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Neratinib: First Global Approval

AdisInsight Report
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Abstract

Neratinib (Nerlynx™) is an oral, irreversible inhibitor of the human epidermal growth factor receptors HER1 (EGFR), HER2 and HER4. The drug originally arose from research by Wyeth (now Pfizer) and is now being developed by Puma Biotechnology primarily for the treatment of HER2-positive (HER+) breast cancer. Neratinib is approved in the USA for the extended adjuvant treatment of patients with HER2+ early-stage breast cancer who have been previously treated with a trastuzumab-based adjuvant regimen, and is in the preregistration phase for this indication in the EU. Neratinib, as monotherapy and/or combination therapy, is also in phase 3 development for metastatic breast cancer and in phase 1/2 development for advanced breast cancer and other solid tumours, including non-small cell lung cancer, colorectal cancer and glioblastoma. This article summarizes the milestones in the development of neratinib leading to this first approval for breast cancer.

References

  1. 1.
    Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release. 2010;146(3):264–75.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Wang T, Xu Y, Sheng S, et al. HER2 somatic mutations are associated with poor survival in HER2-negative breast cancers. Cancer Sci. 2017;108(4):671–7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Schroeder RL, Stevens CL, Sridhar J. Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Molecules. 2014;19(9):15196–212.CrossRefPubMedGoogle Scholar
  5. 5.
    Puma Biotechnology Inc. Nerlynx (neratinib): US prescribing information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf. Accessed 19 July 2017.
  6. 6.
    Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958–65.CrossRefPubMedGoogle Scholar
  7. 7.
    FDA. FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer [media release]. 17 Jul 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm567259.htm.
  8. 8.
    Canonici A, Gijsen M, Mullooly M, et al. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget. 2013;4(10):1592–605.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Menderes G, Bonazzoli E, Bellone S, et al. Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo. Med Oncol. 2017;34(5):91.CrossRefPubMedGoogle Scholar
  10. 10.
    Schwab CL, English DP, Black J, et al. Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo. Gynecol Oncol. 2015;139(1):112–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lopez S, Cocco E, Black J, et al. Dual HER2/PIK3CA targeting overcomes single-agent acquired resistance in HER2-amplified uterine serous carcinoma cell lines in vitro and in vivo. Mol Cancer Ther. 2015;14(11):2519–26.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shimamura T, Ji H, Minami Y, et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res. 2006;66(13):6487–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Schwartz L, Croessmann S, Avogadri-Connors F, et al. Neratinib/fulvestrant but not fulvestrant alone maintain complete responses after treatment with trastuzumab/paclitaxel of mice bearing ER+/HER2+ xenografts [abstract no. 4818]. Cancer Res. 2017;77(13 Suppl.).Google Scholar
  14. 14.
    Montemurro F, Di Cosimo S, Arpino G. Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications. Ann Oncol. 2013;24(11):2715–24.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhao XQ, Xie JD, Chen XG, et al. Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. Mol Pharmacol. 2012;82(1):47–58.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Breslin S, Lowry MC, O’Driscoll L. Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4. Br J Cancer. 2017;116(5):620–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Hug B, Abbas R, Leister C, et al. A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects. Clin Cancer Res. 2010;16(15):4016–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang J, Li-Chan XX, Atherton J, et al. Characterization of HKI-272 covalent binding to human serum albumin. Drug Metab Dispos. 2010;38(7):1083–93.CrossRefPubMedGoogle Scholar
  19. 19.
    Abbas R, Hug BA, Leister C, et al. Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects. Br J Clin Pharmacol. 2011;71(4):522–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Keyvanjah K, DiPrimeo D, Li A, et al. Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects. Br J Clin Pharmacol. 2017;83(3):554–61.CrossRefPubMedGoogle Scholar
  21. 21.
    Chan A, Delaloge S, Holmes FA, et al. 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(3):367–77.CrossRefPubMedGoogle Scholar
  22. 22.
    Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET) [abstract no. S5-02]. Cancer Res. 2016;76(4 Suppl 1).Google Scholar
  23. 23.
    Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375(1):11–22.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Martin M, Bonneterre J, Geyer CE Jr, 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(18):3763–72.CrossRefPubMedGoogle Scholar
  26. 26.
    Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer Research Consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34(9):945–52.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Awada A, Colomer R, Inoue K, 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(12):1557–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Chow LW, Xu B, Gupta S, et al. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Br J Cancer. 2013;108(10):1985–93.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Saura C, Garcia-Saenz JA, Xu B, 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(32):3626–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Awada A, Dirix L, Manso Sanchez L, et al. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol. 2013;24(1):109–16.CrossRefPubMedGoogle Scholar
  31. 31.
    Gajria D, Modi S, Saura C, et al. A phase I/II study of neratinib plus temsirolimus in HER2+ metastatic breast cancer reveals ongoing HER2 pathway dependence in many patients despite several lines of HER2 targeted therapy [abstract no. P5-19-04]. Cancer Res. 2015;75(9 Suppl.).Google Scholar
  32. 32.
    Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: phase II trial of neratinib + capecitabine for patients (pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM) [abstract]. In: ASCO Annual Meeting; 2017.Google Scholar
  33. 33.
    Abraham J, Puhalla SL, Sikov W, et al. NSABP FB-10: phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC) [abstract no. CT013]. Cancer Res. 2017;77(13 Suppl).Google Scholar
  34. 34.
    Jankowitz RC, Abraham J, Tan AR, et al. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol. 2013;72(6):1205–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Ma CX, Bose R, Gao F, et al. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 non-amplified metastatic breast cancer. Clin Cancer Res. 2017. doi:10.1158/1078-0432.CCR-17-0900.Google Scholar
  36. 36.
    Hyman D, Piha-Paul S, Saura C, et al. Neratinib + fulvestrant in ERBB2-mutant, HER2-non-amplified, estrogen receptor (Ex positive, metastatic breast cancer (MBC): preliminary analysis from the phase II SUMMIT trial [abstract no. PD2-08]. Cancer Res. 2017;77(4 Suppl).Google Scholar
  37. 37.
    Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(18):3076–83.CrossRefPubMedGoogle Scholar
  38. 38.
    Gandhi L, Besse B, Mazieres J, et al. Neratinib ± temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study [abstract no. MA04.02]. J Thorac Oncol. 2017;12(1 Suppl.):S358–9.CrossRefGoogle Scholar
  39. 39.
    Jacobs SA, Lee JJ, George Jr TJ, et al. NSABP FC-7: a phase Ib study evaluating neratinib (N) and cetuximab (Cmab) in patients (pts) with quadruple wild-type (quad wt) (KRAS/NRAS/BRAF/PI3KCA wt) metastatic colorectal cancer (mCRC) resistant to Cmab [abstract no. C46]. Mol Cancer Ther. 2015;14(12 Suppl 2).Google Scholar
  40. 40.
    Wong KK, Fracasso PM, Bukowski RM, et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res. 2009;15(7):2552–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Ito Y, Suenaga M, Hatake K, et al. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a phase 1 dose-escalation study. Jpn J Clin Oncol. 2012;42(4):278–86.CrossRefPubMedGoogle Scholar
  42. 42.
    Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014;32(2):68–75.CrossRefPubMedGoogle Scholar
  43. 43.
    Hyman D, Piha-Paul S, Rodon J, et al. Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 “basket” study [abstract no. CT001 and slide presentation]. Cancer Res. 2017;77(13 Suppl).Google Scholar
  44. 44.
    Ibrahim E, Tripathy D, Wilkinson M, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients (pts) with HER2+ early-stage breast cancer (eBC): the CONTROL trial [abstract no. CT128 plus Poster]. Cancer Res. 2017;77(13 Suppl.).Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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