Neratinib, a potent, selective, and irreversible inhibitor of human epidermal growth factor receptor type 2 (HER2), HER4, and epidermal growth factor receptor (EGFR) tyrosine kinases, is an antineoplastic agent.1, 8, 13, 10060
Extended Adjuvant Therapy for Early-stage Breast Cancer
Neratinib is used as extended adjuvant therapy in adults with human epidermal growth factor receptor type 2 (HER2)-positive, early-stage breast cancer who have received adjuvant trastuzumab therapy.1, 2, 13, 10060 Safety and efficacy of neratinib for this indication are supported by a single randomized controlled trial.2, 13 Guidelines generally suggest that neratinib may be used for extended adjuvant therapy in patients with early-stage, HER2-positive breast cancer after receiving treatment with trastuzumab plus chemotherapy.10060
This indication for neratinib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (ExteNET) in women with HER2-positive early-stage breast cancer who completed neoadjuvant and adjuvant trastuzumab therapy within 2 years of randomization.1, 2 In this study, 2840 patients were randomized (stratified by hormone receptor status, nodal status, and adjuvant trastuzumab regimen) to receive either neratinib (240 mg orally once daily) or placebo.1, 2 Treatment was continued for 12 months unless disease progression, new breast cancer, or unacceptable toxicity occurred, or treatment was discontinued for other reasons.1, 2 The primary measure of efficacy was invasive disease-free survival.1, 2 The median age of patients enrolled in the study was 52 years; 81% of the patients were white, 99.7% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, 57% had hormone receptor-positive disease, and 30% had 4 or more positive nodes.1, 2 Most patients (81%) were enrolled within 1 year of completion of adjuvant trastuzumab therapy; the median time from completion of adjuvant trastuzumab therapy to randomization was 4.4 or 4.6 months in patients randomized to neratinib or placebo, respectively.1, 2
At a follow-up of 2 years, invasive disease-free survival rates were 94.2 or 91.9% in patients receiving neratinib or placebo, respectively.1, 7 Subgroup analysis suggested that neratinib had a greater effect on invasive disease-free survival relative to placebo in patients with hormone receptor-positive disease than in those with hormone receptor-negative disease (hazard ratio: 0.49 and 0.93, respectively), in those who received sequential adjuvant trastuzumab therapy than in those who received adjuvant trastuzumab concurrently with chemotherapy (hazard ratio: 0.46 and 0.80, respectively), and in those who completed adjuvant trastuzumab therapy within 1 year of randomization than in those who completed adjuvant trastuzumab therapy 1-2 years prior to randomization (hazard ratio: 0.63 and 0.92, respectively).1 Median overall survival had not been reached at the time of the efficacy analysis.1, 2 A final analysis of the ExteNET study separately reported 5-year rates of invasive disease-free survival among patients who were hormone receptor-positive and received neratinib within 1 year of completion of trastuzumab or in those who received neratinib more than 1 year after completion of trastuzumab.13 In patients who were hormone receptor-positive who received treatment within 1 year of completion of trastuzumab, 5-year rates of invasive disease-free survival were 90.8% in patients treated with neratinib and 85.7% in patients treated with placebo.13 In patients who were hormone receptor-positive who received treatment more than 1 year after completion of trastuzumab, 5-year rates of invasive disease-free survival were 93% in patients treated with neratinib and 91.7% in patients treated with placebo.13 After a median of 8 years of follow-up (median duration of study treatment 11.5 and 11.9 months with neratinib and placebo, respectively), estimated overall survival rates were 91.5% in patients receiving neratinib and 89.4% in those receiving placebo; this difference was not found to be statistically significant.13
In the 2020 American Society of Clinical Oncology (ASCO) guidelines on selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer, adjuvant trastuzumab emtansine is recommended for patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after receiving standard preoperative chemotherapy and HER2-targeted therapy.10060 In this setting, trastuzumab is recommended in combination with chemotherapy for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer with tumors greater than 1 cm.10060 Neratinib is suggested as an option for extended adjuvant therapy in patients with early-stage, HER2-positive breast cancer; the greatest potential benefit appears to be derived when neratinib is administered within 1 year of completion of trastuzumab treatment.10060 The guideline further notes that use of neratinib is preferred in hormone receptor-positive and node-positive patients.10060
Advanced or Metastatic Breast Cancer
Neratinib is used in combination with capecitabine to treat advanced or metastatic HER2-positive breast cancer in adults who have received at least 2 prior anti-HER2 treatment regimens in the metastatic setting.1, 12, 11000 Safety and efficacy of neratinib for this indication are supported by a single randomized controlled trial.12 Guidelines generally recommend neratinib among several potential third-line treatment options in patients whose advanced, HER2-positive breast cancer has progressed during or after 2 previous anti-HER2 regimens.11000
This indication for neratinib is based principally on the results of a randomized, open label, active-controlled multicenter study (NALA) in adults with HER2-positive metastatic breast cancer who had previously received 2 or more anti-HER2-based regimens.1, 12 In this study, 621 patients were randomized (stratified by hormone receptor status, number of previous HER2-directed treatments for metastatic breast cancer, geographic region, and visceral disease) to receive oral administration of either neratinib 240 mg once daily on cycle days 1-21 plus capecitabine 750 mg/m2 twice daily on days 1-14 of each 21-day cycle or lapatinib 1250 mg daily on cycle days 1-21 plus capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle.1, 12 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The co-primary measures of efficacy were independently adjudicated progression-free survival and overall survival.12 At baseline, 59% of enrolled patients were hormone receptor-positive, 69% had received 2 prior anti-HER2 based regimens, and 31% had received 3 or more previous anti-HER2 based regimens;81% of patients had visceral disease.1
At a median follow-up of 29.9 months, median progression-free survival was 5.6 months in the neratinib plus capecitabine group compared with 5.5 months in the lapatinib plus capecitabine group.1, 12 These results were generally consistent across subgroups based on disease location, hormone receptor status, and previous HER2 regimens.1, 12 At the time of follow-up, median overall survival was similar with neratinib plus capecitabine versus lapatinib plus capecitabine (21 or 18.7 months, respectively).1, 12, 1, 12
In the 2022 ASCO guidelines on systemic treatment for advanced HER2-positive breast cancer, first-line recommended treatment includes a combination of trastuzumab, pertuzumab, and a taxane.11000 Trastuzumab deruxtecan is recommended for second-line treatment of patients whose breast cancer progresses after initial HER2-targeted treatment.11000 Multiple potential treatment options are recommended for third-line treatment, including neratinib in combination with capecitabine.11000 Selection of an appropriate regimen should be made after discussing treatment schedules, routes of administration, and adverse effects with the patient.11000
Neratinib maleate is administered orally with food.1 The drug should be taken at approximately the same time each day.1
Neratinib tablets should be swallowed whole; tablets should not be chewed, crushed, or split.1
Store neratinib tablets at a controlled room temperature of 20-25°C (excursions permitted between 15-30°C).1
Dosage of neratinib maleate is expressed in terms of neratinib.1
Extended Adjuvant Therapy for Early-stage Breast Cancer
For extended adjuvant treatment of human epidermal growth factor receptor type 2 (HER2)-positive early-stage breast cancer following adjuvant trastuzumab-based therapy, the recommended adult dosage of neratinib is 240 mg (6 tablets) orally once daily, given continuously for up to one year or until disease recurrence.1
A 2-week dose escalation may be considered to minimize the risk of diarrhea (see Table 1):1
Time on Neratinib | Dose |
|---|---|
Week 1 (days 1-7) | 120 mg daily (three 40-mg tablets) |
Week 2 (days 8-14) | 160 mg daily (four 40-mg tablets) |
Week 3 and onwards | 240 mg daily (six 40-mg tablets)a |
Advanced or Metastatic Breast Cancer
For use in combination with capecitabine in the treatment of HER2-positive advanced or metastatic breast cancer, the recommended adult dosage of neratinib is 240 mg (6 tablets) once daily given orally on days 1-21 of a 21-day cycle.1 Capecitabine 750 mg/m2 is administered orally twice daily on days 1-14 of a 21-day cycle.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
A 2-week dose escalation may be considered to minimize the risk of diarrhea (see Table 2):1
Time on Neratinib | Dose |
|---|---|
Week 1 (days 1-7) | 120 mg daily (three 40-mg tablets) |
Week 2 (days 8-14) | 160 mg daily (four 40-mg tablets) |
Week 3 and onwards | 240 mg daily (six 40-mg tablets)a |
Dosage Modification for Toxicity
Dosage interruption and/or reduction or discontinuance of neratinib therapy may be necessary based on severity of adverse reactions.1 Dosage adjustment of neratinib is recommended based on individual safety and tolerability.1
Discontinue neratinib in patients with persistent grade 2 or greater adverse effects that do not recover to grade 0-1 or baseline and patients with any toxicity that requires a treatment delay of greater than 3 weeks; discontinuance of therapy is also recommended in those who cannot tolerate a dosage of 120 mg daily.1
If dosage modification of neratinib monotherapy is required for toxicity, reduce the dosage of neratinib as described in Table 3.1
Dose Reduction Level | Neratinib Dosage (Starting Dosage = 240 mg once daily) |
|---|---|
First | Restart at 200 mg daily (five 40-mg tablets) |
Second | Restart at 160 mg daily (four 40-mg tablets) |
Third | Restart at 120 mg daily (three 40-mg tablets) |
If an adverse reaction occurs, modify dosage accordingly (see Table 4).1
Adverse Reaction and Severity | Modification |
|---|---|
Diarrhea |
|
Grade 1 (<4 stools per day over baseline) or Grade 2 (4-6 stools per day over baseline) lasting ≤5 days or Grade 3 (≥7 stools per day over baseline, fecal incontinence, need for hospitalization, limiting self-care activities of daily living) lasting ≤2 days | Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration Once diarrhea resolves to ≤ grade 1, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib |
Any grade with additional complicating featuresa or Grade 2 lasting >5 days despite treatment with optimal medical therapy or Grade 3 lasting >2 days despite treatment with optimal medical therapy | Withhold therapy; modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration If diarrhea resolves to ≤grade 1 within 1 week, resume neratinib at same dosage If diarrhea resolves to ≤grade 1 in longer than 1 week, resume neratinib at a reduced dosage (see Table 3) Once event resolves to ≤ grade 1 or baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib |
Grade 4 (life-threatening diarrhea or need for urgent intervention) | Permanently discontinue therapy |
Recurrence of grade 2 or higher diarrhea at a dosage of 120 mg daily | Permanently discontinue therapy |
Hepatotoxicity |
|
Grade 3 ALT or AST (>5-20 × ULN) or Grade 3 bilirubin (>3-10 × ULN) | Withhold therapy until recovery to ≤grade 1 and evaluate for alternative causes If recovery to ≤grade 1 occurs within 3 weeks, resume neratinib at the next lower dose level (see Table 3) If grade 3 hepatotoxicity recurs after one dose reduction, permanently discontinue therapy |
Grade 4 ALT or AST (>20 × ULN) or Grade 4 bilirubin (>10 × ULN) | Permanently discontinue therapy and evaluate for alternative causes |
Other Adverse Effects |
|
Grade 3 | Withhold therapy; if adverse effect resolves to ≤ grade 1 or baseline within 3 weeks, resume at next dose level (see Table 3) |
Grade 4 | Permanently discontinue therapy |
aAdditional complicating features include dehydration, pyrexia, hypotension, renal failure, or grade 3-4 neutropenia
Combination Therapy with Capecitabine
If an adverse reaction occurs when neratinib is used in combination with capecitabine, refer to the prescribing information for capecitabine for dosage modifications of capecitabine and reduce the dosage of neratinib as described in Table 5.1
Dose Reduction Level | Neratinib Dosage (Starting Dosage = 240 mg once daily) |
|---|---|
First | Restart at 160 mg daily (four 40-mg tablets) |
Second | Restart at 120 mg daily (three 40-mg tablets) |
If an adverse reaction occurs when neratinib is used in combination with capecitabine, modify the dosage accordingly (see Table 6).1
Adverse Reaction and Severity | Modification |
|---|---|
Diarrhea |
|
Grade 1 (<4 stools per day over baseline) or Grade 2 (4-6 stools per day over baseline) lasting ≤5 days or Grade 3 (≥7 stools per day over baseline, fecal incontinence, need for hospitalization, limiting self-care activities of daily living) lasting ≤2 days | Continue neratinib and capecitabine at full doses Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration Once diarrhea resolves to grade ≤1 or baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib |
Persistent/intolerable grade 2 lasting >5 days or Grade 3 lasting >2 days Grade 4 (life-threatening diarrhea or need for urgent intervention) | Withhold neratinib and capecitabine until recovery to grade ≤1 or baseline; if recovered within 1 week, resume both drugs at same dosa if recovered in 1-3 weeks, resume neratinib at reduced dosage and continue capecitabine at same dosage (see Table 5) Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydrationb If recovery occurs within 1 week of withholding treatment, resume both drugs at same dosa if recovery occurs within 1-3 weeks of withholding treatment, reduce neratinib dose to 160 mg and maintain same dose of capecitabine If event occurs a second time and the dosage of neratinib has not already been decreased, reduce neratinib dose to 160 mg and maintain same dose of capecitabine; if the dosage of neratinib has already been reduced, reduce the dosage of capecitabine to 550 mg/m2 twice dailya and maintain the same dosage of neratinib If subsequent events occur, reduce the dose of neratinib or capecitabine to the next lower dose level in an alternating fashion Once the event resolves to grade ≤1 of baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib |
Hepatotoxicity |
|
Grade 3 ALT or AST (>5-20 × ULN) or Grade 3 bilirubin (>3-10 × ULN) | Withhold neratinib until recovery to grade ≤1 and evaluate for alternative causes If recovery to grade ≤1 within 3 weeks, resume neratinib at next lower dose level (see Table 5) If grade 3 hepatotoxicity recurs after dosage reduction, permanently discontinue neratinib |
Grade 4 ALT or AST (>20 × ULN) or Grade 4 bilirubin (>10 × ULN) | Permanently discontinue neratinib and evaluate for alternative causes |
Other Adverse Effects |
|
Grade 3 | Withhold neratinib; if adverse effect resolves to grade≤1 or baseline within 3 weeks, resume therapy at the next lower dose level(see Table 5) |
Grade 4 | Permanently discontinue neratinib |
a Since capecitabine is provided as 150-mg or 500-mg tablets, it is recommended to round the dose reduction down to the nearest 500 mg or multiple of 150 mg for the twice daily dose. If the patient's body surface area is >2 m2, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing.
b Fluid intake should be maintained intravenously, if needed
For patients with severe preexisting hepatic impairment (Child-Pugh class C), reduce the initial neratinib dosage to 80 mg once daily.1 No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1
No dosage adjustment is necessary in patients with renal impairment.7
There are currently no specific dosage recommendations for geriatric patients.1
Severe diarrhea associated with dehydration, hypotension, and renal impairment has been reported in patients receiving neratinib.1 In the ExteNET study in patients with human epidermal growth factor receptor type 2 (HER2)-positive early-stage breast cancer, diarrhea was reported in 95% of patients receiving neratinib and was grade 3 in severity in 40% of patients.1 The majority (93%) of patients experienced diarrhea during the first month of therapy; the median time to onset of grade 3 or greater diarrhea was 8 days.1 The median cumulative duration of grade 3 or greater diarrhea was 5 days.1 In a small study, the incidence and time to onset of grade 1 or greater diarrhea were not ameliorated by administering the total daily dosage of neratinib in 2 divided doses (120 mg twice daily) instead of the recommended 240 mg once daily.4
In the NALA study of patients with metastatic breast cancer treated with neratinib plus capecitabine, diarrhea was reported in 83% of patients; all patients received anti-diarrheal prophylaxis in the first 21-day cycle.1 The majority of patients (70%) had diarrhea within the first 21 days of treatment.1 Grade 3 or greater diarrhea occurred in 24% of patients with a median time to first onset of 11 days and a median duration of 3 days.1
The manufacturer recommends antidiarrheal prophylaxis with loperamide during the first 56 days of treatment with neratinib in patients not using a dose escalation approach.1 After day 56, dosage of loperamide should be adjusted to maintain 1-2 bowel movements per day; consider addition of other antidiarrheal agents as clinically indicated.1 As an alternate approach to diarrhea management, a 2-week dosage escalation of neratinib can be considered.1 In patients managed with this approach, grade 3 or greater diarrhea occurred in 13% of patients with a median time to onset of 45 days and a median duration of 2.5 days.1
Patients receiving neratinib should be monitored for development of diarrhea and treated as necessary with appropriate therapy (e.g., antidiarrheal agents, fluid replacement).1 Stool cultures should be performed as clinically indicated to exclude infectious causes in patients experiencing grade 3 or 4 diarrhea or diarrhea of any severity associated with dehydration, pyrexia, or neutropenia.1 Liver function tests also should be evaluated in patients experiencing grade 3 or greater diarrhea.1 Temporary interruption followed by dosage reduction or discontinuance of neratinib may be necessary depending on the severity of the diarrhea.1
Elevations in aminotransferase (ALT or AST) concentrations have been reported in patients receiving neratinib.1 In the ExteNET study, elevations in ALT or AST concentrations ≥2 times the upper limit of normal (ULN) occurred in 10 or 5% of patients of patients receiving neratinib, respectively; severe (grade ≥3 ) elevations occurred in 1.7% of patients.1 Hepatotoxicity or elevations in ALT or AST concentrations led to discontinuance of neratinib in 1.7% of patients.1
In the NALA study in patients treated with neratinib and capecitabine, 7% of patients experienced elevations in ALT or AST to >3 times the ULN, and 2% of patients experienced elevations in ALT or AST to >5 times the ULN; 7 and 1.3% of patients experienced bilirubin elevations >1.5 and >3 times the ULN, respectively.1 Hepatotoxicity or increases in liver enzymes led to treatment discontinuance in 0.3% of patients treated with neratinib and capecitabine.1
Evaluate liver function tests (i.e., serum ALT, AST, total bilirubin, alkaline phosphatase concentrations) prior to initiation of therapy, monthly for the first 3 months of therapy, every 3 months thereafter during therapy, and as clinically indicated.1 Liver function tests should also be evaluated in patients experiencing grade 3 or greater diarrhea or manifestations of hepatotoxicity (e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, pyrexia, rash, eosinophilia).1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of neratinib in pregnant women; however, based on its mechanism of action and animal findings, neratinib may cause fetal harm.1 Embryofetal toxicity (i.e., increased fetal resorption, abortion) and teratogenicity (i.e., external, visceral, and skeletal anomalies) have been demonstrated in animals receiving neratinib at exposure levels approximately 0.2 times the human exposure at the maximum recommended dosage.1 Effects on long-term memory have been observed in male pups when pregnant rats received the drug from day 7 of gestation through day 20 of lactation at a dosage approximately 0.2 times the maximum recommended human dosage based on body surface area.1
Pregnancy should be avoided during neratinib therapy.1 Apprise patients of the potential hazard to the fetus if neratinib is used during pregnancy.1 (See Females and Males of Reproductive Potential under Cautions.)
Neratinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
It is not known whether neratinib or its metabolites are distributed into milk.1 Because of the potential for serious adverse reactions to neratinib in nursing infants, women should be advised to discontinue nursing while receiving neratinib and for at least 1 month after the drug is discontinued.1 The effects of the drug or its metabolites on nursing infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
Advise females of childbearing potential to use effective contraceptive methods while receiving neratinib and for at least 1 month after discontinuance of the drug.1 In addition, advise male patients with such female partners to use effective methods of contraception while receiving neratinib and for 3 months after discontinuance of the drug.1
Safety and efficacy of neratinib have not been established in pediatric patients.1
In the ExteNET study, 12% of patients receiving neratinib in the safety population were ≥65 years of age and 1.8% were ≥75 years of age.1 Patients ≥65 years of age had higher incidences of discontinuance of neratinib due to adverse reactions but similar incidences of serious adverse reactions (e.g., vomiting, diarrhea, renal failure, dehydration) compared with younger adults.1
In the NALA study, 20% of patients receiving neratinib plus capecitabine in the safety population were ≥65 years of age and 4% were ≥75 years of age.1 The incidence of serious adverse reactions was similar between patients ≥65 years of age and younger patients; the most commonly reported serious adverse events in geriatric patients were diarrhea, acute kidney injury, and dehydration.1 No overall differences in efficacy were noted between patients ≥65 years of age and those <65 years of age.1
Systemic exposures of neratinib in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B) were similar to those in individuals with normal hepatic function but were increased in those with severe hepatic impairment (Child-Pugh class C); therefore, dosage adjustment is necessary in patients with severe hepatic impairment.1
Renal function does not have a clinically significant effect on the pharmacokinetics of neratinib.1 No dosage adjustment is necessary in such patients.7
Adverse effects reported in ≥5% of patients receiving neratinib monotherapy include diarrhea, nausea, abdominal pain, abdominal distension, fatigue, vomiting, rash, stomatitis, decreased appetite, nail disorders, dry skin, muscle spasms, epistaxis, decreased weight, increased AST or ALT, urinary tract infections, and dyspepsia.1
Adverse effects reported in ≥5% of patients receiving neratinib in combination with capecitabine include diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue, decreased weight, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distension, renal impairment, and muscle spasms.1
Neratinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by flavin-containing monooxygenase (FMO).1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of neratinib with potent or moderate inhibitors of CYP3A4 may result in increased systemic exposure to neratinib and an increased incidence of adverse effects.1, 5 Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma concentration and AUC of neratinib by 221 and 381%, respectively.1, 5 Concomitant administration of the moderate CYP3A4 inhibitor fluconazole with neratinib increased the peak plasma concentration and AUC of neratinib by 30 and 68%, respectively.1
Avoid concomitant use of neratinib with potent inhibitors of CYP3A4 (e.g., clarithromycin; cobicistat; conivaptan; diltiazem; ritonavir-boosted elvitegravir; grapefruit products; idelalisib; ritonavir-boosted indinavir; itraconazole; ketoconazole; the fixed combination of lopinavir and ritonavir [lopinavir/ritonavir]; nefazodone; nelfinavir; the fixed combination of ombitasvir, paritaprevir, and ritonavir [with or without dasabuvir]; posaconazole; ritonavir; ritonavir-boosted saquinavir; ritonavir-boosted tipranavir; voriconazole) or moderate (e.g., aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, verapamil).1
Concomitant use of neratinib with potent or moderate inducers of CYP3A4 may result in decreased systemic exposure to neratinib and its active N -desmethyl (M6) and dimethylamine N -oxide (M7) metabolites, resulting in reduced neratinib efficacy.1 When the potent CYP3A4 inducer rifampin was administered concomitantly with neratinib, the AUCs of neratinib and its active metabolites (M6 and M7) were decreased by 87 and 37-49%, respectively, and the peak plasma concentration of neratinib was decreased by 76%.1 When the moderate CYP3A4 inducer efavirenz was administered concomitantly with neratinib, the peak plasma concentration and AUC of neratinib were decreased by 36 and 52%, respectively.1
Avoid concomitant use with potent CYP3A4 inducers (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil).1
P-Glycoprotein and Moderate CYP3A4 Dual Inhibitors
Concomitant use of neratinib with P-glycoprotein (P-gp) and moderate CYP3A4 dual inhibitors may result in increased systemic exposure of neratinib and an increased incidence of adverse effects.1 When the P-gp and moderate CYP3A4 dual inhibitor verapamil was administered concomitantly with neratinib, peak plasma concentrations and AUC of neratinib increased by 203 and 299%, respectively.1
Avoid concomitant use of neratinib with P-gp and moderate CYP3A4 dual inhibitors.1
Substrates of P-Glycoprotein Transport Systems
Concomitant use of neratinib with P-gp substrates (e.g., digoxin, dabigatran, fexofenadine) may result in increased systemic exposure of the substrate drug.1 When the P-gp substrate digoxin was administered concomitantly with neratinib, peak plasma concentrations and AUC of digoxin increased by 54 and 32%, respectively.1
Monitor for adverse reactions of certain P-gp substrates for which minimal concentration changes may lead to serious adverse reactions when used concomitantly with neratinib.1, 7
Drugs Affecting Gastric Acidity
Concomitant use of neratinib with drugs affecting gastric acidity may decrease the solubility of neratinib and subsequently reduce its bioavailability and efficacy.1, 7 Concomitant administration of the proton-pump inhibitor lansoprazole with neratinib in healthy individuals decreased the peak plasma concentration and AUC of neratinib by 71 and 65%, respectively.1 Administration of the histamine H2-receptor antagonist ranitidine 2 hours prior to neratinib decreased the peak plasma concentration and AUC of neratinib by 57 and 48%, respectively; administration of ranitidine 2 hours after neratinib reduced the peak plasma concentration and AUC of neratinib by 44 and 32%, respectively.1
Avoid concomitant use of neratinib with proton-pump inhibitors.1 Administer neratinib at least 2 hours before or 10 hours after histamine H2-receptor antagonists.1 Separate administration of neratinib by at least 3 hours after administration of antacids.1
Neratinib, a potent, selective, and irreversible inhibitor of human epidermal growth factor receptor type 2 (HER2), HER4, and epidermal growth factor receptor (EGFR) tyrosine kinases, is an antineoplastic agent.1, 8 In vitro, neratinib and its active metabolites (M3, M6, M7, M11) exhibit inhibitory activity against EGFR, HER2, and HER4.1, 7 In vitro, the drug has been shown to reduce phosphorylation of EGFR and HER2 resulting in inhibition of downstream signaling of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) pathways.1, 8, 9 Neratinib has demonstrated antitumor activity in mice bearing tumor xenografts that expressed EGFR and HER2.1, 11
Neratinib exhibits nonlinear pharmacokinetics.1 Peak plasma concentrations and areas under the serum concentration-time curve (AUCs) of neratinib are less than dose proportional over the dosage range of 40-400 mg once daily.1 Peak plasma concentrations of neratinib and its major active metabolites (M3, M6, and M7) are achieved about 2-8 hours following oral administration of the drug.1 Following repeated doses of neratinib 240 mg once daily, the mean accumulation ratio for the drug was 1.14.10 Oral administration of neratinib with a high-fat meal increased peak plasma concentrations and AUC by 70 and 120%, respectively, compared with administration in the fasting state.1 Oral administration of neratinib with a standard breakfast increased peak plasma concentrations and AUC by 20 and 10%, respectively, compared with administration in the fasting state.1 In vitro, neratinib is highly bound (greater than 99%) to plasma proteins (mainly to albumin and α1-acid glycoprotein), independent of concentration.1 Neratinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by flavin-containing monooxygenase (FMO).1 Major metabolites of the drug include active pyridine N -oxide (M3), N -desmethyl (M6), dimethylamine N -oxide (M7), and bis- N -oxide (M11) derivatives which account for 15, 33, 22, and 4%, respectively, of total plasma concentrations of the drug.1, 7 Following repeated administration of neratinib, the mean elimination half-lives of neratinib, M3, M6, and M7 are 14.6, 21.6, 13.8, and 10.4 hours, respectively.1 Following oral administration of a single radiolabeled dose of neratinib, approximately 97% of the recovered dose is excreted in feces and 1.1% is eliminated in urine.1
Age, sex, and race do not have clinically important effects on the pharmacokinetics of neratinib.1, 12
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Neratinib is available only from designated specialty distributors and pharmacies.3 Consult the manufacturer for additional information.3
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 40 mg (of neratinib) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 28, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Puma Biotechnology Inc. Nerlynx® (neratinib) tablets prescribing information. Los Angeles, CA; 2022 Mar. [Web]
2. 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; 17:367-77. [PubMed 26874901]
3. Puma Biotechnology Inc. Access and support: How to get Nerlynx®. From the Nerlynx website. 2022. Accessed 2022 Jun 14. [Web]
4. Abbas R, Hug BA, Leister C et al. A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol . 2012; 70:191-9. [PubMed 22418773]
5. 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; 71:522-7. [PubMed 21395644]
7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208051Orig1s000: Multi-discipline review. From FDA website. [Web]
8. Echavarria I, López-Tarruella S, Márquez-Rodas I et al. Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther . 2017; 17:669-679. [PubMed 28649882]
9. Chan A. Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness. Ther Adv Med Oncol . 2016; 8:339-50. [PubMed 27583026]
10. Kourie HR, Chaix M, Gombos A et al. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol . 2016; 12:947-57. [PubMed 27284682]
11. 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; 64:3958-65. [PubMed 15173008]
12. Saura C, Oliveira M, Feng YH, et al; NALA investigators. 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 . 2020;38(27):3138-3149. [PubMedCentral] [PubMed 32678716]
13. 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. [PubMed 33183970]
10060. Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(6):685-693. [PubMed 33079579]
11000. Giordano SH, Franzoi MAB, Temin S, et al. Systemic therapy for advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO guideline update. J Clin Oncol. Published online May 31, 2022. [PubMed 35640077]