OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Avapritinib – Ayvakit®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Avapritinib	1703793-34-3	C26-H27-F-N10

ANNOTATED BIBLIOGRAPHY

References updated: 02 September 2023

Abbreviations: GIST, gastrointestinal stromal tumor; KIT, a classical proto-oncogene that encodes a tyrosine kinase receptor that responds to stem cell factor; PDGFRA, platelet-derived growth factor receptor alpha.

• 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. 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 avapritinib).
• 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/2020/212608Orig1s000MultidisciplineR.pdf

  (FDA website with initial multidiscipline clinical review of the safety and efficacy of avapritinib; describes the adverse events observed in a pooled safety population of 335 patients that included edema in 74%, bilirubin elevations 65%, fatigue 57%, nausea 56%, cognitive impairment 43%, diarrhea 36%, abdominal pain 32%, anemia 49%, hair color change 22%, rash 20%, dyspnea 15%, and ALT elevations 20% which were above 5 times ULN in only 1% [n=3], and there were no discontinuations for ALT elevations and no instances of clinically apparent liver injury, hepatic failure, or fatalities due to liver injury).
• Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang YK, Cassier PA, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020;21:935-946. [PubMed: 32615108]

  (Among 56 patients with advanced GIST and PDGFRA D842V-mutations treated with avapritinib in a phase 1 open-label trial, the overall response rate was 88% [complete responses in 9%] and almost all patients had adverse events including nausea in 69%, fatigue 41%, anorexia 38%, hair color change e25%, anemia 22%, and neutropenia 19%; no mention of ALT elevations or hepatotoxicity).
• Dhillon S. Avapritinib: first approval. Drugs. 2020;80:433-439. [PubMed: 32100250]

  (Review of the mechanism of action, history of development, pharmacology, clinical efficacy and safety of avapritinib shortly after its approval for use in advanced or metastatic GIST in the U.S.; no mention of ALT elevations or hepatotoxicity).
• DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, Bose P, Heet al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021;27:2183-2191. [PMC free article: PMC8674134] [PubMed: 34873347]

  (Among 86 patients with advanced systemic mastocytosis enrolled in a phase 1 trial of avapritinib, the overall response rate was 75% and complete remission rate 36% while adverse events were common and included intracranial bleeds in 9 patients, largely in those with preexisting thrombocytopenia [n=7]; no mention of ALT elevations or hepatotoxicity).
• Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, Vannucchi AM, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27:2192-2199. [PMC free article: PMC8674139] [PubMed: 34873345]

  (Among 62 patients with advanced systemic mastocytosis treated in a phase 2 open-label trial excluding those with platelet count below 50,000/uL, the overall response rate was 75% and side effects were common, but there was only one case with intracranial hemorrhage and no mention of ALT elevations or hepatotoxicity).
• Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021;145:132-142. [PMC free article: PMC9518931] [PubMed: 33465704]

  (Among 250 patients [56 with PDGFRA D824V mutant GIST] treated in phase 1 trials of avapritinib, treatment related adverse events occurred in 98% of patients and included cognitive effects in 46%, intracranial bleeding in 3%; no mention of ALT elevations or hepatotoxicity).
• Avapritinib (Ayvakit) for GIST. Med Lett Drugs Ther. 2021;63(1617):23-24. [PubMed: 33647006]

  (Concise review of the mechanism of action, clinical efficacy, adverse effects, drug interactions, and costs of avapritinib shortly after its approval in the U.S. mentions that serious adverse effects occur in 52% of patients and include anemia [9%] and intracranial hemorrhage [1%]; no mention of ALT elevations or hepatotoxicity).
• Reiter A, Schwaab J, DeAngelo DJ, Gotlib J, Deininger MW, Pettit KM, Alvarez-Twose I, et al. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022;6:5750-5762. [PMC free article: PMC9647833] [PubMed: 35640224]

  (Among 53 patients with advanced systemic mastocytosis treated with avapritinib [200 mg daily] for a median of 15 months, the overall response rate was 71% and adverse events arose in most patients resulting in dose reductions in 57% and including thrombocytopenia [32%], periorbital edema [30%], diarrhea [21%], cognitive disorders [15%], change in hair color [15%], and two instances of subdural hematoma; no mention of ALT elevations or hepatotoxicity).
• Cavazos K, Eswaran S, Maidlow C, Keklik Karadag F, Idilman R, Idilman I, et al. Liver fibrosis and its response to avapritinib in 2 patients with systemic mastocytosis. Blood Adv. 2022;6:5630-5633. [PMC free article: PMC9647789] [PubMed: 35839085]

  (Two patients with advanced systemic mastocytosis were found to have advanced hepatic fibrosis or cirrhosis as shown by elastography and liver biopsy, but had normal liver tests and imaging and tolerated therapy with avapritinib, the hepatic stiffness improving with therapy and without any worsening of liver tests suggesting that avapritinib does not worsen hepatic fibrosis and may improve mastocytosis-associated liver disease).
• Li J, Zhang X, Deng Y, Wu X, Zheng Z, Zhou Y, Cai S, et al. Efficacy and safety of avapritinib in treating unresectable or metastatic gastrointestinal stromal tumors: a phase I/II, open-label, multicenter study. Oncologist. 2023;28:187-e114. [PMC free article: PMC9907038] [PubMed: 36477870]

  (Among 56 Chinese patients with unresectable or metastatic GIST treated with avapritinib [300 mg daily] in phase 1 and 2 clinical trials, the overall response rate was 75% in those with PDGFRA D842V mutations, while adverse events arose in 98% of patients including ALT elevations in 14% which were above 5 times ULN in only 1 patient).
• Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol. 2023;98:1097-1116. [PubMed: 37309222]

  (Review of the clinical features, diagnosis, histology, molecular findings, classification and management of systemic mastocytosis including both advanced and indolent forms of the disease condition).