Introduction
Nerlynx (neratinib) is an oral, irreversible tyrosine kinase inhibitor approved by the FDA for the extended adjuvant treatment of early-stage HER2-positive breast cancer. It represents an important advancement in targeted therapy for HER2-positive malignancies, specifically designed to reduce the risk of recurrence following trastuzumab-based therapy.
Mechanism of Action
Neratinib is an irreversible inhibitor of the ErbB receptor tyrosine kinase family, including HER1 (EGFR), HER2, and HER4. By covalently binding to the cysteine residues in the ATP-binding pocket of these receptors, neratinib inhibits autophosphorylation and downstream signaling through the MAPK and PI3K pathways. This targeted inhibition prevents HER2-mediated tumor cell proliferation and survival.
Indications
- Extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy
- In combination with capecitabine for treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens
Dosage and Administration
Standard dosing: 240 mg (6 tablets) orally once daily with food for 12 months Dose escalation: Recommended for first 14 days to manage diarrhea:- Days 1-7: 120 mg once daily
- Days 8-14: 160 mg once daily
- Day 15 onward: 240 mg once daily
- Renal impairment: No dose adjustment recommended
- Hepatic impairment: Not recommended for severe hepatic impairment (Child-Pugh C)
- Geriatric patients: No specific dose adjustment required
Pharmacokinetics
Absorption: Median Tmax approximately 2-8 hours; high-fat meal increases AUC by 1.7-fold Distribution: Volume of distribution ~4,000 L; >99% protein bound Metabolism: Primarily via CYP3A4 with minor contributions from FMO and glucuronidation Elimination: Half-life ~7-17 hours; fecal excretion (97%), renal excretion (<1%)Contraindications
- Hypersensitivity to neratinib or any component of the formulation
Warnings and Precautions
Diarrhea: May be severe with dehydration, hypotension, and renal impairment. Proactive management with loperamide is essential during first 2 cycles Hepatotoxicity: Monitor liver function tests; interrupt and reduce dose for Grade 3 or 4 hepatotoxicity Embryo-fetal toxicity: Can cause fetal harm; verify pregnancy status and use effective contraception Interstitial lung disease: Monitor for pulmonary symptoms; discontinue if diagnosedDrug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): Increase neratinib exposure; avoid concomitant use Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease neratinib exposure; avoid concomitant use Gastric acid reducing agents: PPIs may decrease neratinib absorption; separate administration by至少 3 hoursAdverse Effects
Very common (≥20%): Diarrhea (96%), nausea (43%), abdominal pain (39%), fatigue (27%), vomiting (26%) Common (5-20%): Rash, stomatitis, decreased appetite, muscle spasms, dyspepsia Serious: Severe diarrhea (40% Grade 3), hepatotoxicity, interstitial lung disease, dehydrationMonitoring Parameters
- Diarrhea assessment at each visit during first 2 months
- Liver function tests (ALT, AST, bilirubin) monthly for first 3 months, then quarterly
- Renal function and electrolytes in patients with diarrhea
- Complete blood count periodically
- Pregnancy testing in women of reproductive potential
- Signs/symptoms of interstitial lung disease
Patient Education
- Take with food to improve absorption
- Initiate loperamide prophylaxis as prescribed (typically 4 mg with first dose, then 4 mg every 4 hours or after each loose stool)
- Maintain adequate hydration, especially during episodes of diarrhea
- Report severe or persistent diarrhea, yellowing of skin/eyes, or respiratory symptoms immediately
- Use effective contraception during treatment and for至少 1 month after final dose
- Do not breastfeed during treatment and for 1 month after final dose
- Inform all healthcare providers about Nerlynx use due to potential drug interactions
References
1. FDA Prescribing Information: Nerlynx (neratinib) tablets 2. Chan A, et al. Lancet Oncol. 2016;17(3):367-377 3. Martin M, et al. J Clin Oncol. 2020;38(34):3987-3998 4. Saura C, et al. JAMA Oncol. 2020;6(3):402-408 5. NCCN Guidelines Version 3.2023: Breast Cancer 6. Awada A, et al. Ann Oncol. 2016;27(5):818-824
This information is intended for educational purposes only and should not replace professional medical advice. Always consult with a qualified healthcare provider for personalized medical guidance.