OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Tucatinib – Tukysa®

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
Tucatinib	937263-43-9	C26-H24-N8-O2

ANNOTATED BIBLIOGRAPHY

References updated: 09 September 2023

Abbreviations: HER2, human epidermal growth factor receptor 2.

• 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 tucatinib).
• 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/2020/213411Orig1s000MultidisciplineR.pdf

  (FDA website with initial multidiscipline clinical review of the safety and efficacy of tucatinib given in combination with trastuzumab and capecitabine (T+C) as therapy of metastatic refractory HER2+ breast cancer; states that median overall survival was longer with tucatinib+T+C than with placebo+T+C controls [22 vs 17 months] and adverse event rates were similar in both groups but hepatic events [the combination of ALT, AST, and bilirubin abnormalities] occurred in 39% on tucatinib vs 23% in controls, and 9 subjects had both ALT elevations and jaundice, but none were considered due to therapy as other causes were found so that there were no cases of hepatotoxicity leading to liver failure or death).
• Murthy R, Borges VF, Conlin A, Chaves J, Chamberlain M, Gray T, Vo A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19:880-888. [PubMed: 29804905]

  (Among 60 patients with advanced HER2+ metastatic breast cancer treated with tucatinib with either trastuzumab [T] or capecitabine [C] or both [TC], the objective response rate was 61% with tucatinib+TC compared to 40% with tucatinib+T and 83% with tucatinib+C, while adverse events included diarrhea [67%], hand-foot syndrome [44%], fatigue [38%] and ALT elevations [12%], but there were no instances of clinically apparent liver injury with jaundice).
• Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609. [PubMed: 31825569]

  (Among 612 patients with refractory, HER2+ metastatic breast cancer enrolled in a randomized controlled trial of addition of tucatinib vs placebo to the combination of trastuzumab and capecitabine, the overall survival at 2 years was 45% vs 27% with responses in brain metastases; adverse events were common in both groups [99% vs 97%], but more frequent with tucatinib were diarrhea [81% vs 53%], hand-foot syndrome [63% vs 53%], and ALT elevations [20% vs 7%], particularly values above 5 times ULN [5% vs 0.5%] and one patient developed ALT elevations [134 U/L] with jaundice [bilirubin 2.6 mg/dL] but recovered with dose reduction and was able to continue therapy without recurrence).
• Two drugs for advanced HER2-positive breast cancer (Enhertu and Tukysa). Med Lett Drugs Ther. 2020;62:182-184. [PubMed: 33429416]

  (Concise summary of the mechanism of action, clinical efficacy, adverse effects, and costs of tucatinib shortly after its approval as therapy with trastuzumab and capecitabine for refractory, advanced HER2+ breast cancer, mentions that it can cause severe hepatotoxicity and routine liver tests should be monitored before and every 3 weeks during treatment).
• Shah M, Wedam S, Cheng J, Fiero MH, Xia H, Li F, Fan J, et al. FDA approval summary: tucatinib for the treatment of patients with advanced or metastatic HER2-positive breast cancer. Clin Cancer Res. 2021;27:1220-1226. [PubMed: 33055172]

  (Summary of the data on efficacy and safety of tucatinib that supported its approval as therapy of refractory, advanced or metastatic HER2+ breast cancer mentions that hepatotoxicity was a safety signal of concern and while tucatinib therapy was associated with a high rate of abnormal ALT, AST and bilirubin levels, there were no cases of confirmed clinically apparent drug induced liver injury or liver failure that could be attributed to tucatinib therapy).
• Curigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33:321-329. [PubMed: 34954044]

  (Final results from the pivotal randomized controlled trial of tucatinib vs placebo added to trastuzumab and capecitabine in 612 adults with refractory HER+ metastatic breast cancer [Murthy 2020] reported an overall survival at 2 years of 24.7 vs 19.2 months and that “rates of liver laboratory abnormalities and diarrhea did not increase with additional follow up”).
• Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, Wu C, et al.; MOUNTAINEER investigators. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24:496-508. [PubMed: 37142372]

  (Among 84 patients with refractory, unresectable or metastatic HER2+ colorectal cancer treated with tucatinib and trastuzumab, the objective response rate was 38%, while 95% developed at least one adverse event including ALT elevations in 5 patients [6%] which were above 5 times ULN in 3 [4%], but there were no episodes of clinically apparent liver injury with jaundice).
• In brief: A second indication for tucatinib (Tukysa). Med Lett Drugs Ther. 2023;65:e37-e38. [PubMed: 36877245]

  (Concise summary of the mechanism of action, clinical efficacy, adverse effects, and costs of tucatinib shortly after its approval as therapy with trastuzumab for HER2+ advanced colorectal cancer, mentions that “severe hepatotoxicity can occur” and routine liver tests should be monitored during treatment).