OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Pralsetinib – Gavreto®

DRUG CLASS

Antineoplastic Agents, Kinase Inhibitors

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Pralsetinib	2097132-94-8	C27-H32-F-N9-O2

ANNOTATED BIBLIOGRAPHY

References updated: 12 August 2023

Abbreviations: NSCLC, non-small cell lung cancer; RET, rearranged in transfection.

• 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 protein 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 pralsetinib).
• 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/2020/213721Orig1s000MultidisciplineR.pdf

  (FDA website with product labels and initial multidiscipline review of the safety and efficacy of pralsetinib; states that virtually all patients treated [n=438] had at least one adverse event, but there were only 7 serious hepatic adverse events that were mostly ALT or AST elevations and no patient developed clinically apparent liver injury with jaundice; in the 220 patients with NSCLC treated with pralsetinib, 46% had an ALT elevations but only 2.1% were above 5 times ULN).
• Markham A. Pralsetinib: first approval. Drugs. 2020;80:1865-1870. [PubMed: 33136236]

  (Review of the mechanism of action, chemical structure, history of development, pharmacology, clinical efficacy and safety of pralsetinib mentions that AST and ALT elevations were the most common treatment related adverse events, increased ALT elevations accounting for some dosage interruptions but not discontinuations).
• Kim J, Bradford D, Larkins E, Pai-Scherf LH, Chatterjee S, Mishra-Kalyani PS, Wearne E, et al. FDA Approval Summary: Pralsetinib for the treatment of lung and thyroid cancers with RET gene mutations or fusions. Clin Cancer Res. 2021;27:5452-5456. [PubMed: 34045295]

  (Summary of the data on efficacy and safety of pralsetinib [n=438 patients] that led to its accelerated approval by the FDA mentions that serious hepatic adverse events arose in 2% of patients with ALT or AST elevations above 5 times ULN in 6% and 5%, but that there were no cases of clinically apparent liver injury with jaundice or hepatic related deaths).
• Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, Brose MS, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021;9:491-501. [PubMed: 34118198]

  (Among 122 patients with RET-mutated medullary and 20 with RET-fusion-positive thyroid cancer treated with pralsetinib for a median of 12 months, the overall response rates were 60-71%, while adverse events arose in 97% including ALT elevations in 23% that were above 5 times ULN in 2 patients, but there were no discontinuations for ALT or AST elevations and no liver related deaths).
• Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, Doebele RC, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22:959-969. [PubMed: 34118197]

  (Among 233 patients with RET fusion-positive NSCLC treated with pralsetinib [400 mg daily], overall responses occurred in 61% of previously treated and 70% of treatment-naïve subjects, while virtually all patients had at least one adverse events including ALT elevations in 27% which were above 5 times ULN in 5 patients [3%], but there were no treatment related deaths).
• Passaro A, Russo GL, Passiglia F, D'Arcangelo M, Sbrana A, Russano M, Bonanno L, et al. Pralsetinib in RET fusion-positive non-small-cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP). Lung Cancer. 2022;174:118-124. [PubMed: 36379124]

  (Among 62 patients with RET-fusion positive NSCLC treated with pralsetinib for a median of 10 months in 20 Italian centers in an expanded access program, the objective response rate was 66% and adverse events were frequent including ALT or AST elevations above 5 times ULN in 5%, but there were no hepatic related deaths).
• Griesinger F, Curigliano G, Thomas M, Subbiah V, Baik CS, Tan DSW, Lee DH, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022;33:1168-1178. [PubMed: 35973665]

  (Among 281 with RET fusion-positive NSCLC treated with pralsetinib in the ARROW trial [Gainor 2021], further follow up identified tumor shrinkage in all treatment-naïve and in 97% of previously treated subjects, while adverse events recorded for a total of 528 patients with cancer treated with pralsetinib, included ALT elevations in 29% which were above 5 times ULN in 2%).
• Subbiah V, Cassier PA, Siena S, Garralda E, Paz-Ares L, Garrido P, Nadal E, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022;28:1640-1645. [PMC free article: PMC9388374] [PubMed: 35962206]

  (Among 29 patients with 12 different RET fusion-positive solid tumor types [excluding NSCLC and thyroid cancer] treated with pralsetinib, the overall response rate was 57% and all patients had at least one adverse event including ALT elevations in 10 patients [34%], which were above 5 times ULN in 2 patients [7%] who required dose interruption but not permanent discontinuation).
• Two drugs for RET-altered cancers (Retevmo and Gavreto). Med Lett Drugs Ther. 2023;65:e129-e131. [PubMed: 37418333]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of selpercatinib and pralsetinib, two kinase inhibitors that act on RET gene altered cancers mentions that liver enzyme elevations are frequent and monitoring of ALT and AST levels is recommended).