OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Lorlatinib	1454846-35-5	C21-H19-F-N6-O2

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

Abbreviations used: NSCLC, non-small cell lung cancer; ALK, anaplastic lymphoma kinase.

• 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; crizotinib is listed as causing moderate-to-severe aminotransferase elevations in 4-7% of patients and as having caused fatal hepatotoxicity in some instances, but there is no mention of lorlatinib).
• 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).
• 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).
• Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013; 31: 1105-11. [PMC free article: PMC4209068] [PubMed: 23401436]

  (Review of the history of discovery of ALK mutations and development of crizotinib as therapy of NSCLC patients with this mutation; no discussion of lorlatinib or of hepatotoxicity or ALT elevations).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 cases [6%] were attributed to antineoplastic agents, including 9 due to kinase inhibitors such as imatinib and lapatinib, but none were attributed to any of the small molecule ALK inhibitors).
• Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A, Burke BJ, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med 2016; 374: 54-61. [PMC free article: PMC4773904] [PubMed: 26698910]

  (52 year old woman with metastatic, ALK-mutation positive NSCLC was treated successfully with crizotinib but then developed resistant tumor that did not respond to ceritinib, but did to lorlatinib, only to later develop a lorlatinib resistant mutation that was predicted to be sensitive to crizotinib and responded dramatically to its reintroduction, both response and resistance being predicted by the sequential ALK mutations).
• Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, Gainor JF, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017; 18: 1590-9. [PMC free article: PMC5777233] [PubMed: 29074098]

  (Among 54 patients with NSCLC treated with lorlatinib in different dose regimens, the objective response rate was 42-50% and adverse events included hypercholesterolemia [72%], edema [39%], peripheral neuropathy [39%], cognitive effects [24%] and AST elevations [13%]).
• Betton M, Gounant V, Sannier A, Hanouna G, Goujon JM, Brosseau S, Zalcman G, et al. Minimal change disease induced by lorlatinib. J Thorac Oncol 2018; 13: e154-e156. [PubMed: 30049381]

  (64 year old woman with NSCLC treated with lorlatinib developed leg edema and proteinuria one month after starting, renal biopsy showing minimal change glomerulonephritis, which resolved on stopping and recurred on restarting).
• Chabrol A, Mayenga M, Hamid AM, Friard S, Salvator H, Doubre H, Fraboulet S, et al. Lorlatinib - induced pulmonary arterial hypertension. Lung Cancer 2018; 120: 60-1. [PubMed: 29748016]

  (Two women, ages 55 and 64 years, developed dyspnea 1 and 2 months after starting lorlatinib for NSCLC and right heart catherization showed pulmonary arterial hypertension and decreased cardiac index, both improving upon stopping the ALK inhibitor therapy).
• Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, Chiari R, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018; 19: 1654-67. [PubMed: 30413378]

  (Among 276 patients with NSCLC and ALK or ROS1 mutations, objective response rates varied from 32% to 67% and adverse events were frequent including hypercholesterolemia [81%], edema [43%], peripheral neuropathy [30%], cognitive effects [18%] and ALT elevations [9%], which were above 5 times ULN in only 1% and were not associated with jaundice or symptoms of liver injury).
• Waqar SN, Morgensztern D. Lorlatinib: a new-generation drug for ALK-positive NSCLC. Lancet Oncol 2018; 19: 1555-7. [PubMed: 30413381]

  (Commentary on Solomon [2018] mentions that lorlatinib has shown promise in treatment-naïve as well as experienced patients with NSCLC and ALK mutations).
• Ryser CO, Diebold J, Gautschi O. Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives. Curr Opin Oncol 2019; 31: 8-12. [PubMed: 30394941]

  (Review of the management of NSCLC with ALK mutations using first [crizotinib], second [alectinib, ceritinib, brigatinib] and third generation [lorlatinib] ALK inhibitors; mentions hepatotoxicity of crizotinib and ceritinib).
• Syed YY. Lorlatinib: first global approval. Drugs 2019; 79: 93-8. [PubMed: 30604291]

  (Review of the mechanism of action, history of development, pharmacology, clinical efficacy and safety of lorlatinib shortly after its approval in the US; mentions that 10% of patients had AST elevations during therapy but none required discontinuation or led to serious hepatic adverse events).