May 25, 2016
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Mechanism Of Action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of ≥ 300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non–crossresistance between these two agents.

Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.



Absorption following oral administration of TYKERB is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of TYKERB results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours.

At the dose of 1,250 mg daily, steady-state geometric mean (95% confidence interval) values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL).

Divided daily doses of TYKERB resulted in approximately 2-fold higher exposure at steady state (steady-state AUC) compared to the same total dose administered once daily.

Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.


Lapatinib is highly bound ( > 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.


Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.


At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.

Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible ( < 2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.

Effects of Age, Gender, or Race

Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed.

QT Prolongation

The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-label, dose-escalation study in advanced cancer patients. Eighty-one patients received daily doses of lapatinib ranging from 175 mg/day to 1,800 mg/day. Serial ECGs were collected on Day 1 and Day 14 to evaluate the effect of lapatinib on QT intervals. Analysis of the data suggested a consistent concentration-dependent increase in QTc interval.


The HLA alleles DQA1*02:01 and DRB1*07:01 were associated with hepatotoxicity reactions in a genetic substudy of a monotherapy trial with TYKERB (n = 1,194). Severe liver injury (ALT > 5 times the upper limit of normal, NCI CTCAE Grade 3) occurred in 2% of patients overall; the incidence of severe liver injury among DQA1*02:01 or DRBI*07:01 allele carriers was 8% versus 0.5% in non-carriers. These HLA alleles are present in approximately 15% to 25% of Caucasian, Asian, African, and Hispanic populations and 1% in Japanese populations. Liver function should be monitored in all patients receiving therapy with TYKERB regardless of genotype.

Clinical Studies

HER2-Positive Metastatic Breast Cancer

The efficacy and safety of TYKERB in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) overexpressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab.

Patients were randomized to receive either TYKERB 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m²/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m²/day on Days 1-14 every 21 days. The endpoint was time to progression (TTP). TTP was defined as time from randomization to tumor progression or death related to breast cancer. Based on the results of a pre-specified interim analysis, further enrollment was discontinued. Three hundred and ninety-nine (399) patients were enrolled in this study. The median age was 53 years and 14% were older than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven percent (97%) had stage IV breast cancer, 48% were estrogen receptor+ (ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation. Approximately 95% of patients had prior treatment with anthracyclines, taxanes, and trastuzumab.

Efficacy analyses 4 months after the interim analysis are presented in Table 5, Figure 1, and Figure 2.

Table 5. Efficacy Results

  Independent Assessmenta Investigator Assessment
TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m²/day
(N = 198)
Capecitabine 2,500 mg/m²/day
(N = 201)
TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m²/day
(N = 198)
Capecitabine 2,500 mg/m²/day
(N = 201)
Number of TTP events 82 102 121 126
Median TTP, weeks (25th, 75th, Percentile), weeks 27.1
(17.4, 49.4)
(9.1, 36.9)
(12.0, 44.0)
(6.9, 35.7)
Hazard Ratio (HR) (95% CI) 0.57 (0.43, 0.77) 0.72 (0.56, 0.92)
P value 0.00013 0.00762
Response Rate (%) (95% CI) 23.7
(18.0, 30.3)
(9.5, 19.5)
(25.4, 38.8)
(12.4, 23.4)
TTP = Time to progression.
aThe time from last tumor assessment to the data cut-off date was > 100 days in approximately 30% of patients in the independent assessment. The pre-specified assessment interval was 42 or 84 days.

Figure 1: Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression

Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression - Illustration

Figure 2: Kaplan-Meier Estimates for Investigator Assessment Time to Progression

Kaplan-Meier Estimates for Investigator Assessment Time to Progression - Illustration

At the time of above efficacy analysis, the overall survival data were not mature (32% events). However, based on the TTP results, the study was unblinded and patients receiving capecitabine alone were allowed to cross over to treatment with TYKERB plus capecitabine. The survival data were followed for an additional 2 years to be mature and the analysis is summarized in Table 6.

Table 6: Overall Survival Data

  TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m²/day
(N = 207)
Capecitabine 2,500 mg/m²/day
(N = 201)
Overall Survival
  Died 76% 82%
  Median Overall Survival (weeks) 75.0 65.9
  Hazard ratio, 95% CI 0.89 (0.71, 1.10)
  (P value) 0.276
CI = confidence interval.

Clinical Studies Describing Limitation of Use

In two randomized trials, TYKERB-based chemotherapy regimens have been shown to be less effective than trastuzumab-based chemotherapy regimens. The first randomized, open-label study compared the safety and efficacy of TYKERB in combination with capecitabine relative to trastuzumab in combination with capecitabine in women with HER2-positive metastatic breast cancer (N = 540). The study was stopped early based on the findings of a pre-planned interim analysis showing a low incidence of CNS events (primary endpoint) and superior efficacy of the trastuzumab plus capecitabine. The median progression-free survival was 6.6 months in the group receiving TYKERB in combination with capecitabine compared with 8.0 months in the group receiving the trastuzumab combination [HR = 1.30 (95% CI: 1.04, 1.64)]. Overall survival was analyzed when 26% of deaths occurred in the group receiving TYKERB in combination with capecitabine and 22% in the group receiving the trastuzumab combination [HR = 1.34 (95% CI: 0.95, 1.92)].

The second randomized, open-label study compared the safety and efficacy of taxanebased chemotherapy plus TYKERB to taxane-based chemotherapy plus trastuzumab as first-line therapy in women with HER2-positive, metastatic breast cancer (N = 652). The study was stopped early based on findings from a pre-planned interim analysis. The median progression-free survival was 11.3 months in the trastuzumab combination treatment arm compared to 9.0 months in patients treated with TYKERB in the combination arm for the intent-to-treat population [HR = 1.37 (95% CI: 1.13, 1.65)].

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

The efficacy and safety of TYKERB in combination with letrozole were evaluated in a double-blind, placebo-controlled, multi-center study. A total of 1,286 postmenopausal women with hormone receptor-positive (ER positive and/or PgR positive) metastatic breast cancer, who had not received prior therapy for metastatic disease, were randomly assigned to receive either TYKERB (1,500 mg once daily) plus letrozole (2.5 mg once daily) (n = 642) or letrozole (2.5 mg once daily) alone (n = 644). Of all patients randomized to treatment, 219 (17%) patients had tumors overexpressing the HER2 receptor, defined as fluorescence in situ hybridization (FISH) ≥ 2 or 3+ immunohistochemistry (IHC). There were 952 (74%) patients who were HER2negative and 115 (9%) patients did not have their HER2 receptor status confirmed. The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2-positive population. Progression-free survival was defined as the interval of time between date of randomization and the earlier date of first documented sign of disease progression or death due to any cause.

The baseline demographic and disease characteristics were balanced between the two treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty-four percent (84%) of the patients were white. Approximately 50% of the HER2-positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients had prior trastuzumab.

In the HER2-positive subgroup (n = 219), the addition of TYKERB to letrozole resulted in an improvement in PFS. In the HER2-negative subgroup, there was no improvement in PFS of the combination of TYKERB plus letrozole compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the combination of TYKERB plus letrozole. The overall survival (OS) data were not mature. Efficacy analyses for the hormone receptor-positive, HER2-positive and HER2-negative subgroups are presented in Table 7 and Figure 3.

Table 7: Efficacy Results

  HER2-Positive Population HER2-Negative Population
TYKERB 1500 mg/day + Letrozole 2.5 mg/day
(N = 111)
Letrozole 2.5 mg/day
(N = 108)
TYKERB 1500 mg/day + Letrozole 2.5 mg/day
(N = 478)
Letrozole 2.5 mg/day
(N = 474)
Median PFSa, weeks (95% CI) 35.4
(24.1, 39.4)
(12.0, 23.7)
(48.6, 69.7)
(47.9, 62.0)
Hazard Ratio (95% CI) 0.71 (0.53, 0.96) 0.90 (0.77, 1.05)
P value 0.01 9 0.188
Response Rate (%) (95% CI) 27.9
(19.8, 37.2)
(8.7, 22.9)
(28.4, 37.0)
(27.5, 36.0)
PFS = progression-free survival; CI = confidence interval.
aKaplan-Meier estimate.

Figure 3: Kaplan-Meier Estimates for Progression-Free Survival for the HER2-Positive Population

Kaplan-Meier Estimates for Progression-Free Survival for the HER2-Positive Population - Illustration

Last reviewed on RxList: 4/21/2015
This monograph has been modified to include the generic and brand name in many instances.

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