OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ivosidenib – Tibsovo®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 06 January 2024

Abbreviation: AML, acute myelogenous leukemia; IDH, Isocitrate dehydrogenase.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of kinase inhibitors).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013 before the availability of ivosidenib and enasidenib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan 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/drugsatfda_docs​/nda/2018/211192Orig1s000MultidisciplineR.pdf

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy).
• Birendra KC, DiNardo CD. Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 2016; 16: 460-5. [PMC free article: PMC4983480] [PubMed: 27245312]

  (Three patients with AML and mutant IDH1 who were treated with ivosidenib developed clinically apparent differentiation syndrome during the first two cycles of therapy manifested by neutrophil-predominant leukocytosis, fever, cough, shortness of breath, pulmonary failure, pleural and pericardial effusions; treated successfully with corticosteroids and hydroxyurea which allowed subsequent courses of ivosidenib; no mention of ALT elevations or hepatic involvement).
• Upadhyay VA, Brunner AM, Fathi AT. Isocitrate dehydrogenase (IDH) inhibition as treatment of myeloid malignancies: Progress and future directions. Pharmacol Ther 2017; 177: 123-8. [PubMed: 28315358]

  (Review of the role of mutations in IDH-1 and -2 in oncogenesis which act as “oncometabolites” causing accumulation of 2-hydroxyglutarate which inhibits histone demethylases causing epigenetic changes in cellular differentiation genes, factors that make these mutation enzymes promising targets for anticancer therapeutics).
• DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018; 378: 2386-98. [PubMed: 29860938]

  (Among 258 patients with relapsed or refractory, IDH1 mutant AML who were treated with ivosidenib, the overall response rate was 42% and adverse events included diarrhea [21%], leukocytosis [30%], febrile neutropenia [29%], fatigue [26%], dyspnea [25%], QTc prolongation [25%], peripheral edema [22%], anemia [22%], cough [21%] and differentiation syndrome [5%, none fatal], while ALT elevations occurred in 27% of patients, but values were above 5 times ULN in less than 1%).
• Fathi AT, DiNardo CD, Kline I, Kenvin L, Gupta I, Attar EC, Stein EM, de Botton S; AG221-C-001 Study Investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 2018; 4: 1106-10. [PMC free article: PMC5885269] [PubMed: 29346478]

  (Among 281 patients with AML treated with enasidenib [50-650 mg daily] in open label trials, 33 [12%] were judged to have developed differentiation syndrome marked by dyspnea, fever, lung infiltrates and hypoxia with onset after 7-129 days [median 30 days], usually responding to corticosteroid therapy, half requiring dose interruption, none dying acutely, and all able to restart enasidenib after its resolution).
• Norsworthy KJ, Luo L, Hsu V, Gudi R, Dorff SE, Przepiorka D, Deisseroth A, et al. FDA approval summary: ivosidenib for relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-1 mutation. Clin Cancer Res. 2019;25:3205-3209. [PubMed: 30692099]

  (Review of the data on safety and efficacy of ivosidenib that supported its approval as therapy of relapsed or refractory AML with mutant IDH1, mentions that adverse events occurred in 99% of patients and included serious cases of differentiation syndrome [13%], QT prolongation [10%], dyspnea [9%], leukocytosis [8%], tumor lysis syndrome [6%], resulting in therapy interruption in 38%, discontinuation 13%; no mention of ALT elevations or hepatotoxicity).
• Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, et al. Ivosidenib IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796-807. [PMC free article: PMC7523268] [PubMed: 32416072]

  (Among 185 adults with IDH1 mutant, refractory cholangiocarcinoma treated with ivosidenib or placebo, the objective response rate was only 2% vs 0% and progression free survival minimally longer [2.7 vs 1.4 months] while adverse event rates were high, ALT elevations arising in 9% vs 2% and bilirubin elevations in 10% vs 7%).
• DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, Döhner H, et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2021;39:57-65. [PMC free article: PMC7771719] [PubMed: 33119479]

  (Among 23 patients with refractory IDH1 mutant AML treated with ivosidenib and azacytidine, the objective response rate was 71% and all patients had at least one adverse event, most commonly thrombocytopenia, anemia, febrile neutropenia, nausea, diarrhea, constipation, and pyrexia, but there were no treatment related deaths; no mention of ALT elevations or hepatotoxicity).
• Stemer G, Rowe JM, Ofran Y. Efficacy and safety profile of ivosidenib in the management of patients with acute myeloid leukemia (AML): an update on the emerging evidence. Blood Lymphat Cancer. 2021;11:41-54. [PMC free article: PMC8235936] [PubMed: 34188585]

  (Review of the efficacy and safety of ivosidenib does not mention ALT elevations or hepatotoxicity).
• Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy Trial. JAMA Oncol. 2021;7:1669-1677. [PMC free article: PMC8461552] [PubMed: 34554208]

  (Final survival results from the randomized controlled trial of ivosidenib vs placebo in 187 adults with irresectable or metastatic cholangiocarcinoma with mutant IDH1, provides the overall survival of 10.3 vs 7.5 months with serious treatment related adverse events in 42% vs 24%, including three cases of hyperbilirubinemia during ivosidenib therapy, one of which was considered due to cholestatic hepatitis, but there were no treatment related deaths).
• Woods A, Norsworthy KJ, Wang X, Vallejo J, Chow ECY, Li RJ, Sun J, et al. FDA approval summary: ivosidenib in combination with azacitidine for treatment of patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. Clin Cancer Res. 2023 Nov 27. Epub ahead of print. [PubMed: 38010220]

  (Review of the data on safety and efficacy of the combination of ivosidenib and azacytidine as therapy for newly diagnosed AML in patients above the age of 75, found an improved overall survival with the combination of 24 vs 9 months with azacytidine alone, but similar rates of adverse events, with dose interruptions in 56%, dose modifications in 14%, and discontinuations in 31%, the major serious adverse events being differentiation syndrome and prolongation of the QTc interval; no mention of ALT elevations or hepatotoxicity).