OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Atezolizumab – Tecentriq®

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.

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-54.

  (Expert review of hepatotoxicity published in 1999, well before the availability of most monoclonal antibody therapies).
• Reuben A. Biological immunosuppressives. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 580-2.

  (Review of hepatotoxicity of immunosuppressive agents; mentions that "the biological immunosuppressants are largely free from hepatotoxicity, except for the TNF alpha antagonists"; checkpoint inhibitors such as atezolizumab were not specifically discussed).
• 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​=761034.

  (FDA website with current and previous product labels and the 2016 initial FDA medical review of the New Drug Application for atezolizumab).
• 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 checkpoint inhibitor [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, Ipilimumab).
• Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol. 2010;37:499–507. [PubMed: 21074065]

  (Review of immune related adverse events including hepatitis associated with ipilimumab therapy; recommends stopping therapy for grade 3 toxicity [ALT >5 times ULN] and initiating corticosteroids for at least 30 days).
• Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26. [PubMed: 21639810]

  (Control trial of ipilimumab and dacarbazine vs dacarbazine alone in 502 patients with metastatic melanoma found ALT elevations in 33% on the combination vs 6% on dacarbazine alone, and ALT values above 5 times ULN in 16% vs 0.7%, but no deaths were due to liver failure).
• 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 to 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, Ipilimumab).
• Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7. [PubMed: 22614989]

  (Review of the immune related adverse events associated with ipilimumab therapy and their management mentions that hepatotoxicity occurs in 3-9% of patients usually with asymptomatic increases in ALT and bilirubin, but some with symptoms; authors recommend use of high doses of corticosteroids for 2 days followed by tapering doses to at least 30 days; multiple courses may be necessary and ipilimumab should not be restarted).
• Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS. MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119:1675–82. [PubMed: 23400564]

  (In clinical trials of ipilimumab in 676 patients with melanoma, immune related adverse events occurred in ~60% of patients arising 3-9 weeks after starting and often mild, but severe in 12% and fatal in 1%, including one case of acute liver failure).
• Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013;18:733–43. [PMC free article: PMC4063401] [PubMed: 23774827]

  (Thorough review of side effects of ipilimumab therapy of melanoma states that common adverse events include fatigue, nausea, vomiting, diarrhea, fever, headache, dizziness, rash and pruritus occurring in 70-88% of patients and that hepatotoxicity occurs in 2-9% that can be self-limited, but also can be severe and require corticosteroid therapy).
• McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S. MDX010-20 Investigators. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013;24:2694–8. [PubMed: 23942774]

  (Among 676 patients with melanoma enrolled in the phase III trial of ipilimumab, 94 [20%] survived for 2 years and 42 [16%] for 3 years; late onset immune related adverse events occurred in 11 patients [14%], but were usually mild and none were hepatic).
• Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62. [PubMed: 25428503]

  (Among 68 patients with metastatic bladder cancer treated with atezolizumab, the objective response rate was 26% and was higher in patients whose tumors stained strongly positive for PD-L1 [43%] than not [11%]; adverse events included transient AST elevations in 3%, but levels were less than 5 times ULN in all).
• Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, Ott PA, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122:3344–53. [PMC free article: PMC5767160] [PubMed: 27533448]

  (Among 58 patients with metastatic ocular melanoma treated with various monoclonal checkpoint inhibitors, the objective response rate was only 3%, well below rates in non-uveal melanoma; only 1 patient had ALT elevations, but they were less than 5 times ULN and there were no hepatic severe adverse events).
• Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, Kawakami T, et al. Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest New Drugs. 2016;34:596–603. [PMC free article: PMC5007272] [PubMed: 27363843]

  (Among 6 patients with advanced solid cancers treated with atezolizumab [10-20 mg/kg every 3 weeks], adverse events were generally mild and ALT elevations occurred in only 2 patients, both with levels less than 3 times ULN and not requiring drug discontinuation).
• Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20. [PMC free article: PMC5480242] [PubMed: 26952546]

  (Among 315 patients with refractory metastatic bladder cancer treated with atezolizumab [1200 mg every 3 weeks], the objective response rate was 15% and adverse events included fatigue [30%], nausea [14%], anorexia [12%], pruritus [10%], fever [9%], diarrhea [8%] and rash [7%], while immune mediated events occurred in 23 [7%] including AST elevations in 10 [3%] which were above 5 times ULN in 2 [<1%]).
• Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, et al. POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. [PubMed: 26970723]

  (Among 277 patients with refractory NSCLC treated with atezolizumab or docetaxel every 3 weeks, overall survival was 12.6 vs 9.7 months, but adverse events were more common with docetaxel; 6 atezolizumab-treated patients [4%] had ALT elevations above 5 times ULN and one had mild "hepatitis").
• McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, Powderly JD, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016;34:833–42. [PubMed: 26755520]

  (Among 70 patients with metastatic renal cell cancer treated with atezolizumab every 3 weeks for 1 year, the objective response rate was 15%; ALT elevations above 5 times ULN occurred in 1 patient only, and immune mediated adverse events occurred in 30 [43%], 6 of whom required corticosteroid therapy).
• Abdel-Rahman O, Helbling D, Schmidt J, Petrausch U, Giryes A, Mehrabi A, Schöb O, et al. Treatment-related death in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Clin Oncol (R Coll Radiol). 2017;29:218–30. [PubMed: 27894673]

  (Review of 18 trials of checkpoint inhibitors found a lower rate of treatment related deaths from anti-PD-1/-PD-L1 than for anti-CTLA-4 inhibitors).
• 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 cholangitis patterns found on liver biopsy).
• 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).
• 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).
• 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).
• 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 to 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, histologic findings of inflammation and scarring of bile duct epithelium, found most frequently with pembrolizumab and atezolizumab).
• Tsukita Y, Miyauchi E, Fukudo M, Sasaki T, Ichinose M. Immunotherapy-related hepatitis and thrombocytopaenia induced by the very low dose of only 90 mg of atezolizumab. Eur J Cancer. 2020;133:22–24. [PubMed: 32422505]

  (76 year old woman with NSCLC developed bradycardia during an initial infusion of atezolizumab which was discontinued [total dose 90 mg] but she then developed fatigue 15 days later with liver abnormalities and thrombocytopenia [bilirubin not given, ALT 130 U/L, Alk P 768 U/L, platelets 38,000/µL], which responded promptly to prednisolone with normal ALT and platelets in follow up).
• 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).
• 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 of 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).
• 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%]).
• 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%]).
• Fujii M, Ozato T, Mizukawa S, Nasu J, Kawai H, Fujioka SI, Yoshioka M, et al. A rare case of immunotherapy-induced cholangitis and gastritis. Clin J Gastroenterol. 2020;13:1083–1090. [PubMed: 32886336]

  (50 year old Japanese man with undifferential carcinoma of unknown source who developed refractory biliary disease after 2 months of therapy with atezolizumab and ramucirumab with thickened walls of gallbladder and dilation of bile ducts without obstruction, endoscopic biopsy of bile duct epithelium showing inflammation with CD8+ lymphocytic infiltrates [ALT 45 U/L, Alk P 1295 U/L, bilirubin not given], with ultimate recovery with corticosteroid therapy).
• 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]).
• Nabeshima S, Yamasaki M, Matsumoto N, Takaki S, Nishi Y, Kawamoto K, Taniwaki M, et al. Atezolizumab-induced sclerosing cholangitis in a patient with lung cancer: a case report. Cancer Treat Res Commun. 2021;26:100270. [PubMed: 33338849]

  (77 year old Japanese woman with advanced adenocarcinoma of the lung developed nausea after 13 cycles of atezolizumab [bilirubin 2.6 mg/dL, ALT 193 UL, Alk P 2837], liver biopsy resembling sclerosing cholangitis with minimal response to ursodiol and marked response to prednisone although Alk P remained elevated).
• Honma Y, Shibata M, Gohda T, Matsumiya H, Kumamoto K, Miyama A, Morino K, et al. Rapid progression of liver fibrosis Induced by acute liver injury due to immune-related adverse events of atezolizumab. Intern Med. 2021;60:1847–1853. [PMC free article: PMC8263175] [PubMed: 33456046]

  (72 year old Japanese woman with advanced lung cancer developed liver injury after 3 monthly cycles of atezolizumab and bevacizumab with carboplatin and paclitaxel [bilirubin 0.6 mg/dL, ALT 208 U/L, Alk P 1075 U/L, INR 1.12], biopsy showing a panlobular hepatitis, treated with ursodiol with partial effect [bilirubin 3.2 mg/dL, ALT ~180 U/L, Alk P ~850 U/L], with second biopsy showing bridging fibrosis; addition of prednisolone resulted in further but incomplete biochemical improvement).
• 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).
• Mustafayev K, Torres H. Hepatitis B virus and hepatitis C virus reactivation in cancer patients receiving novel anticancer therapies. Clin Microbiol Infect. 2022 Mar 10: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).
• Tzadok R, Levy S, Aouizerate J, Shibolet O. Acute liver failure following a single dose of atezolizumab, as assessed for causality using the updated RUCAM. Case Rep Gastrointest Med. 2022;2022:5090200. [PMC free article: PMC8967548] [PubMed: 35368450]

  (46 year old man with refractory, locally invasive adenocarcinoma of lung developed weakness and pain 2 weeks after an initial dose of atezolizumab [bilirubin 0.3 mg/dL, ALT 485 rising to 2124 U/L, Alk P 253 U/L, creatinine 2.8, INR 1.32 rising to 2.91], with progressive lactic acidosis and hepatic failure, biopsy showing severe zone 3 necrosis and slight inflammation and sinusoidal dilation but no fibrosis, dying within 5 days of presentation).
• Kotha S, Zen Y, Berry P. Diagnostic, therapeutic and prognostic challenges in a jaundiced patient treated with a checkpoint inhibitor. Clin J Gastroenterol. 2022;15:446–450. [PubMed: 35152370]

  (42 year old man with metastatic NSCLC on treatment with maintenance atezolizumab developed jaundice, diffuse biliary dilatation without obstruction, and ascites [bilirubin 10.0 rising to 16.4 mg/dL, ALT 603 U/L, Alk P 889 U/L], biopsy showing marked cholestasis with little inflammation and malignant cells in hepatic vessels suggestive of malignant rather than checkpoint induced cholangiopathy).