OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Neratinib	698387-09-6	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. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; mentions that tyrosine kinase inhibitors have been linked to cases of clinically apparent liver injury, some of which were fatal).
• 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).
• Martin M, Bonneterre J, Geyer CE Jr, Ito Y, Ro J, Lang I, Kim SB, et al. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer 2013; 49: 3763-72. [PubMed: 23953056]

  (Among 233 women with HER2 positive breast cancer and previous trastuzumab treatment, median overall survival was 20 months in those receiving neratinib vs 24 months in those on lapatinib with capecitabine, while side effects, dose reductions and discontinuations were less with neratinib including ALT elevations [7% vs 13%]; there were no liver related serious adverse events or deaths in either group).
• Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, et al. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2014; 32: 3626-33. [PubMed: 25287822]

  (Among 104 women with HER2 positive breast cancer treated with varying doses of neratinib and capecitabine for up to 99 weeks, ALT elevations arose in 3 [3%], but there were no cases of ALT elevations with jaundice).
• Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer 2015; 88: 74-9. [PubMed: 25704957]

  (In a pooled analysis of 21 trials of tyrosine kinase inhibitors of EGFR found higher reported rates of "grade 3" hepatotoxicity with gefitinib [18%] than with erlotinib [5.4%] and afatinib [1.7%], and hepatotoxicity was listed as the cause of drug discontinuation in 25% of cases).
• Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G, Lee SC, et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: The NEfERT-T Randomized Clinical Trial. JAMA Oncol 2016; 2: 1557-64. [PubMed: 27078022]

  (Among 479 women with metastatic HER2 positive breast cancer treated with paclitaxel and either neratinib or trastuzumab, progression free survival was similar in the two groups while adverse events were more frequent with neratinib including diarrhea [93% vs 33%], nausea [44% vs 30%], weight loss [16% vs 5%] and ALT elevations [any elevation: 13% vs 11%; above 5 times ULN: 5% vs 2%]).
• Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, et al.; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17: 367-77. [PubMed: 26874901]

  (Among 2840 women with HER2 positive breast cancer after trastuzumab adjuvant therapy, invasive disease free survival was greater with a one year course of neratinib than with placebo therapy [94% vs 92%], but was also associated with a higher rate of adverse events including diarrhea [40% vs 1.6%] and ALT elevations above 5 times ULN [1.1% vs 0.3%], but there were no cases of clinically apparent liver injury).
• Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, et al.; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med 2016; 375: 11-22. [PMC free article: PMC5259558] [PubMed: 27406346]

  (Among 193 women with early breast cancer treated with standard neoadjuvant chemotherapy with or without neratinib, adverse events were more frequent with neratinib including diarrhea [96% vs 50%] and ALT elevations [37% vs 12%], which were above 5 times ULN in 11% vs 1%, although there were no liver related severe adverse events in either group).
• Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, et al.; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18: 1688-1700. [PubMed: 29146401]

  (A 5 year follow up on 2840 women with HER2 positive breast cancer treated with a one year course of neratinib vs placebo [Chan 2016] found continued improved invasive disease free survival [90% vs 88%] and no new safety signals).
• Ding PN, Lord SJ, Gebski V, Links M, Bray V, Gralla RJ, Yang JC, et al. Risk of treatment-related toxicities from EGFR tyrosine kinase inhibitors: a meta-analysis of clinical trials of gefitinib, erlotinib, and afatinib in advanced EGFR-mutated non-small cell lung cancer. J Thorac Oncol 2017; 12: 633-43. [PubMed: 28007626]

  (In a systematic review of 16 trials of EGFR tyrosine kinase inhibitors, liver enzyme elevations were highest for gefitinib [62%] vs afatinib [20%] and erlotinib [18%]; does not mention neratinib).
• Singh H, Walker AJ, Amiri-Kordestani L, Cheng J, Tang S, Balcazar P, Barnett-Ringgold K, et al. U.S. Food and Drug Administration approval: neratinib for the extended adjuvant treatment of early stage HER2-positive breast cancer. Clin Cancer Res 2018; 24: 3486-91. [PubMed: 29523624]

  (Summary of evidence for the safety and efficacy of neratinib that led to its approval for the extended adjuvant treatment of women with early stage, HER2 positive breast cancer; mentions but does not discuss ALT and AST elevations during therapy).
• Neratinib (Nerlynx) for HER2-positive breast cancer. Med Lett Drugs Ther 2018; 60 (1539): 23. [PubMed: 29364199]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of neratinib shortly after its approval in the US for therapy of breast cancer; mentions that diarrhea is the most common side effect and that ALT and AST elevations occurred in 5-9% of treated patients versus 3-4% of controls).