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.

Pharmacokinetics

Absorption

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 hour). 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.hr/mL (23.4 to 56 mcg.hr/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.

Distribution

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.

Metabolism

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.

Elimination

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.

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

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

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

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 TYKERB plus capecitabine treatment. 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

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 HER2 negative 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 TYKERB plus letrozole combination compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the TYKERB plus letrozole combination therapy. 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

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

Last reviewed on RxList: 2/24/2012
This monograph has been modified to include the generic and brand name in many instances.