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heading-Nerlynx-Neratinib--HER2-Breast-Cancer

Mechanism of action

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NERLYNX^® is a small molecule that provides irreversible, intracellular pan-HER signaling inhibition^1,9-14

Trastuzumab, pertuzumab and trastuzumab emtansine share a common target, the extracellular domains of the HER2 receptor.^1,9-11NERLYNX^® has a different mechanism of action.^1,9,10

By irreversibly binding to the intracellular domain of all active HER receptors, HER1, HER2 and HER4, NERLYNX ensures steady and prolonged blockade of HER signalling.^9-13

HER, human epidermal growth factor receptor.

This is a simplified illustration of the mechanism of action.

This is a simplified illustration of the mechanism of action.

NERLYNX^® Mechanism of action video

In HER2+/HR+ patients, NERLYNX^® in combination with endocrine therapy addresses HER2-ER crosstalk by targeting both signaling pathways^9,12,14-20

Nerlynx-Neratinib--HER2-Breast-Cancer-Mechanism-of-action-2

This is a simplified illustration of the mechanism of action, that only features one of the HER2 receptors.

The family of human epidermal growth factor receptors (HER1, HER2, HER3 and HER4) play a central role in the pathogenesis of several cancers.¹⁴

The estrogen receptor and the HER2 signaling pathways are the dominant drivers of cell proliferation in the majority of breast cancers.^16,17

While endocrine therapy blocks the estrogen signaling pathway, this can lead to crosstalk between the estrogen receptor and the HER2 receptor, which in turn can lead to upregulation of the HER2 signaling pathway.^17-20

The addition of NERLYNX^® to endocrine therapy prevents this crosstalk, forming a dual blockade of both HER2 and ER signaling pathways, resulting in permanent inhibition of cancer cell growth.^9,12,14

ER, estrogen receptor; HER, human epidermal growth factor receptor; HR, hormone receptor.

Learn about…

NERLYNX
Efficacy

Nerlynx-Neratinib--Read-Also

NERLYNX
Safety

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NERLYNX
Dosing

Nerlynx-Neratinib--Read-Also

This medicinal product is subject to risk minimization measures.

References
1. Chan A, et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021;21(1):80–91.
2. Chan A, 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):367−377.
3. Martin M, et al. 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(12):1688−1700.
4. Holmes FA, et al. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET). European Journal of Cancer 184 (2023) 48e59.
5. Nerlynx (neratinib 40 mg film-coated tablets) Summary of Product Characteristics, 2023. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/nerlynx. Accessed: 2023.
6. Cameron D, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the Herceptin Adjuvant (HERA) trial. Lancet. 2017;389:1195–1205.
7. Von Minckwitz G, et al. Trastuzumab Emtansine for residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380:617–628.
8. Cortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;383(9938):164−172
9. Collins DM, et al. Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer. Cancers. 2019;11(6);737. doi:10.3390/cancers11060737.
10. Feldinger K and Kong A. Profile of neratinib and its potential in the treatment of breast cancer. Breast Cancer: Targets Ther. 2015;7:147–162.
11. Kourie HR, et al. Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib. OncoTargets Ther. 2017;10:3363–3372.
12. Wissner A and Mansour TS. The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm (Weinheim). 2008;341(8):465–477.
13. Canoici A, et al. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget. 2013;4(10):1592–1605.
14. Rabindran SK, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958–3965.
15. Iqbal N and Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748.
16. Gutierrez C and Schiff R. HER 2: Biology, Detection, and Clinical Implications. Arch Pathol Lab Med. 2011;135(1):55–62.
17. Giuliano M, et al. Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications. Breast Care. 2013;8:256–262.
18. Shou J, et al. Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2–Positive Breast Cancer. J Natl Cancer Inst. 2004;96(12):926–935.
19. Harari D and Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 2000;19:6102–6114.
20. Paplomata E, et al. Systemic Therapy For Early-Stage HER2-Positive Breast Cancers: Time for a Less-Is-More Approach? Cancer. 2015;121(4):517–526.
21. Barcenas CH, et al. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020;31(9):1223−1230.
22. European Medicines Agency Public Assessment Report (EPAR). Nerlynx EMA/CHMP/525204/2018.
23. Barcenas CH, et al. CONTROL trial Supplementary Table S7, available at Ann Oncol online.
24. Cancer.Net. Doctor-Approved Patient Information from ASCO on Diarrhoea. Available at: https://www.cancer.net/coping-with-cancer/physical-emotional and-social-effects-cancer/managing-physical-side-effects/diarrhea. Accessed: June 2020.
25. National Cancer Institute. Diarrhoea and Cancer Treatment. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/diarrhea. Accessed: December 2022.
26. Chan A, et al. Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhoea and tolerability in patients with HER2-positive early stage breast cancer: phase II CONTROL trial. Poster P5-14-03 presented at SABCS 2019.
27. Mortimer J, et al. Patterns of occurrence and implications of neratinib-associated diarrhoea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial. Breast Cancer Res. 2019;21(1):32. Electronic Supplementary Material.
28. Pinter M, et al. Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open. 2016:1(2)e000042. eCollection 2016.
29. Breastcancer.org. How to read hormone receptor test results. Available at: https://www.breastcancer.org/symptoms/diagnosis/hormone_status/read_results. Accessed: December 2022.
30. National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed: December 2022.
31. Bradley R, et al. EBCTCG. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13864 women in seven randomised trials. Lancet Oncol 2021; 22: 1139-50.
32. Loibl S, et al. VP6-2022 : Adjuvant pertuzumab and trastuzumab in patients with early HER-2 positive breast cancer in APHINITY: 8.4 years’ follow-up. Ann Oncol. 2022.
33. Goldhirsch A, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomized controlled trial. Lancet. 2013;382:1021–1028.
34. Von Minckwitz G, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377:122–131.
35. Piccart M, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years’ Follow-Up. J Clin Oncol. 2021. doi:10.1200/JCO.20.01204. [Online ahead of print].
36. Piccart-Gebhart MJ, et al. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. N Engl J Med. 2005;353(16):1659–1672.
37. Untch M, et al. How to Optimise Extended Adjuvant Treatment with Neratinib for HER2+ Early Breast Cancer Patients. Oncol Ther J. 2021.
38. EU PAS Register, EUPAS41584. Available at: https://www.encepp.eu/encepp/viewResource.htm?id=44630. Accessed: January 2023.

This is an international website for NERLYNX^®. IMPORTANT: the information on this website is based on the European Summary of Product Characteristics. Prescribing Information and indication may vary per country. You must refer to your country prescribing information. Please be aware we do not take responsibility for accessing such information which may not comply with the regulation or usage in your country.

Last update: 09/2023