Lapatinib, an inhibitor of human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases, is an antineoplastic agent.1
Advanced or Metastatic Breast Cancer
Lapatinib ditosylate is used in combination with letrozole (an aromatase inhibitor) for the treatment of hormone receptor-positive metastatic breast cancer that overexpresses the HER2 protein in postmenopausal women who are candidates for hormonal therapy.1, 5, 8, 11, 11000 Lapatinib also is used in combination with capecitabine for the treatment of advanced or metastatic breast cancer that overexpresses the HER2 protein in patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1, 2, 11000 Lapatinib plus capecitabine should only be initiated in patients with a history of disease progression on trastuzumab.1, 9, 10
Combination Therapy with Lapatinib and Letrozole
Lapatinib is used in combination with letrozole for the treatment of hormone receptor-positive metastatic breast cancer that overexpresses the HER2 protein in postmenopausal women who are candidates for hormonal therapy.1, 5, 8, 11 Safety and efficacy of lapatinib for this indication are supported by 2 randomized phase 3 trials.1, 5, 8, 11 In patients with hormone receptor-positive, HER2-positive breast cancer, guidelines generally recommend HER2-targeted therapy plus chemotherapy, endocrine therapy plus trastuzumab or lapatinib (in selected cases), or endocrine therapy alone (in selected cases).11000
Safety and efficacy of lapatinib in combination with letrozole for this indication have been evaluated in a phase 3, randomized, double-blind, controlled clinical study in postmenopausal women with hormone receptor-positive (estrogen- and/or progesterone-positive) metastatic breast cancer; 17% of patients enrolled in this study had HER2-positive tumors.1, 5, 8 Patients were randomized to receive lapatinib (1.5 g once daily) and letrozole (2.5 mg once daily) or letrozole (2.5 mg once daily) and placebo.1, 5, 8 Patients who had received prior therapy for advanced or metastatic disease were excluded from the study.1, 5, 8 However, prior adjuvant or neoadjuvant chemotherapy, radiation therapy, or antiestrogen therapy was allowed; adjuvant use of aromatase inhibitors and trastuzumab was allowed if such treatment was completed at least one year prior to study entry.5, 8 Approximately one-half of the 219 patients with HER2-positive tumors had previously received antiestrogens and/or chemotherapy, approximately one-third had received adjuvant antiestrogen therapy within 6 months of study entry, and less than 1% had received prior trastuzumab therapy.1, 8
In the subgroup of patients with HER2-positive tumors, those receiving combined therapy with lapatinib and letrozole had longer median progression-free survival (35.4 versus 13 weeks) and a higher objective response rate (28 versus 15%) compared with those receiving letrozole alone.1, 5, 8 However, in the subgroup of patients with HER2-negative tumors, combined therapy with lapatinib and letrozole did not improve progression-free survival or response rate over that observed with letrozole alone.1, 5
The efficacy and safety of combination therapy with lapatinib and an aromatase inhibitor were confirmed in another randomized, phase 3 trial (ALTERNATIVE) in postmenopausal women with hormone receptor-positive/HER2-positive metastatic breast cancer that had progressed after prior treatment with trastuzumab-containing chemotherapy and endocrine therapies in the metastatic setting.1, 11 Patients were randomized to one of the following regimens: lapatinib (1 g once daily) plus trastuzumab and an aromatase inhibitor, trastuzumab plus an aromatase inhibitor, or lapatinib 1.5 g once daily plus an aromatase inhibitor.1, 11 In all trastuzumab-containing arms, trastuzumab was administered with a loading dose of 8 mg/kg IV followed by a maintenance dosage of 6 mg/kg IV every 3 weeks; patients receiving an aromatase inhibitor were administered letrozole 2.5 mg once daily, exemestane 25 mg once daily, or anastrozole 1 mg once daily based on the investigator's choice.1, 11
The primary efficacy endpoint was progression-free survival comparing lapatinib plus trastuzumab and an aromatase inhibitor to trastuzumab plus an aromatase inhibitor.1, 11 The median duration of treatment was 53.6 weeks across all arms.11 At the time of data cutoff, patients receiving lapatinib plus trastuzumab and an aromatase inhibitor had longer median progression-free survival (11 versus 5.6 months) and a higher overall response rate (22.5 versus 8.5%) compared with those receiving trastuzumab plus an aromatase inhibitor.1 Median overall survival had not been reached at the time of the efficacy analysis.1, 11
Combination Therapy with Lapatinib and Capecitabine
Lapatinib is used in combination with capecitabine for the treatment of advanced or metastatic breast cancer that overexpresses the HER2 protein in patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1, 2, 13, 11000 Safety and efficacy of lapatinib for this indication are supported by a single randomized controlled trial.2 Guidelines generally recommend lapatinib among several potential third-line treatment options in patients with advanced, HER2-positive breast cancer who have trialed 2 previous anti-HER2 regimens.11000
Safety and efficacy of lapatinib (in combination with capecitabine) in the treatment of HER2-positive advanced or metastatic breast cancer have been evaluated in a phase 3, open-label, randomized, controlled clinical study.1, 2 The study enrolled patients with locally advanced or metastatic breast cancer that had progressed following treatment with regimens that included an anthracycline, a taxane, and trastuzumab.1, 2 Patients were randomized to receive lapatinib (1.25 g once daily, continuously) in conjunction with capecitabine (2 g/m2 daily on days 1-14 every 21 days) or capecitabine monotherapy (2.5 g/m2 daily on days 1-14 every 21 days).1, 2
Enrollment in this study was terminated early1 when a planned interim analysis indicated that patients receiving lapatinib in combination with capecitabine had a longer median time to progression (8.4 versus 4.4 months) and longer median progression-free survival (8.4 versus 4.4 months) than did those receiving capecitabine alone.2 At the time of the interim analysis, overall survival and overall response rates did not differ substantially between the 2 treatment groups.2 Overall response rates were 22% for patients receiving lapatinib in combination with capecitabine and 14% for those receiving capecitabine monotherapy.2 Two efficacy analyses performed 4 months later (one an independent assessment and the other an investigator assessment that incorporated updated tumor assessment data) indicated that response rates were higher in patients receiving lapatinib in combination with capecitabine than in those receiving capecitabine alone (23.7 versus 13.9%, respectively [independent analysis]); 31.8 versus 17.4%, respectively [investigator analysis]).1 These analyses, like the interim analysis, indicated that median time to progression was longer in patients receiving lapatinib in combination with capecitabine than in those receiving capecitabine alone (27.1 versus 18.6 weeks, respectively [independent analysis]; 23.9 versus 18.3 weeks, respectively [investigator analysis]).1 Based on these results, the study was unblinded and combination therapy with lapatinib and capecitabine was offered to all patients who had been receiving capecitabine alone.1 Early termination of the study and patient crossover resulted in insufficient power to detect a survival benefit with the combination regimen; at 2 years after the independent and investigator analyses, median overall survival was 75 weeks for patients receiving lapatinib in combination with capecitabine compared with 65.9 weeks for those receiving capecitabine alone.1, 7
A randomized, open-label, active-controlled multicenter study (NALA) compared oral neratinib plus capecitabine to oral lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer who had previously received 2 or more anti-HER2-based regimens.13 In this trial, neratinib was associated with longer progression-free survival than lapatinib (median 5.6 versus 5.5 months, respectively).13 At the time of follow-up, median overall survival was similar with neratinib plus capecitabine and lapatinib plus capecitabine (21 or 18.7 months, respectively).13
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 lapatinib in combination with trastuzumab and lapatinib 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 In patients with hormone receptor-positive, HER2-positive breast cancer, the guidelines recommend HER2-targeted therapy plus chemotherapy, endocrine therapy plus trastuzumab or lapatinib (in selected cases), or endocrine therapy alone (in selected cases).11000
Lapatinib is administered orally once daily.1 Administer the drug at least 1 hour before or 1 hour after meals.1 Do not divide the daily dosage because such administration may increase systemic exposure to the drug (by approximately twofold).1 Advise patients not to double the next dose if a dose is missed.1 Store lapatinib tablets at 20-25°C (excursions permitted between 15-30°C).1
Dosage of lapatinib ditosylate monohydrate is expressed in terms of lapatinib.1
Advanced or Metastatic Breast Cancer
For use in combination with letrozole for the treatment of hormone receptor-positive, HER2-positive metastatic breast cancer in postmenopausal women, the recommended dosage of lapatinib is 1.5 g orally once daily, given continuously in combination with letrozole 2.5 mg once daily.1 In a clinical trial evaluating this regimen, treatment was continued until disease progression occurred or the patient withdrew from the study.5, 8
For use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab, the recommended adult dosage of lapatinib is 1.25 g orally once daily on days 1-21 in combination with capecitabine 2 g/m2 daily (administered orally in 2 divided doses approximately 12 hours apart) on days 1-14 of each 21-day cycle.1 Continue treatment until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during lapatinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of lapatinib should be reduced as described in Table 1.1
Adverse Reaction | Recommended Dosage Reduction of Lapatinib when Used in Combination with Letrozole for Hormone Receptor-positive, HER2-positive Metastatic Breast Cancer | Recommended Dosage Reduction of Lapatinib when Used in Combination with Capecitabine for HER2-positive, Advanced or Metastatic Breast Cancer |
|---|---|---|
Cardiac events | 1.25 g once daily | 1 g once daily |
Diarrhea | 1.25 g once daily in patients previously receiving 1.5 g once daily 1 g once daily in patients previously receiving 1.25 g once daily | 1.25 g once daily in patients previously receiving 1.5 g once daily 1 g once daily in patients previously receiving 1.25 g once daily |
Other toxicity | 1.25 g once daily | 1 g once daily |
Table 2 indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.1
Adverse Reaction and Severitya | Modification |
|---|---|
Cardiac Events |
|
Grade ≥2 decreased LVEF or LVEF that decreases below institution's lower limit of normal (LLN) | Discontinue lapatinib; may restart at a reduced dosage (see Table 1) after ≥2 weeks if LVEF returns to normal and the patient is asymptomatic |
Diarrhea |
|
Grade 3 or Grade 1-2 with complicating featuresb | Withhold therapy; may restart at a reduced dosage (see Table 1) once diarrhea resolves to ≤grade 1 |
Grade 4 | Permanently discontinue lapatinib |
Interstitial Lung Disease/Pneumonitis |
|
Grade ≥3 | Discontinue lapatinib |
Other Toxicity |
|
Grade ≥2 | Consider interruption or discontinuance of lapatinib May restart at the standard dosage of 1.25 or 1.5 g once daily once the toxicity improves to grade ≤1; If the toxicity recurs, restart lapatinib at a reduced dosage (see Table 1) |
aSeverity is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
bComplicating features include moderate to severe abdominal cramping, nausea or vomiting of grade ≥2, decreased performance status, sepsis, fever, neutropenia, frank bleeding, or dehydration
Dosage Modification with Concomitant Therapy
Avoid concomitant use of lapatinib with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4.1 If concomitant therapy cannot be avoided, consider reduction of the lapatinib dosage to 500 mg daily.1 This recommendation is based on pharmacokinetic considerations; no clinical data on this dosage adjustment are available.1 If the potent CYP3A4 inhibitor is discontinued, a period of approximately 1 week should elapse before lapatinib dosage is increased to the usual recommended dosage.1
Avoid concomitant use of lapatinib with potent CYP3A4 inducers .1 If concomitant therapy cannot be avoided, consider an increase in lapatinib dosage.1 Lapatinib dosage should be increased gradually as tolerated from a dosage of 1.5 g daily up to 5.5 g daily when given in combination with letrozole for the treatment of hormone receptor-positive, HER2-positive metastatic breast cancer and from a dosage of 1.25 g daily up to 4.5 g daily when given in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer.1 These recommendations are based on pharmacokinetic considerations; no clinical data on these dosage adjustments in these patient populations are available.1 If the potent CYP3A4 inducer is discontinued, reduce the lapatinib dosage to the usual recommended dosage.1
In patients with severe preexisting hepatic impairment (Child-Pugh class C), consider a reduced dosage of lapatinib based on pharmacokinetic considerations.1 Consider a reduced dosage of 1 g once daily when lapatinib is given in combination with letrozole for the treatment of hormone receptor-positive, HER2-positive metastatic breast cancer; consider a reduced dosage of 750 mg once daily when lapatinib is given in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer.1 These dosage reductions in patients with severe hepatic impairment have been predicted to adjust AUC to the normal range.1 However, no clinical data on these dosage adjustments in these patient populations are available.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1 However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib since less than 2% of the dose is eliminated renally.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A boxed warning about the risk of hepatotoxicity is included in the prescribing information for lapatinib.1 Hepatotoxicity may be severe and deaths have been reported in patients receiving lapatinib.1, 13 The cause of the deaths is uncertain.1, 13
Hepatotoxicity indicated by abnormal liver function test results, including serum concentrations of ALT or AST >3 times the upper limit of normal and serum concentrations of total bilirubin >2 times the upper limit of normal, have been observed in <1% of patients receiving lapatinib in clinical trials and in postmarketing experience.1, 13 Hepatotoxicity may occur within days to several months following initiation of lapatinib therapy.1, 13
Monitor liver function tests (serum concentrations of transaminases, bilirubin, and alkaline phosphatase) before initiation of lapatinib therapy, every 4-6 weeks during therapy, and as clinically indicated.1, 13 If severe changes in liver function occur, discontinue lapatinib therapy permanently.1, 13
Pharmacogenomics of Lapatinib-induced Hepatotoxicity
In a genetic substudy of a trial evaluating lapatinib monotherapy, the human leukocyte antigen (HLA) alleles DQA1*02:01 and DRB1*07:01 were associated with hepatotoxicity reactions.1, 12 Severe liver injury (ALT >5 times the upper limit of normal, National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] grade 3) occurred in 2% of patients overall; the incidence of severe liver injury was 8 versus 0.5% among carriers of the DQA1*02:01 or DRB1*07:01 alleles versus non-carriers, respectively.1, 12 The DQA1*02:01 and DRB1*07:01 alleles are present in approximately 15-25% of Caucasian, Asian, African, and Hispanic populations and in 1% of Japanese populations.1 Monitor liver function in all patients receiving lapatinib regardless of genotype.1
Decreased Left Ventricular Ejection Fraction
Lapatinib has been reported to cause decreased LVEF.1 Clinical studies indicate that the majority (more than 57%) of decreases in LVEF associated with the drug occur within the first 12 weeks of lapatinib treatment.1 Data on long-term exposure are limited.1 Caution should be exercised if lapatinib is administered to patients with conditions that could impair LVEF.1 Evaluate LVEF in patients prior to the initiation of lapatinib and periodically during treatment.1
Discontinue lapatinib in patients with decreased LVEF of NCI-CTCAE grade 2 or greater and in patients with an LVEF that drops below the institution's lower limit of normal.1
Diarrhea, including severe diarrhea and deaths, have been reported in patients receiving lapatinib.1 Diarrhea typically occurs early in the course of treatment, with approximately half of patients in clinical trials experiencing diarrhea within the first 6 days of lapatinib therapy.1 Diarrhea associated with lapatinib therapy typically lasts 4-5 days and is low-grade; severe diarrhea of grade 3 or 4 occurred in less than 10 or 1% of patients, respectively, in clinical trials.1
Early identification and intervention is crucial for optimal management of diarrhea.1 Instruct patients to report any change in bowel habits immediately and treat diarrhea promptly with antidiarrheal agents (e.g., loperamide) after the first unformed stool.1 Management of severe diarrhea may include oral or IV electrolytes and fluids, administration of antibiotics (especially for diarrhea that persists beyond 24 hours or when there is a fever or grade 3-4 neutropenia), and interruption or discontinuance of lapatinib therapy.1
Interstitial Lung Disease/Pneumonitis
Lapatinib therapy (alone or in combination with other antineoplastics) has been associated with interstitial lung disease and pneumonitis.1 Monitor patients for pulmonary symptoms, and discontinue the drug if symptoms suggestive of grade 3 or higher interstitial lung disease or pneumonitis develop.1
QT interval prolongation has been reported in patients receiving lapatinib.1 Monitor patients taking lapatinib who have or may develop prolongation of the corrected QT (QTc) interval (e.g., patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome; those receiving concomitant drugs that may prolong the QTc interval, or are associated with torsades de pointes; those with cumulative high-dose anthracycline therapy).1 Prior to administration of lapatinib, correct hypokalemia or hypomagnesemia.1
Severe cutaneous reactions have been reported in patients receiving lapatinib.1 Discontinue treatment if life-threatening cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis) are suspected.1
Fetal/Neonatal Morbidity and Mortality
Lapatinib can cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings; fetal anomalies, abortion, and death of offspring within days after birth have been demonstrated in animals.1 A significant decrease in the number of live fetuses or fetal body weights was seen in female rats given oral doses of lapatinib at exposure levels approximately 6.4 or 3.3 times the human exposure at the recommended dosage, respectively.1
Pregnancy should be avoided during therapy.1 (See Females and Males of Reproductive Potential under Cautions.)Perform a pregnancy test prior to initiation of lapatinib in females of reproductive potential.1 Inform pregnant women and females of reproductive potential of the potential hazard to the fetus.1
Lapatinib can 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.) Inform pregnant women and females of reproductive potential of the potential hazard to the fetus.1 (See Females and Males of Reproductive Potential under Cautions.)
It is not known whether lapatinib is distributed into human milk.1 Because of the potential for serious adverse reactions to lapatinib in nursing infants, advise women to discontinue nursing while receiving lapatinib and for at least 1 week after the drug is discontinued.1 The effects of the drug on nursing infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
The effect of lapatinib on human fertility is not known.1 In animal studies, no effects on male or female fertility were found in rats receiving lapatinib at exposure levels approximately 2.6-6.4 times the human exposure at the recommended dosage.1 However, a significant decrease in the number of live fetuses or fetal body weights was seen in female rats given oral doses of lapatinib at exposure levels approximately 6.4 or 3.3 times the human exposure at the recommended dosage, respectively.1
Lapatinib may cause fetal harm.1 Advise females of childbearing potential to use effective contraceptive methods while receiving lapatinib and for at least 1 week after discontinuance of the drug.1 In addition, advise males with such female partners to use effective methods of contraception while receiving lapatinib and for 1 week after discontinuance of the drug.1
Safety and efficacy have not been established in children.1
No substantial differences in safety or efficacy have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out.1
Use lapatinib with caution in patients with severe preexisting hepatic impairment (Child-Pugh class C); systemic exposure to the drug may be increased.1 Consider dosage reduction in such patients.1 Permanently discontinue lapatinib in patients who develop severe hepatotoxicity while on therapy.1
Safety and efficacy have not been established in patients with renal impairment or in patients undergoing hemodialysis.1 However, renal impairment is unlikely to affect lapatinib pharmacokinetics since less than 2% of the drug and its metabolites are eliminated by the kidneys.1
Adverse effects reported in ≥20% of patients receiving lapatinib in combination with capecitabine include diarrhea, palmar-plantar erythrodysesthesia, nausea, vomiting, rash, and fatigue.1
Adverse effects reported in ≥20% of patients receiving lapatinib in combination with letrozole include diarrhea, rash, nausea, and fatigue.1
Lapatinib is metabolized by cytochrome P-450 (CYP) isoenzymes, principally by CYP3A4 and 3A5.1, 13 Lapatinib inhibits CYP3A4 and CYP2C8, but does not substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, and 2D6 or uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes in vitro.1
Lapatinib is a substrate and inhibitor of efflux transporter P-glycoprotein (P-gp).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Potent inhibitors of cytochrome CYP3A4: Avoid concomitant use of lapatinib with potent inhibitors of CYP3A4 (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).1 In drug interaction studies with ketoconazole (200 mg twice daily for 7 days), systemic lapatinib exposure increased approximately 3.6-fold, and lapatinib half-life increased 1.7-fold.1 If concomitant use of lapatinib with a potent CYP3A4 inhibitor cannot be avoided, consider reducing the dosage of lapatinib.1
Potent inducers of CYP3A4: Avoid concomitant use of lapatinib with potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]).1 In drug interaction studies, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days) decreased systemic lapatinib exposure approximately 72%.1 If concomitant use of lapatinib with a potent CYP3A4 inducer cannot be avoided, adjust the dosage of lapatinib.1
Substrates of CYP isoenzymes: Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo, but does not appear to substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, and 2D6, or UGT enzymes in vitro.1 Concomitant administration of lapatinib with oral or IV midazolam (a CYP3A4 substrate) increased midazolam exposure (as measured by AUC over 24 hours) by 45 or 22%, respectively.1 Exercise caution and consider a dosage reduction of the substrate drug when lapatinib is administered concomitantly with a CYP2C8 or CYP3A4 substrate with a narrow therapeutic index.1
Drugs that are Substrates or Inhibitors of P-glycoprotein Transport System
Lapatinib is both a substrate and an inhibitor of the efflux transporter P-gp, ABCB1.1 Exercise caution if lapatinib is administered with drugs that are substrates or inhibitors of P-gp; increased plasma concentrations of the substrate drug or lapatinib are likely.1 When lapatinib is used concomitantly with a P-gp substrate with a narrow therapeutic index, consider reducing the dosage of the P-gp substrate drug.1
Drugs that Prolong the QT Interval
Because lapatinib may cause prolongation of the QT interval, use lapatinib with caution in patients receiving concomitant therapy with other drugs (e.g., antiarrhythmic agents) known to prolong the QT interval.1
Drugs Affecting Gastric Acidity
Concomitant use of lapatinib with drugs affecting gastric acidity may decrease the solubility of lapatinib.1 However, concomitant administration of lapatinib and esomeprazole, a proton pump inhibitor, did not result in a clinically meaningful reduction in lapatinib exposure.1
Concomitant administration of lapatinib and oral digoxin (a P-gp substrate) increased systemic exposure (AUC) of digoxin by approximately 2.8-fold.1 In patients receiving digoxin, measure serum digoxin concentrations prior to initiation of lapatinib therapy and monitor concentrations throughout concomitant therapy.1 If serum digoxin concentrations exceed 1.2 ng/mL, reduce the digoxin dosage by 50%.1
In patients receiving lapatinib and paclitaxel (a CYP2C8 and P-gp substrate) concomitantly, systemic exposure (AUC over 24 hours) of paclitaxel was increased by 23%.1 However, the manufacturer states that because of limitations of the study design, these data may underestimate the potential increase in paclitaxel exposure during concomitant use.1
Avoid grapefruit products because of the potential for increased plasma lapatinib concentrations.1
Lapatinib, a tyrosine kinase inhibitor, is an antineoplastic agent.1, 2 The drug inhibits the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2).1 Lapatinib has been shown to inhibit ERBB-driven tumor cell growth in vitro and in various animal models.1 The drug also has exhibited additive antineoplastic activity with fluorouracil (the active metabolite of capecitabine) in vitro.1 Lapatinib has been shown in vitro to retain significant antineoplastic activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium, suggesting a lack of cross-resistance between lapatinib and trastuzumab.1
Hormone receptor-positive breast cancer cells that overexpress EGFR and HER2 tend to be resistant to endocrine (antiestrogen) therapies.1, 5, 6, 8 Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 may upregulate these receptor pathways as the tumor becomes resistant to endocrine therapy.1, 5, 8 In vitro data indicate that complex interactions between pathways involving the estrogen receptor and epidermal growth factor receptors (e.g., EGFR, HER2) may result in enhanced signal transduction and eventually lead to sustained tumor growth.5, 6, 8 Therefore, combined use of endocrine therapy (e.g., letrozole) and therapy targeting EGFR/HER2 (e.g., lapatinib) in women with hormone receptor-positive, HER2-positive breast cancer may delay or prevent the emergence of acquired endocrine resistance resulting from increased EGFR and HER2 signaling.5, 6, 8
Steady-state concentrations of lapatinib are reached in approximately 6-7 days, indicating an effective half-life of 24 hours.1 Systemic exposure of lapatinib is increased threefold or fourfold when the drug is administered with a low-fat or high-fat meal, respectively, and is increased approximately twofold when the total daily dose is administered in divided doses instead of once daily.1 Lapatinib is highly bound (greater than 99%) to plasma proteins (mainly to albumin and α1-acid glycoprotein).1 Lapatinib is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 3A5 and, to a lesser extent, by CYP2C19 and 2C8 to several oxidated metabolites.1 Following oral administration of lapatinib, a median of 27% (ran 3-67%) of the oral dose is excreted unchanged in feces; less than 2% of the drug is eliminated via renal excretion.1
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg (of lapatinib) | Novartis |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 14, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Novartis. Tykerb® (lapatinib) prescribing information. East Hanover, NJ;2022 Mar. [Web]
2. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med . 2006; 355:2733-43. [PubMed 17192538]
5. Johnston S, Pippen J, Pivot X et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol . 2009; 27:5538-46. [PubMed 19786658]
6. Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer . 2006; 13 Suppl 1:S15-24. [PubMed 17259554]
7. Cameron D, Casey M, Oliva C et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist . 2010; 15:924-34. [PubMedCentral][PubMed 20736298]
8. Schwartzberg LS, Schwarzberg LS, Franco SX et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist . 2010; 15:122-9. [PubMedCentral][PubMed 20156908]
9. Gelmon KA, Boyle FM, Kaufman B, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31. J Clin Oncol. 2015;33(14):1574-1583.
10. Pivot X, Manikhas A, Zurawski B, et al. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33(14):1564-1573.
11. Johnston SRD, Hegg R, Im SA, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: updated results of ALTERNATIVE. J Clin Oncol. 2021;39(1):79-89.
12. Schaid DJ, Spraggs CF, McDonnell SK, et al. Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. J Clin Oncol. 2014;32(22):2296-2303.
13. 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.
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.