OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Copanlisib	1032568-63-0	C26-H23-N7-O2

ANNOTATED BIBLIOGRAPHY

References updated: 20 October 2018

• 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 tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Gefitinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; does not discuss copanlisib).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/scripts/cder/daf/

  (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).
• Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997-1007. [PMC free article: PMC4161365] [PubMed: 24450857]

  (Among 220 patients with relapsed CLL treated in a placebo controlled trial, progression free survival improved with idelalisib and rituximab compared to rituximab alone, but side effects were more common with the combination including ALT or AST elevations [35% vs 19%], which were above 5 times ULN in 5% vs 1% and led to drug discontinuations in some patients, but there were no clinically apparent cases of liver injury).
• Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Weiss GJ. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol 2016; 27: 1928-40. [PMC free article: PMC5035790] [PubMed: 27672108]

  (Dose ranging studies in patients with diabetes and patients with various forms of cancer identified the maximum tolerated dose and yielded promising results in follicular lymphoma; adverse events were frequent but generally mild-to-moderate in severity, transient and asymptomatic ALT elevations occurring in 34% of subjects but only one had levels above 5 times ULN).
• Greenwell IB, Ip A, Cohen JB. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park) 2017; 31: 821-8. [PubMed: 29179250]

  (Review of the toxicities of PI3K inhibitors, their pathogenesis, frequency and management; mentions that idelalisib is associated with autoimmune hepatitis-like reactions that generally respond to drug discontinuation and that liver injury is less frequent and milder with copanlisib therapy).
• Markham A. Copanlisib: first global approval. Drugs 2017; 77: 2057-62. [PubMed: 29127587]

  (Review of the mechanism of action, history of development, clinical efficacy and safety of copanlisib does not mention ALT elevations or hepatotoxicity).
• Dreyling M, Santoro A, Mollica L, Leppä S, Follows GA, Lenz G, Kim WS, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 2017; 35: 3898-905. [PubMed: 28976790]

  (Among 142 patients with relapsed or refractory indolent lymphoma treated with copanlisib, the objective response rate was 59% and adverse events were frequent including ALT elevations in 23% which were above 5 times ULN in 2 patients [2%]).
• Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol 2017; 28: 2169-78. [PMC free article: PMC5834070] [PubMed: 28633365]

  (Among 84 patients with lymphoma treated with copanlisib on days 1, 8 and 15 of 28-day cycles, the objective response rate was 44% in patients with indolent lymphoma and 27% with aggressive lymphoma and common adverse events were hyperglycemia [57%], hypertension [55%] and diarrhea [41%]; ALT elevations occurred in 26% of patients and were above 5 times ULN in 4%).
• Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol 2018; 15: 273-91. [PubMed: 29508857]

  (Thorough review of the role of PI3K in cellular pathways and the promise of specific inhibitors as therapy of metabolic and neoplastic diseases).
• Copanlisib (Aliqopa) for relapsed follicular lymphoma. Med Lett Drugs Ther 2018; 60 (1545): e74-e75. [PubMed: 29667951]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of copanlisib shortly after its approval in the US for relapsed follicular lymphoma mentions adverse effects including hyperglycemia, leukopenia, hypertension and lung infections, but not ALT elevations or hepatotoxicity).