• 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 trastuzumab-based therapy.
    • 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.
  • Assessing the risk of recurrence in patients with early-stage HER2+ breast cancer

    photo of a patient

    “When I found out I was cancer free, for a moment, I felt some kind of relief . . . but the reality is that I can never really stop worrying.”

    Real patient with HER2+ HR+ breast cancer who had a pCR. NERLYNX was not commercially available at the time of treatment. Photograph taken April 2013.

    Just 1 risk factor at initial presentation is enough to increase the risk of recurrence1-5

    Disease characteristics

    1 or more positive nodes5

    • 25% of patients with 1-3 positive nodes experienced recurrence within 10 years
    • 45% of patients with ≥4 positive nodes experienced recurrence

    Tumor size1,*

    • 53% increase in the risk of recurrence for patients with tumors 2-5 cm in diameter
    • 81% increase in the risk of recurrence for patients with tumors >5 cm in diameter

    Patient characteristics

    • Young age at diagnosis2
    • High BMI3
    • Smokes4

    Acting with urgency can help give patients with HER2+ eBC the chance to live disease free6

    • Compared with tumors less than 2 cm in diameter.1
    • BMI: body mass index; eBC: early-stage breast cancer; HR+: hormone receptor–positive.

    Despite advances in the treatment of HER2+ eBC, the risk of recurrence remains—regardless of pCR status1,5,7,8

    Recurrence rates in HER2+ eBC clinical trials

    Joint Analysis (NSABP B-31 and NCCTG N9831)1

    26%

    At 10 years in the ITT population (node-positive or high-risk node-negative disease)

    in the ITT population (node-positive or high-risk node-negative disease)

    Trastuzumab in combination with AC➞T (n=2028) vs 38% with AC➞T (n=2018)

    Katherine7

    12%

    At 3 years in the ITT population

    in the ITT population

    Trastuzumab emtansine (n=743) vs 23% with trastuzumab (n=743)

    17%

    At 3 years in patients with residual node-positive disease

    in patients with residual node-positive disease

    Trastuzumab emtansine (n=343) vs 32% with trastuzumab (n=346)

    Neosphere9

    15%

    At 5 years in patients with a pCR

    in patients with a pCR

    Neoadjuvant treatment with various combinations of trastuzumab, docetaxel, and pertuzumab (n=94)

    • AC➞T: doxorubicin and cyclophosphamide followed by paclitaxel; eBC: early-stage breast cancer; ITT: intent to treat; pCR: pathologic complete response.

    An analysis of HER2+ eBC studies showed no reduction in risk of CNS metastases as first site of recurrence10

    Trial and populationAnalysis
    timepoint
    NNeoadjuvant
    population
    CNS recurrence, %
    ComparatorTreatment
    Adjuvant trastuzumab meta-analysis-9020N/A1.942.56
    ALTTO*3 years5190~8%22
    APHINITY node (+) or high-risk node (-)3 years480501.81.9
    No pCR post neoadjuvant treatment
    KATHERINE high-risk3 years1486N/A4.35.9
    • A literature analysis of randomized adjuvant or neoadjuvant phase 2 or 3 trials, in which patients were randomized to 1 year of trastuzumab or a control arm without trastuzumab, and contained adequate reporting for CNS disease as a site of first relapse10
    • ALTTO was a phase 3, randomized trial in patients with HER2+ eBC that randomized subjects into 4 treatment groups, including sequential trastuzumab followed by oral lapatinib and the combination of trastuzumab and lapatinib10
    • APHINITY was a phase 3, randomized, double-blind, placebo-controlled trial of chemotherapy and 1 year of trastuzumab ± pertuzumab10
    • KATHERINE was a phase 3, randomized trial of adjuvant trastuzumab emtansine or trastuzumab in patients with residual disease (stage T1-T4, N0-N3, M0, excluding T1a/bN0 at presentation) after HER2-directed neoadjuvant therapy10

    Limitations: This report is a retrospective analysis of data from the published literature. Due to the relative low incidence of CNS disease as the site of first recurrence, the number of patients in each study was low. The analysis did not allow for a true cross-trial comparison as the patient populations differed among the trials.10

    • Sequential 12 doses of trastuzumab (loading dose 4 mg/kg then 2 mg/kg weekly or 8 mg/kg loading dose then 6 mg/kg every 3 weeks), followed by a 6-week washout and 34 weeks of oral lapatinib 1500 mg/day (comparator) or the combination of trastuzumab and oral lapatinib 750 mg/day (treatment).10
    • Trastuzumab (loading dose 8 mg/kg then 6 mg/kg IV) + pertuzumab (840 mg loading dose then 420 mg) (treatment) or placebo (comparator) every 3 weeks (maximum 18 cycles).10
    • Trastuzumab 6 mg/kg (comparator) or trastuzumab emtansine 3.6 mg/kg (treatment), each administered every 3 weeks for 14 cycles.10
    • CNS: central nervous system; eBC: early-stage breast cancer; pCR: pathologic complete response.

    The CNS is a sanctuary site for HER2+ breast cancer metastases11

    CNS recurrence rates in patients who experienced distant recurrence in HER2+ eBC trials12,13

    Katherine

    (trastuzumab emtansine)
    56%

    had CNS metastases
    as the first site of recurrence (44/78)12

    APHINITY

    (pertuzumab)
    35%

    had CNS metastases
    as the first site of recurrence (49/141)13

    up to50%

    of patients with HER2+ breast cancer experiencing recurrence develop brain metastases at some point14

    View eBC clinical data
    • CNS: central nervous system; eBC: early-stage breast cancer.
    References:
    1. 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. doi:10.1200/JCO.2014.55.5730
    2. Recurrent breast cancer. Mayo Clinic. Updated January 21, 2021. Accessed May 26, 2022. https://www.mayoclinic.org/diseases-conditions/recurrent-breast-cancer/symptoms-causes/syc-20377135
    3. 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. doi:10.1097/MD.0000000000011220
    4. 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. doi:10.1093/jnci/djt359
    5. 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. doi:10.1016/S0140-6736(16)32616-2
    6. 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. doi:10.1016/j.clbc.2020.09.014
    7. 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. doi:10.1056/NEJMoa1814017
    8. 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. March 10, 2016. Accessed May 26, 2022. https://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/
    9. Gianni L, Pienkowski T, Im Y-H, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800. doi:10.1016/S1470-2045(16)00163-7
    10. Lin NU, Lüftner D, Brufsky AM, et al. Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer. Poster presented at: San Antonio Breast Cancer Symposium (SABCS); December 7-10, 2021; San Antonio, TX.
    11. Leone JP, Leone BA. Breast cancer brain metastases: the last frontier. Exp Hematol Oncol. 2015;4:33. doi:10.1186/s40164-015-0028-8
    12. Untch M, Geyer CE Jr, Huang C-S, et al. Peripheral neuropathy, thrombocytopaenia, and central nervous system recurrence: an update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab in patients with residual invasive HER2-positive breast cancer. Presented at: European Society for Medical Oncology (ESMO) Annual Meeting; September 27-October 1, 2019; Barcelona, Spain.
    13. Piccart M, Procter M, Fumagalli D, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years’ follow-up. J Clin Oncol. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204
    14. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res. 2013;19(23):6404-6418. doi:10.1158/1078-0432.CCR-13-0790

    Important Safety Information and Indications

    Contraindications: None

    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 contraception.

    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 muscle spasms.

    To report suspected adverse reactions, contact Puma Biotechnology, Inc. at 1-844-Nerlynx (1-844-637-5969) or FDA at 1-844-332-1088 or www.fda.gov/medwatch.

    Drug Interactions:

    • 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.

    Use In Specific Populations:

    • Lactation: Advise women not to breastfeed.

    Please see Full Prescribing Information.

    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 trastuzumab-based therapy.
    • 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.
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