NERLYNX in combination with capecitabine is for the treatment of
adult patients with advanced or metastatic HER2+ breast cancer who
have received two or more prior anti-HER2 based regimens in the
*Median PFS of 5.6 months with NERLYNX + capecitabine vs 5.5 months
with lapatinib + capecitabine (HR=0.76; 95% CI: 0.63, 0.93;
CI: confidence interval; HER2: human epidermal growth factor
receptor 2; HR: hazard ratio; mBC: metastatic breast cancer; PFS:
Select IMPORTANT SAFETY INFORMATION
NERLYNX can cause fetal harm. Advise patients of potential risk to
a fetus and to use effective contraception.
Lactation: Advise women not to breastfeed.
Please see additional IMPORTANT SAFETY INFORMATION below.
INDICATIONS: NERLYNX® (neratinib) tablets, for oral use,
is a kinase inhibitor indicated:
As a single agent, for the extended adjuvant treatment of adult patients
with early-stage HER2-positive breast cancer, to follow adjuvant
In combination with capecitabine, for the treatment of adult patients with
advanced or metastatic HER2-positive breast cancer who have received two
or more prior anti-HER2 based regimens in the metastatic setting.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS:
Diarrhea: Manage diarrhea through either NERLYNX dose
escalation or loperamide prophylaxis. If diarrhea occurs despite
recommended prophylaxis, treat with additional antidiarrheals, fluids, and
electrolytes as clinically indicated. Withhold NERLYNX in patients
experiencing severe and/or persistent diarrhea. Permanently discontinue
NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥2 diarrhea
that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for
the first 3 months of treatment, then every 3 months while on treatment
and as clinically indicated. Withhold NERLYNX in patients experiencing
Grade 3 liver abnormalities and permanently discontinue NERLYNX in
patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm.
Advise patients of potential risk to a fetus and to use effective
ADVERSE REACTIONS: The most common adverse reactions
(reported in ≥5% of patients) were:
NERLYNX as a single agent: diarrhea, nausea, abdominal pain, fatigue,
vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia,
AST or ALT increased, nail disorder, dry skin, abdominal distention,
epistaxis, weight decreased, and urinary tract infection.
NERLYNX in combination with capecitabine: diarrhea, nausea, vomiting,
decreased appetite, constipation, fatigue/asthenia, weight decreased,
dizziness, back pain, arthralgia, urinary tract infection, upper
respiratory tract infection, abdominal distention, renal impairment, and
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at
1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-FDA-1088 or
Gastric acid reducing agents: Avoid concomitant use with proton pump
inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after
H2-receptor antagonists. Or separate NERLYNX by at least 3
hours after antacids.
Strong CYP3A4 inhibitors: Avoid concomitant use.
P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates
for which minimal concentration change may lead to serious adverse
reactions when used concomitantly with NERLYNX.
Chan A, Moy B, Mansi J, 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.e7.
Martin M, Holmes FA, Ejlertsen B, 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.
NERLYNX [package insert]. Los Angeles, CA: Puma Biotechnology, Inc.
Cameron D, Piccart-Gebhart MJ, Gelber RD, 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(10075):1195-1205.
Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752.
Yee D. Pathological complete response predicts event-free and distant disease free survival in the I-SPY 2 TRIAL. Slides presented at: 2017 San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX.
Recurrent breast cancer. Mayo Clinic website. https://www.mayoclinic.org/diseases-conditions/ recurrent-breast-cancer/symptoms-causes/syc-20377135. Accessed July 14, 2021.
Sun L, Zhu Y, Qian Q, Tang L. Body mass index and prognosis of breast cancer: an analysis by menstruation status when breast cancer diagnosis. Medicine (Baltimore). 2018;97(26):e11220.
Pierce JP, Patterson RE, Senger CM, et al. Lifetime cigarette smoking and breast cancer prognosis in the After Breast Cancer Pooling Project. J Natl Cancer Inst. 2014;106(1):djt359.
Helwick C. Final analysis of BCIRG-006 supports use of non–anthracycline-containing regimen in treatment of women with early breast cancer. The ASCO Post website. https://www .ascopost.com/issues/march-10-2016/final-analysis-of-bcirg-006-supports-use-of-nonanthracycline-containing-regimen-in-treatment-of-women-with-early-breast-cancer. Accessed July 14, 2021.
von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.
Singh JC, Jhaveri K, Esteva FJ. HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development. Br J Cancer. 2014;111(10):1888-1898.
Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res. 2011;17(14):4834-4843.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283.
Untch M, Geyer CE Jr, Huang C-S, et al. Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: an update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC). Slides presented at: 2019 European Society for Medical Oncology (ESMO) Congress; September 30, 2019; Barcelona, Spain.
Chien J. HER2+ early breast cancer: balancing risk and toxicity. Slides presented at: 2019 San Antonio Breast Cancer Symposium (SABCS); December 11, 2019; San Antonio, TX.
Lin NU. Breast cancer brain metastases: new directions in systemic therapy. Ecancermedicalscience. 2013;7:307.
Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res. 2007;13(6):1648-1655.
Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22(4):525-531.
Hegedüs C, Truta-Feles K, Antalffy G, et al. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochem Pharmacol. 2012;84(3):260-267.
Puma Biotechnology, Inc. Data on file.
Barcenas CH, Hurvitz SA, Di Palma JA, 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. doi:10.1016/j.annonc.2020.05.012
US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed July 14, 2021.
Saura C, Oliveira M, Feng Y-H, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. Published online July 17, 2020. doi:10.1200/JCO.20.00147
Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-1089.
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):3958-3965.
Wissner A, Mansour TS. The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm (Weinheim). 2008;341(8):465-477.
Canonici A, Gijsen M, Mullooly M, et al. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget. 2013;4(10):1592-1605.
Segovia-Mendoza M, González-González ME, Barrera D, Díaz L, García-Becerra R. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence. Am J Cancer Res. 2015;5(9):2531-2561.
Martin TA, Alani AS, Connors FA, et al. Neratinib as a putative therapy in metastatic brain disease. Poster presented at: 2017 San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX.
Zhao X-Q, Xie J-D, Chen X-G, 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.
Collins DM, Conlon NT, Kannan S, 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 (Basel). 2019;11(6):737.
Prat A, Baselga J. The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nat Clin Pract Oncol. 2008;5(9):531-54238.
Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer Res. 2009;15(24):7479-7491.
Giuliano M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer: molecular basis and clinical implication. Breast Care. 2013;8:256-262.
Chung A, Cui X, Audeh W, Giuliano A. Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. Clin Breast Cancer. 2013;13(4):223-232.
Paplomata E, Nahta R, O'Regan RM. Systemic therapy for early-stage HER2-positive breast cancers: time for a less-is-more approach? Cancer. 2015;121(4):517-526.
Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29(2):217-233.
Loi S, Dafni U, Karlis D, et al. Effects of estrogen receptor and human epidermal growth factor receptor-2 levels on the efficacy of trastuzumab: a secondary analysis of the HERA trial. JAMA Oncol. 2016:2(8):1040-1047.
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