).
• Sawada K, Shonaka T, Nishikawa Y, Hasegawa K, Hayashi H, Hasebe T, Nakajima S, et al. Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature. Intern Med. 2019;58:1747–1752. [PMC free article: PMC6630117] [PubMed: 30799364]

  (76 year old man with advanced gastric cancer developed marked Alk P elevations after 4 cycles of nivolumab [bilirubin 0.8 mg/dL, ALT 68 U/L, Alk P 2427 U/L], biopsy showing eosinophilic cholangitis and prednisolone therapy followed by a rapid improvement).
• Cheung V, Gupta T, Payne M, Middleton MR, Collier JD, Simmons A, Klenerman P, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterol. 2019;10(4):364–371. [PMC free article: PMC6788136] [PubMed: 31656561]

  (Among 453 patients treated with checkpoint inhibitors for cancer between 2022 and 2018, 20 [4%] developed immune related hepatitis, with highest rates with the combination of ipilimumab and nivolumab, 18 treated with immunosuppression using corticosteroids, 8 with addition of mycophenolate and 2 with infliximab, none fatal).
• Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019;36:434–440. [PubMed: 31358424]

  (Liver histology from 7 patients with checkpoint inhibitor [CPI] induced hepatitis [4 nivolumab, 2 ipilimumab, arising after 1-6 doses] and classical autoimmune hepatitis showed similar rates of lobular hepatitis, but less confluent necrosis with CPIs and absence of autoantibodies and IgG elevations).
• Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE. Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors. Eur J Cancer. 2019;123:112–115. [PubMed: 31678768]

  (Review of the VigiBase registry of adverse drug reactions through September 2018 identified 531 cases of immune related hepatitis, 85% due to CPIs alone with an increase in fatality rate over time, being 14% between 2011 to 2016 and 34% in 2017-2018, time to onset median of 42 days, arising after 1-4 courses [median=2] and with concurrent other organ immune related injury in 31%, usually thyroid or skin).
• Zhang D, Hart J, Ding X, Zhang X, Feely M, Yassan L, Alpert L, et al. Histologic patterns of liver injury induced by anti-PD-1 therapy. Gastroenterol Rep (Oxf). 2019;8:50–55. [PMC free article: PMC7244961] [PubMed: 32467761]

  (Liver histology in 8 cases of immune mediated liver injury after monoclonal anti-PD-1 therapy revealed a lobular hepatitis without features of autoimmune hepatitis).
• Imoto K, Kohjima M, Hioki T, Kurashige T, Kurokawa M, Tashiro S, Suzuki H, et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol. 2019;2019:6391712. [PMC free article: PMC6935806] [PubMed: 31929981]

  (Among 343 Japanese patients with cancer treated with checkpoint inhibitors, 56 [16%] developed evidence of liver injury, arising after 21-94 [median=46] days, with initial ALT 39 to 136 [mean 60] U/L, Alk P 263 to 857 [471] U/L, bilirubin 0.4 to 1.0 [0.7] mg/dL, and thus a cholestatic pattern was found in most patients, and there was a low rate of high grade liver injury [3.2%] and no fatalities).
• Onoyama T, Takeda Y, Yamashita T, Hamamoto W, Sakamoto Y, Koda H, Kawata S, et al. Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review. World J Gastroenterol. 2020;26:353–365. [PMC free article: PMC6969883] [PubMed: 31988594]

  (Review of literature on secondary sclerosing cholangitis due to anti-PD-1/PD-L1 therapy identified 31 cases with male:female ratio of 2:1, median age 67 [range 43-89] years, arising after a median of 5.5 [range 1-27] cycles of nivolumab [19], pembrolizumab [10], avelumab [1], or durvalumab [1], with median bilirubin 0.8 [0.3-15.9] mg/dL, ALT 125 [31-1536] U/L, AST 129 [49-961] U/L, Alk P 1543 [237-5066] U/L, GGT 452 [114-2094] U/L, cholangiography demonstrating biliary dilation without obstruction [77%], hypertrophy of the extrahepatic biliary tree [90%], and biliary strictures [30%] and biopsy demonstrating CD8+ infiltrates around bile ducts, and adequate response to corticosteroids in only 11%).
• Zen Y, Chen YY, Jeng YM, Tsai HW, Yeh MM. Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes. Histopathology. 2020;76:470–480. [PubMed: 31550390]

  (Description of 10 cases of second generation checkpoint inhibitor induced immune liver injury mentions 3 patterns, hepatocellular, cholestatic and granulomatous injury, the cholestatic form often with a delayed latency and poor response to corticosteroids).
• Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology. 2020;72:315–329. [PubMed: 32167613]

  (Review of the clinical features, biochemical findings, histology, pathogenesis, diagnosis and management of immune related liver injury due to the checkpoint inhibitors).
• Miller ED, Abu-Sbeih H, Styskel B, Nogueras Gonzalez GM, Blechacz B, Naing A, et al. Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors. Am J Gastroenterol. 2020;115:251–261. [PubMed: 31789632]

  (Among 5762 recipients of checkpoint inhibitor therapy of cancer at the MD Anderson Cancer Center between 2010 and 2018, 433 [8%] developed ALT levels and 100 had levels above 5 times ULN [2%), the rate being 8% with combination therapy, 1.7% with anti-CTLA agents and 1.1% with PD-1 and PD-L1 blockers, the abnormalities arising after a median 59 days; all had the checkpoint inhibitor therapy held, 67 received corticosteroids [for a median of 43 days], 3 with mycophenolate, and 31 were rechallenged after resolution of the hepatitis, of whom 8 [26%] had a recurrence).
• Mathew Thomas V, Bindal P, Ann Alexander S, McDonald K. Nivolumab-induced hepatitis: A rare side effect of an immune checkpoint inhibitor. J Oncol Pharm Pract. 2020;26:459–461. [PubMed: 30909794]

  (74 year old woman with recurrent, metastatic renal cell carcinoma developed jaundice 2 weeks after starting nivolumab [bilirubin 2 mg/dL, ALT 112 U/L, Alk P not given] and was treated with high doses of corticosteroids which led to improvement, but she died shortly thereafter of gastrointestinal bleeding and multiorgan failure ).
• Nordness MF, Hamel S, Godfrey CM, Shi C, Johnson DB, Goff LW, O'Dell H, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant. 2020;20:879–883. [PMC free article: PMC10176099] [PubMed: 31550417]

  (65 year old man with cirrhosis due to successfully treated chronic hepatitis C and hepatocellular carcinoma on long term nivolumab therapy underwent liver transplantation but developed severe hepatic necrosis starting on post-transplant day 5 [AST 6,000 rising to 19,000 U/L, bilirubin 2.0 rising to 17.0 mg/dL and INR to 10], leading to multiorgan failure and death).
• Sawada K, Hayashi H, Nakajima S, Hasebe T, Fujiya M, Okumura T. Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020 Jun;35(6):1042–1048. [PubMed: 31752049]

  (Among 135 patients with cancer treated with nivolumab or pembrolizumab, 8 developed immune mediated hepatitis of whom 3 [37.5%] had preexisting chronic liver disease versus 14 of the total [10.3%]).
• Anugwom C, Leventhal T. Nivolumab-induced autoimmune-like cholestatic hepatitis in a liver transplant recipient. ACG Case Rep J. 2020;7:e00416. [PMC free article: PMC7363460] [PubMed: 32766358]

  (62 year old man with alcohol and HCV related cirrhosis and HCC underwent liver transplantation but had recurrence of HCC and de novo metastatic NSCLC after transplant, which was refractory to conventional chemotherapy and who developed severe cholestatic hepatitis within 2 months of starting nivolumab [bilirubin 8.3 rising to 24 mg/dL, ALT 1265 U/L, Alk P 813 U/L], with subsequent infection, multiorgan failure and gastrointestinal bleeding and death within two weeks of presentation).
• Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, et al. Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. J Gastroenterol Hepatol. 2020;35:1782–1788. [PubMed: 32187734]

  (Among 202 patients with cancer treated with checkpoint inhibitors at a single referral center in Japan, 17 [8.5%] developed immune related hepatitis, which was severe in 8 [4.5%] often requiring corticosteroids, 2 receiving mycophenolate as well, but none died).
• Ruggiero R, Fraenza F, Scavone C, di Mauro G, Piscitelli R, Mascolo A, Ferrajolo C, et al. Immune checkpoint inhibitors and immune-related adverse drug reactions: data from Italian Pharmacovigilance Database. Front Pharmacol. 2020;11:830. [PMC free article: PMC7295943] [PubMed: 32581796]

  (Among 2088 safety reports of check point inhibitors enrolled in an Italian pharmacovigilance registry, 801 were immune related including gastrointestinal [33%], skin [17%] and liver [2.7%] due to nivolumab [70%], pembrolizumab [11%], ipilimumab [15%], atezolizumab [4%] and avelumab [<1%]).
• Riveiro-Barciela M, Barreira-Díaz A, Vidal-González J, Muñoz-Couselo E, Martínez-Valle F, Viladomiu L, Mínguez B, et al. Immune-related hepatitis related to checkpoint inhibitors: clinical and prognostic factors. Liver Int. 2020;40:1906–1916. [PubMed: 32329119]

  (Among 414 patients treated with checkpoint inhibitors, 28 developed high grade liver injury but 19 were considered mild, 7 moderate, 1 severe and 1 fatal).
• Vitale G, Lamberti G, Comito F, Di Nunno V, Massari F, Morelli MC, Ardizzoni A, et al. Anti-programmed cell death-1 and anti-programmed cell death ligand-1 immune-related liver diseases: from clinical pivotal studies to real-life experience. Expert Opin Biol Ther. 2020;20:1047–1059. [PubMed: 32425081]

  (Review of the hepatic complications of anti-PD-1 and anti-PD-L1 checkpoint inhibitors that includes immune mediated hepatitis [typically panlobular inflammation and injury], small and large duct cholangitis [similar to primary biliary and sclerosing cholangitis], immune mediated cholecystitis, nodular regenerative hyperplasia and vanishing bile duct syndrome).
• Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, et al. Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. J Gastroenterol Hepatol. 2020;35:1782–1788. [PubMed: 32187734]

  (Among 202 patients with cancer treated with checkpoint inhibitors at a single referral center in Japan, 17 [8.5%] developed immune related hepatitis which was severe in 8 [4.5%], often requiring corticosteroids, 2 receiving mycophenolate as well, but none died).
• Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies. J Gastroenterol. 2020;55:653–661. [PubMed: 32124082]

  (Among 546 patients with advanced malignancies treated with checkpoint inhibitors at two Japanese referral centers between 2014 and 2019, high grade, immune mediated liver injury occurred in 29 [5%], mean age 69 years, 73% male, mean onset 52 [range 1-273] days, after 3 [1-15] doses of ipilimumab [6%], nivolumab [54%], pembrolizumab [30%], atezolizumab [6%], durvalumab [2.4%], combination [1.3%], presenting with hepatocellular [21%], cholestatic [59%] or mixed [21%] enzyme elevations, 4 with cholangitis and biliary dilatation without obstruction, only 1 case fatal; predictive factors for injury included ipilimumab [hazard ratio 4.2]).
• Lee PC, Chao Y, Chen MH, Lan KH, Lee IC, Hou MC, Huang YH. Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunother Cancer. 2020;8:e001072. [PMC free article: PMC7462159] [PubMed: 32863270]

  (Among 62 Taiwanese patients with HBsAg or anti-HBc without HBsAg treated with checkpoint inhibitors for advanced HCC, reactivation of HBV rose in none of 56 given prophylaxis vs 1 of 6 not given antiviral prophylaxis: the one case in an HBsAg positive patient with HBV DNA 8960 IU/mL at baseline rising to 168,000 IU/mL, peak ALT 174U/L, bilirubin 5.2 mg/dL, resolving with tenofovir therapy).
• Wong GL, Wong VW, Hui VW, Yip TC, Tse YK, Liang LY, Lui RN, et al. Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection. Am J Gastroenterol. 2021;116:1274–1283. [PubMed: 33560651]

  (Among 990 patients in Hong Kong with advanced malignancies treated with checkpoint inhibitors between 2014 and 2019 [397 HBsAg positive, 482 with anti-HBc or anti-HBs, 111 negative for both at baseline], 39% of HBsAg-positive vs 30% of HBsAg-negative patients developed ALT elevations during therapy, but only two cases [both HBsAg positive and on prophylaxis] were due to HBV reactivation).
• Cho YA, Han JM, Kang SY, Kim DC, Youn YJ, Choi KH, Gwak HS. Analysis of risk factors for hepatotoxicity induced by immune checkpoint Inhibitors. J Immunother. 2021;44:16–21. [PubMed: 33290362]

  (Among 194 patients with cancer treated with checkpoint inhibitors at two Korean referral centers, 125 [64%] developed liver test abnormalities, more frequently in younger patients vs older [30-50 years - 80% vs 50-70 years - 72%, and >70 years - 50%] and in men than women [68% vs 58%]).
• Gauci ML, Baroudjian B, Bédérède U, Zeboulon C, Delyon J, Allayous C, Madelaine I, et al. PATIO group. Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal. Clin Res Hepatol Gastroenterol. 2021;45:101491. [PubMed: 32773362]

  (Among 339 patients treated at a single French referral center with checkpoint inhibitors, 21 [6.2%] developed high grade liver toxicity, including 8% [7/86] receiving ipilimumab, 3% [3/105] nivolumab, 1% [1/122] pembrolizumab and 38% [10/26] combination therapy; 13 patients received corticosteroids, all except one with severe biliary lesions recovered and 8 restarted therapy none of whom relapsed).
• Yoshikawa Y, Imamura M, Yamaoka K, Kosaka Y, Murakami E, Morio K, Fujino H, et al. A case with life-threatening secondary sclerosing cholangitis caused by nivolumab. Clin J Gastroenterol. 2021;14:283–287. [PubMed: 33200345]

  (75 year old man with metastatic NSCLC developed marked liver abnormalities after 3 cycles of nivolumab [bilirubin 0.6 mg/dL, ALT 162 U/L, Alk P 1721 U/L, ANA negative] with biliary imaging showing diffuse dilation of the common bile duct and multifocal stenosis, with progressive cholestatic liver injury and death from liver failure despite therapy with corticosteroids and ursodiol).
• Au M, Body A, Mant A, Nicoll A. Checkpoint inhibitor induced steroid refractory drug-induced liver injury. Intern Med J. 2021;51:810–811. [PubMed: 34047030]

  (75 year old man with metastatic melanoma developed ALT elevations [peak 451 U/L] starting 4 weeks after starting ipilimumab and nivolumab, treated with corticosteroids with a prompt improvement but relapse once prednisone was tapered [ALT 647 U/L], which responded with addition of mycophenolate).
• Ortland I, Mirjalili M, Kullak-Ublick GA, Peymani P. Drug-induced liver injury in Switzerland: an analysis of drug-related hepatic disorders in the WHO pharmacovigilance database VigiBase™ from 2010 to 2020. Swiss Med Wkly. 2021;151:w20503. [PubMed: 34000058]

  (Among 2042 cases of drug induced liver injury reported from Switzerland to VigiBase between 2010 and 2020, average age 57 years, males and females similar proportions, 10% were fatal and the most common causes included acetaminophen [5.8%], amoxicillin/clavulanate 3.1%, esomeprazole [2.0%], atorvastatin [1.9%], and nivolumab [1.3%]).
• Yamamoto A, Yano Y, Ueda Y, Yasutomi E, Hatazawa Y, Hayashi H, Yoshida R, et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers. J Cancer Res Clin Oncol. 2021;147:1747–1756. [PubMed: 33222015]

  (Among 250 patients with cancer treated with checkpoint inhibitors, 21 [9.5%] developed immune mediated liver injury, most frequently with ipilimumab [60%], ipilimumab and nivolumab [57%] compared to nivolumab alone [7%] or pembrolizumab [3%], and rates were higher in patients with melanoma [35%] compared to renal cell cancer [10%] and others).
• Aya F, González-Navarro EA, Martínez C, Carcelero E, Arance A. Safe anti-programmed cell death-1 rechallenge with antibody switching after immune-related adverse events: brief communication. Immunotherapy. 2021;13:745–752. [PubMed: 33906373]

  (68 year old woman with metastatic melanoma developed ALT elevations [215 U/L] after an initial dose of nivolumab, which resolved rapidly with prednisone therapy and she was later tolerated pembrolizumab without recurrent hepatic injury).
• da Silva JA, Falcão D, Cardoso C, Pires AL, Araújo A, Castro-Poças F. Hepatic immune-mediated adverse effects of immune checkpoint inhibitors: analysis of real-life experience. Ann Hepatol. 2021;26:100561. [PubMed: 34653687]

  (Among 151 patients treated with checkpoint inhibitors, 8 [5%] developed liver injury, 5 due to metastases and 3 from immune mediated hepatitis, 2 from nivolumab and 1 pembrolizumab, with latency of 84 days, all three cholestatic and responding to immunosuppression).
• Arai K, Matsuda M, Nakayasu H, Meguro S, Kurokami T, Kubota A, Iwasaki T, et al. Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: an autopsy case report. Clin Case Rep. 2021;9:e05174. [PMC free article: PMC8697699] [PubMed: 34987810]

  (75 year old man with refractory, advanced mesothelioma, developed liver injury during a second cycle of nivolumab [ALT 397 U/L, Alk P 272 U/L, bilirubin 0.4 to 0.7 mg/dL] who had progressive liver injury despite immunosuppression).
• Mustafayev K, Torres H. Hepatitis B virus and hepatitis C virus reactivation in cancer patients receiving novel anticancer therapies. Clin Microbiol Infect. 2022: S1198-743X (22)00119-7. [PubMed: 35283317]

  (Review of the literature on reactivation of HBV and HCV in patients on “novel” anticancer therapy concludes that reactivation can occur with checkpoint inhibitor therapy, but largely among HBsAg positive patients and only rarely in patients with resolved hepatitis B).
• Yoo S, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Yoo C, et al. Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment. Clin Gastroenterol Hepatol. 2022;20:898–907. [PubMed: 34182151]

  (Among 3,465 patients with advanced malignancies treated with checkpoint inhibitors between 2015 and 2020 at a single referral center in Korean, 511 [15%] were HBsAg positive at baseline, reactivation of HBV occurred in 5 of 511 [1%] HBsAg positive vs none of 2,954 HBsAg negative patients, arising in 2 of 464 [0.4%] patients given prophylaxis [both having stopped antivirals] vs 3 of 47 not given prophylaxis [6.4%]; reactivation arising after 3-141 weeks [median=54 weeks] of nivolumab [n=2], pembrolizumab [n=2] or ipilimumab and nivolumab [n=1] treatment, ALT peak 53 to 1768 IU/mL, HBV DNA 6,100 to 3.9 million IU/mL, resolving with 2 to 6 weeks of starting antiviral therapy).