lapatinib

Clinical Therapeutics/Volume 30, Number 8, 2008

New Drug

Lapatinib: A Dual Inhibitor of Human Epidermal Growth Factor Receptor Tyrosine Kinases

PatrickJ. Medina, PharmD, BCOp1; and Susan Goodin, PharmD, FCCP, BCOP 2,3

1College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; 2Divi- sion of Pharmaceutical Sciences, The Cancer Institute of New Jersey, New Brunswick, New Jersey; and 3Divi- sion of Medical Oncology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey

ABSTRACT Background: Lapatinib, the first dual inhibitor of

epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Ad- ministration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab.

Objective: This review summarizes the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies.

Methods: Relevant English-language publications were identified through searches of MEDLINE (1966- May 2008), the American Society of Clinical Oncology abstracts database (2000-2007), abstracts from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (January 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clinical trials.

Results: The Tma:~ of lapatinib after oral administration is 3 to 4 hours. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P450 3A4 isozyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the tu2 of lapatinib is 24 hours with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-positive, locally advanced breast cancer or MBC that had progressed

after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was associated with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, respectively; P = NS) and a significant increase in time to progression (6.2 vs 4.3 months; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1250 mg PO QD given continuously in combination with capecitabine 2000 mg/m -~ daily administered in 2 divided doses on days i to 14 of a 21-day cycle. The most common clinical toxicities of all grades associated with lapatinib used in combination with capecitabine in the pivotal clinical trial were diarrhea (65 %), hand-foot syndrome (53 %), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab.

Conclusions: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-positive MBC that has progressed with standard treatment. In clinical trials, this combination was associated with a significant improvement in the time to progression in patients with MBC. Lapatinib's efficacy in other malignancies that

Accepted for publication June 9, 2008. doi:l 0.1016/j.clinthera.2008.08.008 0149-2918/$32.00

© 2008 Excerpta Medica Inc. All rights reserved.

1426 Volume 30 Number 8

p.J. Medina and S. Goodin

overexpress EGFR and/or HER2 is under evaluation. (Clin Ther. 2008;30:1426-1447) © 2008 Excerpta Medica Inc.

Key words: lapatinib, GW572016, HER2, EGFR, dual-receptor inhibitor, pharmacokinetics, adverse events, clinical trials.

I N T R O D U C T I O N Breast cancer is the leading form of cancer and the second leading cause of cancer death in women in the United States. In 2007, there were an estimated 178,480 new cases and 40,460 deaths resulting from breast cancer in the United States.1 Although the majority of diagnosed cases are local or regional, metastatic breast cancer (MBC) is present at the initial diagnosis in -5% to 10% of patients. In addition, 10% to 20% of patients will have a recurrence after breast- conservation surgery plus radiation therapy, with up to 25% being locally extensive or metastatic at the time of recurrence, e Although advances in adjuvant therapy have decreased relapse rates, the treatment of metastatic disease, both at the initial diagnosis and after initial therapy, remains a significant challenge.

Approximately 25% of breast cancers diagnosed are human epidermal growth factor receptor 2 (HER2, or ErbB2) positive. 3 Compared with patients with non-HER2-positive tumors, patients with HER2- positive tumors have been reported to have more ag- gressive disease that is more often lymph-node positive. HER2 overexpression has been reported to be a poor prognostic factor and a predictive risk factor for decreased disease-flee survival and overall survival (OS) in patients with breast cancer. 3,4 Trastuzumab was approved in 1998 for the treatment of MBC and more recently for use in the adjuvant setting in patients whose tumors overexpress HER2. 5 Trastuzumab is a humanized immunoglobulin G antibody that targets the extracellular domain of the HER2 receptor. Al- though the exact mechanism of action is unknown, HER2 concentrations at the cellular level may be decreased, preventing both homodimerization and heterodimerization of HER2 receptors, thereby preventing downstream signal transduction. 6 Unfortunately, trastuzumab is associated with both de novo and ac- quired resistance; therefore, there is a need for new agents that target the HER family of receptors through a different mechanism of action and have a different pharmacokinetic profile.

Lapatinib* was approved by the US Food and Drug Administration (FDA) on March 13, 2007, for use in combination with capecitabine in the treatment of patients with advanced breast cancer or MBC whose tumors overexpress HER2 and who have received previous therapy including an anthracycline, a taxane, and trastuzumab. On December 17, 2007, the Euro- pean Medicines Agency issued a positive opinion rec- ommending conditional marketing approval for lapatinib.

This article reviews the pharmacology, spectrum of activity, and pharmacokinetics of lapatinib; potential drug interactions; and the results of clinical trials evaluating the efficacy and tolerability of lapatinib in MBC. Because the HER family of receptors is involved in numerous malignancies in addition to breast cancer, including renal cell carcinoma, colon cancer, head and neck cancers, glioblastoma, and others, 6 clinical trials of lapatinib in other malignancies that overexpress HER2 and/or epidermal growth factor receptor (EGFR) are also reviewed.

M E T H O D S Relevant English-language literature was identified through searches of MEDLINE (1966-May 2008), the American Society of Clinical Oncology abstracts database (2000-2007), abstracts from the San Anto- nio Breast Cancer Symposium (2005-2007), and the FDA Web site (January 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clinical trials. Abstracts and posters presented at national and international scientific meetings were also reviewed. All identified clinical-trial data and presentations were reviewed, as were preclinical data that supported the clinical observations or were felt to be clinically relevant.

CHEMISTRY Lapatinib (GW572016) is a compound developed from the quinazoline core found in other ErbB tyrosine kinase (TK) inhibitors. Its chemical name is N-{3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}-6-[5- ({ [2-(methyls ulfonyl)ethyl] amino }methyl)- 2-furyl]- 4-quinazolinamine. 7 Its molecular formula is C29H26CIFN404S, and its molecular weight is 581.06.

*Trademark: Tykerb ~ in the United States, Tyverb ~ in Europe (GlaxoSmithKline, Research Triangle Park, North Carolina).

August 2008 1427

Clinical Therapeutics

In humans, lapatinib is administered as the mono- hydrate ditosylate derivative(C29H26C1FN404S[CrH803S]2 H)O), which has a molecular weight of 943.5. 8 The structural formula of lapatinib ditosylate is shown in Figure 1.

MECHANISM O F A C T I O N The HER, or ErbB, family of receptors contains 4 known members, HER1, HER2, HER3, and HER4. 9 HER1 (also called EGFR) and HER2 are often overexpressed, or have increased activity, in breast, lung, and colon cancers, among others. <9 Although HER3 and HER4 are assumed to be involved in cancer growth and proliferation, their exact role is currently undefined.

Structurally, all members of the HER family contain 3 regions, an extracellular ligand binding site, a trans- membrane domain, and a TK tail. 9,1° Receptor di- merization is required for TK phosphorylation to occur, which in turn activates signal transduction. Dimeriza- tion can occur with a member of the same family, re- suiting in a homodimer, or with a member of a different subtype, resulting in a heterodimer. The type of dimer that is formed affects the downstream signal event; heterodimers of HER2 and EGFR lead to strong mito- genic signals and cellular proliferation when HER2 is overexpressed, whereas homodimers of the HER family may lead to weak or no signaling.ll When the HER2 gene is amplified, HER2 is overexpressed on the sur- face of breast cancer cells and is able to drive the growth of the malignancy through homodimerization.

The interaction between HER2 and EGFR provides a strong rationale for targeting both receptors of this signaling pathway, particularly in clinical circumstances in which HER2 is overexpressed.

Lapatinib is an orally administered small-molecule inhibitor that targets both EGFR and HER2.1-),13 It targets the TK domain of these receptors by reversibly binding to the adenosine triphosphate binding site of the kinase. This interaction prevents the phosphorylation and subsequent signal transduction of both the Ras/Raf mitogen-activated protein kinase and the phosphoinositol-3-kinase/Akt pathways, leading to an increase in apoptosis and decreased cellular proliferation.i-),13 Figure 2 depicts the mechanism of action of lapatinib.

In addition to inhibiting wild-type HER receptors, lapatinib is able to inhibit truncated forms of these receptors. 14 Truncated forms of HER2 have been identified that lack the extracellular binding domain. These fragments, which may develop through shed- ding of the extracellular domain of the HER2 receptor, are collectively known as p95HER2 receptors. 14 They have been identified in MBC cell lines and have potent TK activity. In vitro and in vivo evidence sug- gests that lapatinib is able to reduce downstream phosphorylation and to inhibit cell growth in cell lines transfected with p95HER2.14

SPECTRUM OF ACTIVITY In the United States, lapatinib is approved for use in patients with MBC whose tumors overexpress HER2. 8

o c

H3C - - S

II o o

Figure 1. Structural Formula of lapatinib ditosylate.


P.J. M e d i n a a n d S. G o o d i n

EGF TG F-e Amphiregulin 13-Cellulin HB-EGF Epiregulin

T

A

Extracellular

Heregulin No known NRG1 ligands

HER2 HER2 EGFR HER3 EGFR EGFR HER2 HER2 p95HER2 EGFR

I'I I'I I'F LapatinibxN~/p ~ P ' ' P LapatinibxN~/ ¢ ~ / / LapatinibN~,~/p ~p Lapatinib

S ~ PI3-K Ras ~ Raf-1 ~ ' ~

Akt M EK Intracellular

MAPK

Gene transcription Cell cycle progression Cell survival

Figure 2. Mechanism of action of lapatinib. Activation of human epidermal growth factor receptor (HER) 2 can occur through homodimerization or heterodimerization with another member of the HER family. On ligand binding to an epidermal growth factor receptor (EGFR) (eg, EGG transforming growth factor-(* [TGF-cx], amphiregulin) or HER3 (eg, heregulin, neuregulin 1 [NRG1]), HER2 forms a heterodimer to activate downstream signaling. Lapatinib is a dual inhibitor of both EGFR and HER2 tyrosine kinases, inhibiting phosphorylation of the receptors and preventing downstream signal transduction of phosphoinositol-3-kinase (PI3-K) (cell survival) and Ras (cell proliferation). In addition, lapatinib is active against truncated forms of HER2 (p95HER2). HB-EGF = heparin-binding EGF; PTEN = phosphatase and tensin homologue; Raf-1 = murine leukemia viral oncogene homologue 1; M EK = mitogen-activated protein kinase kinase; MAPK = mitogen-activated protein kinase.

However, EGFR and HER2 are implicated in the development and progression of many tumor types, suggesting that lapatinib may have a range of antitumor activity. 10

Early in vitro kinase assays indicated that lapatinib was highly selective for EGFR and HER2 enzymes, with 50% inhibitory concentrations (IC50) of 10.8 nmol/L and 9.2 nmol/L, respectively.15 The additional kinases tested were not inhibited until IC50 values reached >3500 nmol/L, with the exception of HER4, for which the IC50 was 367 nmol/L. The same investigative group examined the efficacy of lapatinib in cell lines over-

expressing EGFR and HER2. Growth of BT474 (breast), HN5 (head and neck), A-431 (vulva), CaLu-3 (lung), and N87 (gastric) cell lines was inhibited, with a mean IC50 <0.16 p.mol/L.16 Dose-dependent inhibition of HN5 and BT474 tumor xenograft growth was also seen at doses of 30 and 100 mg/kg, both given twice daily, with complete inhibition of tumor growth at the higher dose. 16

Lapatinib's activity in breast cancer was further tested against a panel of 22 breast cancer cell lines having varying degrees of EGFR and HER2 expression. 17 Sensitivity to lapatinib was directly related to expres-

August 2008 1429


sion of HER2 but not EGFR. Breast cancer cell lines containing HER2 gene amplification and increased HER2 expression were most sensitive to lapatinib's inhibitory effects compared with EGFR-overexpressing cell lines (IC50 <1.0 vs 4.7-18.6 btmol/L, respectively). 17 Lapatinib was associated with dose- and time- dependent phosphorylation of EGFR, HER2, Akt, and ERK (extracellular signal-regulated kinases) in HER2- overexpressing breast cancer cell lines (BT474). 17

Lapatinib has also been reported to have activity against trastuzumab-resistant cells. In HER2-overexpressing cell lines conditioned with trastuzumab, lapatinib at concentrations of 5 btmol/L significantly inhibited tumor growth, as measured in terms of percent cell viability, compared with controls (P < 0.001); in the same cell line, trastuzumab did not have a significant effect on cell viability compared with controls. 17 The combination of lapatinib + trastuzumab was also reported to have synergistic activity in HER2- overexpressing cell lines, enhancing apoptosis of these cell lines. 17,18 The ability of lapatinib to inhibit trastuzumab-resistant cells may be a result of its ability to inhibit p95HER2 receptors, as mentioned earlier, or its effects on insulinlike growth factor-1 (IGF-1) signaling. 14,19

IGF-1 signaling has recently been identified as a potential mechanism of resistance to trastuzumab, with the ability to signal downstream independently of the HER2 receptor.19 In trastuzumab-resistant SKBR3 cells, lapatinib decreased phosphorylation of EGFR and HER2, along with decreasing downstream signals. 19 After the introduction of IGF-1, lapatinib at concentrations of i btmol/L inhibited IGF-l-stimulated phosphorylation of the IGF-1 receptor, blocked the cross-signaling and activation of HER2, inhibited cell growth, and induced apoptosis. 19 The cytotoxic effects of lapatinib were increased when it was combined with c~IR3, a monoclonal antibody against the IGF-1 receptor. > In addition, elevated IGF-1 levels predicted a response to lapatinib in a subset of 15 patients from a Phase I trial (N = 33). 12

Overexpression of both EGFR and HER2 has been associated with tamoxifen resistance. 2° Lapatinib has been reported to restore tamoxifen sensitivity in estrogen receptor-positive, tamoxifen-resistant cell lines. Lapatinib + tamoxifen was associated with a 2.5- to 5-fold increase in p27 and a synergistic 5-fold decrease in cyclin D 1 compared with either agent alone, leading to decreased cell-cycle progression in MCF-7

breast cancer cell lines. 21 This strategy is currently being evaluated in clinical trials.

P HARMACO KI N ETICS Phase I trials evaluating the pharmacokinetics of lapatinib have been conducted in healthy volunteers as well as in adult and pediatric cancer patients. Single- dose studies may not accurately predict systemic exposure (AUC) or the tl/2 of lapatinib, as concentrations accumulate with multiple doses. 22 The relation- ship between concentration and response has not been adequately defined, but the incidence of diarrhea has been found to increase at higher doses, not at higher serum concentrations, suggesting that this adverse effect was the result of unabsorbed drug. 23 The development of rash did not appear to be dose or serum related. 23 The pharmacokinetic properties of lapatinib are discussed in the following paragraphs and summa- rized in Table I.

Absorption Lapatinib was developed as an oral agent and has

no intravenous equivalent for assessment of its bio- availability. On administration of doses of 25, 100, or 175 mg for 8 days in 27 healthy men, oral absorption was delayed by -30 minutes and the Tma:~ was 3 to

Table I. Summary of the pharmacokinetic pa- rameters oflapatinib when administered at the doses approved by the US Food and Drug Administration. 8,23,24

Parameter Value

Absorption Tma x 3-4 h Cma x 2.43 I~g/m L AUC 36.2 I~g • h/mL

Distribution Vd/L >2200 L

Metabolism CYP3A4,* CYP3A5, CYP2C19, and CYP2C8

Elimination tl/2 Single dose 14.2 h Multiple doses 24 h

*Primary metabolic route.


P.J. Medina and S. Goodin

4 hours, ee Time-dependent increases in Cma x and AUC were detected at the higher doses (100 and 175 mg) but not at the lower dose.

Lapatinib has also exhibited delayed absorption in 67 patients with various advanced solid tumors, with Cm~ x occurring at 3 to 6 hours after administration and 2-fold accumulation at day 20. e3 Patients in this Phase I trial were assigned to 1 of 5 dosing cohorts for assessment of pharmacokinetics and toxicity. Concen- trations, including Cm~ x and AUC, increased with higher doses, although the effects were variable, pos- sibly as a result of food intake not being controlled on days 2 to 19. The median dose required to produce a Cmi n of 0.3 to 0.36 pg/mL (the m e a n Cmi n of responders) was 900 mg. e3 This Cmi n w a s above concentrations required to exert antitumor effects in preclinical models, le

At the FDA-approved dose of 1250 mg/d, the steady-state Cm~ x and AUC were 2.43 t~g/mL and 36.2 t~g " h/mL, respectively.S, > Administering lapatinib in divided daily doses increased the steady-state AUC ~2-fold compared with the same total dose administered once daily. 8,e4 With multiple daily dosing of lapatinib, steady state was achieved within 6 to 7 days. 8 Systemic exposure to lapatinib was increased when the drug was administered with food, the greatest effect occurring with a high-fat meal. 8,e3-e5 The AUC was increased by 325% and 167% when taken with high- and low-fat meals, respectively, e3,e5 However, because clinical studies of lapatinib were performed with dosing on an empty stomach, it is recommended that the drug be taken in this way. 8

Distribution At concentrations of 1 btmol/L, lapatinib was highly

bound (>99%) to albumin and (*-1 acid glycoprotein. 8,> The results of in vitro studies have indicated that lapatinib is a substrate for and an inhibitor of P-glycoprotein (pgp).8 The volume of distribution (Vd/L) of the ter- minal phase of lapatinib was >2200 L, much greater than the volume of body water, indicating good drug distribution.S, 24

Metabolism The findings of in vitro studies indicate that lapa-

tinib is primarily metabolized to oxidated metabolites by the cytochrome P450 (CYP) 3A4, 3A5, 2C19, and 2C8 isozymes. 8,23,24 Approximately 70% of its metabolism is through CYP3A4. 24 No metabolite consti-

tutes >15% of recovered drug. One metabolite (GW690006) remains active against EGFR but not HER2, whereas other metabolites appear to be inactive. 24

Elimination Lapatinib is primarily eliminated hepatically, with

27% of an oral dose recovered in feces and <2% recovered in the urine. 8 The elimination tl/2 was 14.2 hours in single-dose studies 8 and ~24 hours with repeated dosing (as a result of drug accumulation). 8,24

Special Populations Lapatinib was administered at oral doses ranging

from 300 to 1150 mg/m 2 per dose BID in 34 pediatric patients with central nervous system (CNS) tumors. 26 Lapatinib Cma x occurred 3 to 4 hours after dosing, with a delay in absorption similar to that seen in adults. 23,26 The lapatinib AUC0_12 was linearly related to the administered dose after the second course of therapy, but not after the first. Clearance was not dose related but was related to dexamethasone coadministration and the course of therapy, with the second course of therapy and dexamethasone both significantly decreasing lapatinib clearance (P < 0.005). After the second course of therapy, the elimination rate constant was 0.17 h -1, indicating a tl/2 of 4 hours, and the Vd/L was 65.6 L/m-). 8,-)6 These values did not differ significantly from those after the first course of lapatinib.

No publications were identified concerning the effects of sex, race, ethnicity, or age on the pharmacokinetics of lapatinib. In patients with severe hepatic dysfunction (Child-Pugh class C), the AUC of lapatinib was increased by >60% and the tl/2 was ~3 times that in individuals without hepatic dysfunction. 8,24 Dose reductions to 750 mg/d are recommended in this patient population. 8 The effect of renal dysfunction on the pharmacokinetics of lapatinib is currently unknown, but is expected to be minimal based on the limited renal elimination of lapatinib.

DRUG INTERACTIONS Lapatinib is a major substrate for and inhibitor of CYP3A4 and an inhibitor of CYP2C8. In healthy volunteers receiving ketoconazole, a CYP3A4 inhibitor, the AUC of lapatinib was increased 3.6-fold relative to control, and the tl/2 increased 1.7-fold relative to control, s,> In contrast, carbamazepine, a CYP3A4 inducer, decreased the AUC of lapatinib by ~75%. 8'24

August 2008 1431


Few data were found on the use of lapatinib and other CYP inducers or inhibitors, although similar interactions may be expected. The package insert recommends avoidance of strong CYP3A4 inhibitors (eg, azole an- tifungals, clarithromycin, HIV medications [eg, indi- navir], and grapefruit), s If coadministration of a strong CYP3A4 inhibitor is necessary, reduction of the lapatinib dose to 500 mg/d is predicted to adjust the lapatinib AUC within the target range, s If the strong CYP3A4 inhibitor is discontinued, a washout period of -1 week should be allowed before adjusting the lapatinib regimen to the indicated dose. Similarly, strong CYP3A4 inducers (eg, dexamethasone, pheny- toin, carbamazepine, rifampin, phenobarbital, St. John's wort) should be avoided in patients taking lapatinib. In patients receiving a strong CYP3A4 inducer in combination with lapatinib, the lapatinib dose should be titrated gradually from 1250 up to 4500 mg/d based on tolerability, s

Limited data regarding drug interactions with lapatinib and other anticancer agents were identified by the literature search. In a Phase I trial of lapatinib in combination with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan), the AUC of SN-38, the active metabolite of irinotecan, was increased by - 4 0 % . 27 No other notable interactions occurred. A Phase I trial of lapatinib + paclitaxel reported 21% and 23% increases in the AUCs of lapatinib and paclitaxel, respectively. -)8 Pharmacokinetic studies of lapatinib in combination with docetaxel, capecitabine, letrozole, and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) reported no significant interactions. -)8-31 Based on preclinical data indicating synergy between the 2 agents, the combination of lapatinib + trastuzumab was studied in a Phase I dose-escalation trial in 54 patients with advanced breast cancer. 3-) No pharmacokinetic interaction was observed between the 2 agents; however, the optimally tolerated dose of lapatinib was 1000 mg/d with standard-dose trastuzumab.

Lapatinib has been reported to inhibit Pgp, which may increase concentrations of Pgp substrates (eg, anthracyclines, taxanes, vinca alkaloids). 8,-)4 No for- mal pharmacokinetic studies of this interaction have been published, but care may be warranted when coadministering lapatinib with substrates of Pgp.

CLI NICAL EFFICACY Lapatinib has been evaluated in Phase II and III trials in various forms of breast cancer (MBC, 33~1 inflam-

matory breast cancer [IBC], 42,43 and breast cancer with CNS metastases 44~6) (Table II). Because of its dual-receptor activity at HER2 and EGFR, lapatinib also has been evaluated in a number of other tumor types in which EGFR plays a role, including Phase II trials in non-small cell lung c a n c e r ( N S C L C ) , 47 malignant tumors of the salivary glands, 48 biliary tree and hepatocellular cancer, 49 squamous cell carcinoma of the head and neck, s° hormone-sensitive prostate cancer,51 gastric cancer, 52 metastatic colorectal cancer, 53 and transitional cell carcinoma of the urothehum, ~ " ~4 and a Phase III trial in advanced renal cell carcinoma 55 (Table III). Most Phase II trials involved lapatinib monotherapy; the majority of data from these trials is available in abstract form only, and no statistical analyses were performed.

M e t a s t a t i c Breas t Cancer Evidence for the efficacy of lapatinib in MBC was

derived from trials of monotherapy and combination therapy involving patients with trastuzumab-refractory MBC; patients with MBC refractory to an anthracycline, a taxane, capecitabine, and trastuzumab; and as first-line therapy for MBC.

Monotherapy Burstein et a133 reported on a multinational, open-

label Phase II trial of the efficacy and tolerability of lapatinib monotherapy in patients with advanced or refractory MBC who had previously been treated with an anthracycline, a taxane, capecitabine, and (in HER2-positive tumors only) trastuzumab. The study involved 2 cohorts: cohort A enrolled 140 patients with tumors that overexpressed HER2 (HER2 positive), defined as either 3+ on immunohistochemistry (IHC), or 2+ on IHC and HER2 amplified or positive on fluorescent in situ hybridization (FISH); cohort B enrolled 89 patients with tumors that did not overexpress HER2 (HER2 negative). The majority (76%) of patients had received >4 previous lines of therapy, and 95% had stage IV disease at study entry. The median trastuzumab exposure in patients with HER2-positive tumors was 76 weeks, and most patients (97%) had received >12 weeks of previous trastuzumab therapy. Patients in each cohort received oral lapatinib 1500 mg QD at least 1 hour before or after the morning meal. According to the response evaluation criteria in solid tumors (RECIST), 56 no objective responses occurred in any of the patients with HER2-negative tumors in



Table II. Clinical trials o f lapatinib in patients with advanced or metastatic breast cancer (M BC).

No. of Treatment Authors Patient Population Patients Regimens

Burstein et a133 Cohort A: HER2-posiuve 140 Lapaunib Phase II, MBC refractory to an 1500 mg QD international, anthracycline, a taxane, OL capecitabine, and

trastuzumab

Cohort B: HER2-negauve 89 MBC refractory to an anthracycline, a taxane, and capecitabine

Lapatinib 1500 mg QD

Response

RR: 4.3%~; clinical benefid: 5.7%; median TTP: 9.1 wk; median PFS: 9.1 wk; median survival: 29.4 wk

No objective responses; median TTP: Z6 wk; median PFS: Z6 wk; median survival: 18.6 wk

Blackwell et a134 HER2-posiuve MBC 78 Lapaunib Phase II, refractory to 1500 mg QD MC, OL trastuzumab

PR: 7.7%; clinical benefitt: 21.8%

Iwata et al 3s HER2-positive MBC 45 Lapatinib Phase II, refractory to an 1500 mg QD MC, OL anthracycline, a taxane,

capecitabine, and trastuzumab

Clinical benefitf: 33.3%

Gomez et a136 Phase II, MC, R, OL

First-line treatment of HER2-posiuve advanced breast cancer or MBC

138 Lapatinib 1500 mg QD (n = 69) o r

Lapat in ib 500 mg BID (n = 69)

RR: 24%; clinical benefid: 31%; PFS at 6 mo: 43%~ no difference in clinical activity between doses

Geyer et a137 39 and Cameron el: al 4°

Phase III, MC, R, OL

HER2-posiuve locally advanced breast cancer or MBC that had progressed with regimens including an anthracycline, a taxane, and trastuzumab

399 Lapaunib 1250 mg QD + capeckabine 1000 mg/m 2 PO BID on days 1-14 of a 21-day cycle OF

Capecitabine 1250 mg/m 2 PO BID on days 1-14 of a 21-day cycle

Median TTP: 6.2 mo (combination) vs 4.3 mo (capecitabine alone) (HR = 0.57~ 95% CI, 0.43-0.77~ P < 0.001)~ improved PFS with combination vs capeckabine alone (HR = 0.55; 95% CI, 0.4-0.74~ P < 0.001)

Di Leo et a141 Phase III, MC, R, DB, PC

First-line therapy o f HER2-negauve or unknown advanced breast cancer or MBC

580 Lapadnib 1500 mg QD + paclitaxel 175 mg/m 2 IV q3wk OF

Placebo + paclitaxel 175 mg/m 2 IV q3wk

RR: 35.1% vs 25.3%, combination vs paclitaxel monotherapy, respectively (P = 0.008)~ clinical benefitf: 40.5% vs 31.9% (P = 0.025)~ no difference in TTP or OS

(continued)

August 2008 1433


Table II (continued).

Authors

Johnston et a142 Phase II, MC, OL

Cristofanil l i et a143 Phase II, MC, OL

L inet a144

Phase II, MC, OL

L inet al 4s

Phase II, MC, OL

Patient Population

ErbB2-positive (cohort A) or ErbB2-negative (cohort B) recurrent or refractory I BC

Newly diagnosed IBC

HER2-positive MBC with CNS metastases

No. of Patients

Cohort A: 30 Cohort B: 15

ErbB2 positive: 21 ErbB2 negative: 2

39

Treatment Regimens


Neoadjuvant lapatinib 1500 mg QD + paclitaxel 80 mg/m 2 IV qwk for 12 wk

Lapatinib 750 mg BID

Response

Cohort A: 2 CRs, 13 PRs; cohort B: 1 PR

Clinical response: ErbB2 positive, 95%; ErbB2 negative, 100%; pathologic response: not reported

PR: 2.6%

Lapatinib 750 mg BID

HER2-positive MBC 241 with CNS metastases and previous CNS radiotherapy

Lin et a146 Extension o f previous 51 Lapatinib + PR: 20%; SD >8 wk: Phase II, study 4s in patients capecitabine 35%; median PFS: MC, OL whose disease 15.8 wk

progressed during lapat inib monotherapy

PR: 6%; SD >8 wk: 42%; median PFS: 15.1 wk; PFS at 6 mo: 22%

OL = open label; HER2 = epidermal growth factor receptor 2 (ErbB2); RR = response rate (complete response [CR] + partial response [PR]); TTP = time to progression; PFS = progression-free survival; MC = multicenter; R = randomized; HR = hazard ratio; DB = double blind; PC = placebo controlled; OS = overall survival; IBC = inflammatory breast cancer; CNS = central nervous system; SD = stable disease. *As determined by investigators' assessment. fCR, PR, and SD _>24 weeks. t PR and SD _>16 weeks.

cohort B. In HER2-positive patients, there were 3 partial responses (PRs) and 3 complete responses (CRs), for a response rate of 4.3% by the investigators' assessment or 1.4% (2 PRs) by independent review. 33 All responders according to the investigators' assessment exhibited HER2 overexpression of 3+ by IHC, and 5 of the 6 responders were HER2 amplified by FISH. A clinical benefit (CR, PR, + stable disease [SD] >24 weeks) occurred in 5.7% of HER2-positive patients according to both the investigators' and independent reviews. The median time to progression (TTP) and median progression-free survival (PFS) were both 9.1 weeks in HER2-positive patients and 7.6 weeks in

HER2-negative patients by independent review; median survival was 29.4 weeks in HER2-positive patients and 18.6 weeks in HER2-negative patients.

A planned interim analysis of a similar open-label, Phase II trial of lapatinib monotherapy in 78 HER2- positive patients with refractory MBC found a clinical benefit rate (PR + SD >16 weeks) of 21.8%. 34 Simi- larly, preliminary results from an open-label, Phase II trial conducted in Japan in 45 patients with HER2- overexpressing MBC refractory to an anthracycline, a taxane, capecitabine, and trastuzumab indicated a clinical benefit (CR, PR, + SD >24 weeks) of 33.3%. 35 Collectively, these studies support the activity of lapa-



Table III. Clinical trials of lapat in ib for solid tumors other than breast cancer.

No. of Treatment Authors Patient Population Patients Regimen Response

Smylie el: a147 First- or second-line treatment 131 Lapal:inib 1500 mg Phase II, of advanced or metastatic QD MC, R, OL NSCLC with BAC or no or

smoking history (target Lapal:inib 500 mg population: n = 56) or no BAC BID or a smoking history (nonl:argel: population: n = 75)

Malignant salivary gland cancer 36 Agulnik el: a148 Phase II, MC, OL

Ramanal:han el: a149 Phase II, MC, OL

Abidoye el: al so Phase II, MC, OL

Sridhar el: a151 Phase II, MC, OL

lqbal el: al s2 Phase II, OL

Fields el: al s3 Phase II, MC, OL

WOlfing el: al g4 Phase II, MC, OL

Ravaud et al ss

Phase III, MC, R, OL

Biliary tree cancer 17

Hepatocellular carcinoma

Head and neck cancer with (arm A) and without (arm B) previous exposure to an EGFR inhibitor

37

42

Hormone-sensitive prostate 23 cancer, no previous hormonal therapy, corticosteroid therapy, or chemotherapy

First-line treatment of advanced 47 or metastatic gastric cancer







Target population: PR, 2%; SD _>24 wk, 25% Nontarget population: PR, 1%; SD _>24 wk, 37%

No objective responses; SD _>6 mo: 36%

No PRs; SD: 29%; median PFS: 1.8 mo; median OS: 5.2 mo

PR: 5%; SD: 35%; median PFS: 2.3 mo; median OS: 6.2 mo

No objective responses; SD: 37% (arm A) and 20% (arm B)

No responses

PR: 7%; SD: 20%

Second-line treatment of metastatic colorectal cancer

86 Lapatinib 1250 mg PR: 1% QD

Second-line treatment of locally 59 advanced or metastatic transitional cell carcinoma of the urothelium

Advanced renal cell carcinoma 416


PR: 2%; SD: 31%; median TI-P: 8.6 wk; median OS: 1Z9 wk

Lapatanib 1250 mg QD o r

Hormonal therapy (tamoxifen or megestrol acetate)

TTP: 15.3 wk (lapatinib) vs 15.4 wk (hormonal therapy) (P = NS); OS: 46.9 vs 43.1 wk, respectively (P = NS)

MC = multicenter; R = randomized; OL = open label; NSCLC = non-small cell lung cancer; BAC = bronchioloalveolar carcinoma; PR = partial response; SD = stable disease; PFS = progression-flee survival; OS = overall survival; EGFR = epidermal growth factor receptor; TTP = time to progression.

August 2008 1435


tinib monotherapy in this heavily pretreated population that had progressed with previous trastuzumab- containing regimens.

Gomez et a136 reported the results of an international, randomized, open-label Phase II study of lapatinib monotherapy as first-line treatment in patients with HER2-positive advanced breast cancer or MBC. Patients were randomized to receive oral lapatinib either as 1500 mg QD (n = 69) or 500 mg BID (n = 69). Patients had a median age of 53 years and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (33%) or 1 (67%). The majority of patients (76%) had estrogen receptor- and progesterone receptor-negative tumors. Overall, there was a 24% response rate (CR + PR) and a clinical benefit (CR, PR, + SD >24 weeks) of 31%, with no significant differences in these outcomes between treatment groups. Most responses (32/33) occurred by week 12, with a median time to response of 7.9 weeks. The responses were durable, with a median duration of response of 28.4 weeks and a 6-month PFS of 43%. The response rate to lapatinib monotherapy administered as either 1500 mg QD or 500 mg BID in the first-line setting in this trial was comparable to historical data for trastuzumab in the first-line treatment of HER2- overexpressing MBC. 57

In this trial, the biomarkers ErbB1-4, PTEN (phosphatase and tensin homologue), and c-myc were evaluated as predictors of response in patient tumor blocks. 58 For the first 65 blocks analyzed, an elevation in HER2 expression was significantly associated with a response to lapatinib treatment (P = 0.02) and with clinical benefit (P < 0.01). These data support further investigation of lapatinib as first-line treatment for MBC with HER2 overexpression.

Combination Therapy Lapatinib's efficacy in the monotherapy trials led

to its evaluation in combination with capecitabine in HER2-positive MBC that was refractory to regimens including an anthracycline, a taxane, and trastuzumab, and in combination with paclitaxel as first-line treatment for HER2-negative or unknown MBC.

Lapatinib was approved by the FDA based on the interim results of a randomized, open-label, Phase III trial for 324 women with HER2-positive (3+ by IHC or 2+ by IHC and amplified by FISH), locally advanced breast cancer or MBC that had progressed after treatment with regimens that included an an-

thracycline, a taxane, and trastuzumab. 8,37 Patients were randomly assigned in a 1:1 ratio to receive oral lapatinib 1250 mg QD on an ongoing basis and oral capecitabine 2000 mg/m -) given in 2 divided doses on days 1 through 14 of a 21-day cycle, or monotherapy with capecitabine 2500 mg/m -) given in 2 divided doses on days 1 through 14 of a 21-day cycle. The primary end point, TTP, was defined as the time from randomization to tumor progression or death related to breast cancer.

Geyer et a137 performed a prespecified interim analysis after the occurrence of 146 investigator-reported disease-progression events. After data validation, analysis of the primary end point by an independent data safety and monitoring committee included 121 disease- progression events. The baseline characteristics of the combination lapatinib + capecitabine and capecitabine monotherapy groups were well balanced, with a median age of 54 and 51 years, respectively; an ECOG performance status of 0 in 59% and 55%; hormone receptor (estrogen and progesterone) negativity in 49% and 50%; metastatic disease in 96% each; and a median duration of previous trastuzumab therapy of 42 and 44 weeks.

After independent review, the interim analysis of TTP met the prespecified criteria for early reporting based on the superiority of lapatinib + capecitabine relative to capecitabine monotherapy. 37 There were 49 disease-progression events in the combination- therapy group and 72 in the monotherapy group, and the median TTP was 8.4 and 4.4 months, respectively. The hazard ratio (HR) for TTP with combination therapy was 0.49 (95% CI, 0.34-0.71; P < 0.001). Combination therapy was also associated with a numerically, but not statistically significantly, higher response rate (22% vs 14%). Because the interval since the last exposure to trastuzumab differed between patients, persistent levels of trastuzumab may have enhanced the activity of lapatinib. However, a planned exploratory analysis found that the interval between administration of trastuzumab and randomization had no effect on TTP in either treatment group. 38 At the time of the interim analysis, there were no differences in OS between groups, and 22% of patients in both groups had died.

In an update of efficacy data and biomarker analyses from the preceding pivotal Phase III trial, 399 women had been randomized to treatment at the time of accrual closure by the independent data and safety



monitoring committee. 39,4° The updated analysis included 82 disease-progression events with the combination of lapatinib + capecitabine and 102 events with capecitabine monotherapy. 4° Baseline characteristics and the median duration of previous trastuzumab therapy remained balanced in the 2 groups after the accrual of an additional 75 patients. The median TTP for combination therapy was 6.2 months, compared with 4.3 months for capecitabine alone (HR = 0.57; 95% CI, 0.43-0.77; P < 0.001), indicating a 43% reduction in the relative risk of progression with the addition of lapatinib to capecitabine. Similarly, there was an improvement in PFS (HR = 0.55; 95% CI, 0.40- 0.74; P < 0.001), indicating a 45% relative risk reduction in PFS with combination therapy. There were no associations between PFS and any of the clinical characteristics of visceral disease, the number of metastatic sites, hormone-receptor positivity, or the duration of previous trastuzumab treatment. Although there was a reported improvement in OS with combination therapy (HR = 0.78), the difference did not reach statistical significance. An exploratory analysis found fewer cases with CNS involvement at first progression in the combination-therapy group compared with the monotherapy group (4 vs 13, respectively; P = 0.045). Exploratory analyses of biomarkers for PFS in 241 patients with centrally confirmed eligible HER2 status found that increased levels of circulating extracellular- domain HER2 predicted a benefit from combination therapy relative to capecitabine alone (HR = 0.45; 95% CI, 0.31-0.65; P < 0.001). The results of this trial support continuing development of lapatinib as a component of combination therapy and investigation in early-stage breast cancer.

In a Phase III, multicenter, randomized, double- blind, placebo-controlled trial of first-line treatment for untested or HER2-negative advanced breast cancer or MBC, 41 580 patients were randomized in a 1:1 ratio to receive oral lapatinib 1500 mg QD + paclitaxel 175 mg/ m -) q3wk, or placebo + paclitaxel 175 mg/m -) q3wk. No patients had received previous trastuzumab therapy, 87% presented with metastatic disease, and 55% had received previous adjuvant chemotherapy or hormonal therapy. At the time of data analysis, 97% (561) of patients had progression or withdrew from the study. In an intent-to-treat analysis of investigators' assess- ments, there was a significantly higher response rate (CR + PR) in the HER2 untested or unknown population with combination therapy compared with pacli-

taxel monotherapy (35.1% vs 25.3%, respectively; P = 0.008). Similarly, the rate of clinical benefit at 6 months was significantly higher with combination therapy than with monotherapy (40.5% vs 31.9%; P = 0.025), but there were no significant differences in the median duration of response, TTP, or OS. After centralized HER2 testing by IHC or FISH, 19% (52) of the combination group and 15% (39) of the monotherapy group had confirmed HER2-positive disease. On analysis by HER2 status, patients with HER2- positive disease who received combination therapy had significant improvements versus monotherapy with respect to response rate (60% vs 36%; P = 0.027); median duration of response (7.4 vs 5.5 months; P = NS); and median TTP (6.1 vs 5.8 months; P = 0.011). Although dual inhibition was hypothesized to have an effect in HER2-negative disease, combination therapy did not achieve the primary end point of a significant improvement in TTP compared with monotherapy in the HER2-untested population (6.7 vs 5.3 months). However, the results in patients with HER2-positive disease were encouraging, and ongoing trials by this investigative group are evaluating lapatinib in combination with weekly paclitaxel in HER2-positive advanced breast cancer.

Inflammatory Breast Cancer Results from preclinical studies and the response

rate (3 PRs and 1 CR) in a Phase I study of lapatinib in 5 heavily pretreated patients with IBC 23 led to the evaluation of lapatinib monotherapy in patients with recurrent or refractory IBC. Johnston et a142 reported the final results of a multicenter, open-label, Phase II study of oral lapatinib 1500 mg QD in 2 patient cohorts---cohort A included 30 patients with tumors that were HER2 positive (IHC 2+/3+ or FISH positive), and cohort B included 15 patients with tumors that were IHC 1+ for HER2 overexpression or did not overexpress HER2. This patient population was heavily pretreated, with a median of 4 and 3 previous chemotherapy regimens in cohorts A and B, respectively, 86% and 80% of whom had received previous therapy with an anthracycline. In cohort A, 50% of patients had previously received trastuzumab. The study population had a median age of 54 years, and dermal lymphatic invasion was present in the majority of tumor biopsies in cohorts A and B (73% and 80 % ). In cohort A, 50 % (15) o f patients had a clinical response in the skin and/or in measurable disease

August 2008 1437


(RECIST). With respect to the best clinical response in individual patients, there were 2 CRs and 13 PRs in the chest wall/skin or by RECIST, with all responses in the skin occurring in the first 4 weeks. The median duration of overall response in cohort A was 16.9 weeks (range, 8-31.7 weeks at the time of the evaluation), and the median PFS was 14 weeks (95% CI, 15-32). In cohort B, only 1 patient had a clinical response (PR), and this cohort was subsequently closed. An evaluation of biomarkers in clinical responders in cohort A found that 67% were PTEN deficient and 83% were positive for IGF-1R42, both of which have been associated with resistance to trastuzumab monotherapy in small studies. 59 Phosphorylated HER3 expression and lack of p53 expression were significantly associated with response (P < 0.05 by multivariate analysis; P = 0.021 and 0.033, respectively, by univariate analysis). These biomarker analyses suggested the possibili- ty of a lack of cross-resistance with trastuzumab, but this requires evaluation in larger clinical trials.

Preliminary data from an open-label, Phase II study in 23 patients with newly diagnosed IBC indicated that the neoadjuvant combination of oral lapatinib 1500 mg QD and paclitaxel 80 mg/m 2 IV weekly for 12 weeks was associated with a 95% (20/21) clinical response in patients with ErbB2-overexpressing tumors and a 100% (2/2) response in patients with ErbB1- positive/ErbB2-nonoverexpressing tumors. 43 Accord- ing to the preliminary data from this small study, lapatinib was clinically active neoadjuvantly in these heavily pretreated patients with IBC, the most aggres- sive and lethal form of breast cancer.

Breast Cancer with Central Nervous System Metastases

CNS metastases represent a challenge in the management of patients with MBC, and there is no con- sensus on what medical therapy to offer patients whose CNS metastases have progressed after radiotherapy. Although both stereotactic radiosurgery and whole- brain radiotherapy (WBRT) are effective palliatively, death may occur in these patients due to progressive disease within the CNS. 6° Unlike trastuzumab, lapatinib is a small molecule that is hypothesized to cross the blood-brain barrier and, therefore, may have clinical activity in brain metastases. 61

In an open-label, Phase II trial, Lin et a144 evaluated oral lapatinib at a starting dose of 750 mg BID in 4-week cycles in patients with HER2-positive breast

cancer and new or progressive brain metastases. All 39 patients had developed brain metastases while receiving trastuzumab (median of 2 previous trastuzumab- containing chemotherapy regimens), and 37 had progression after radiation, with a median time of 5.9 months from the last radiation to study entry. There was 1 PR, constituting an objective response rate (RECIST) of 2.6%, which did not achieve the prespecified level of activity. Sixteen patients had measurable non-CNS disease and 4 achieved a PR in non-CNS sites. The median TTP was 3 months (95% CI, 2.3-3.7); in the 1 patient with a CNS objective response, the TTP was 11.3 months. Although the data were exploratory, there was some evidence of clinical benefit, with 7 patients free of progression in both CNS and non-CNS sites at 16 weeks and 3 patients with CNS volumetric declines of >30%. Based on the volumetric results from this study, exploration of lapatinib in HER2- positive CNS disease is continuing.

To further characterize the activity of oral lapatinib 750 mg BID in patients with HER2-positive breast cancer with metastatic CNS disease, the same investigative group conducted a larger trial with a design and eligibility criteria similar to those in the previous trial, except that patients must have received previous radiotherapy to the eNg. 45 Instead of using the RECIST criteria, response was defined as a volumetric reduction of CNS lesions (by 50% for a PR) in the absence of new lesions, need for an increased dose of steroids, progressive neurologic signs/symptoms, or progressive extra-CNS disease. The 241 patients in this study had a median age of 49 years and an ECOG performance status of 0 (25%), 1 (44%), or 2 (31%); 87% had concurrent non-CNS disease. Patients had been heavily pretreated, with 88% having received >3 chemotherapy regimens, 44% having received >3 trastuzumab + chemotherapy regimens, and 73% having received WBRT. Using the CNS composite criteria, a PR was reported in 6% (15) of patients, and 42% (102) of patients had SD of >8 weeks. CNS volumetric reductions of >50% occurred in 7% of patients. The median PFS for all patients was 15.1 weeks, and the 6-month rate of PFS was 22%. Among CNS responders, the median PFS was longer than in non- responders (25.3 vs 15.3 weeks, respectively).

An extension of this trial was conducted in patients with either CNS or non-CNS disease that progressed radiographically during lapatinib monotherapy. 45,46 These patients were treated with lapatinib + capecita-



bine at the FDA-approved combination doses. Results have been reported for 51 patients, of whom 20% (10) had a PR (volumetric reduction of >50% in the CNS), and 35% (18) had SD (volumetric reduction of >20% in the CNS). 46 Median PFS was 15.8 weeks. Although, as in the previous trial, lapatinib did not achieve the target response rate, it had modest but durable activity in the management of CNS metastases. Preliminary data from the extension study suggest a potential for improved responses with lapatinib combined with other agents in this patient population. Ongoing trials of lapatinib + capecitabine or topotecan and lapatinib + radiotherapy should provide further insight into the role of lapatinib in the management of this difficult- to-treat population.

Other Malignancies Non-Small Cell Lung Cancer

Smylie et a147 presented the results of a Phase II, multicenter, randomized, open-label trial comparing oral lapatinib 1500 mg QD with lapatinib 500 mg BID as first- or second-line therapy in 2 populations of patients with advanced or metastatic NSCLC: those with bronchioloalveolar carcinoma (BAC) or no smoking history (target population), and patients who did not have BAC or had a smoking history (nontarget population). Efficacy was assessed in these 2 populations, and tissue was analyzed for mutations and/or amplifications. Of the 131 patients in this trial, 56% were female, and the median age was 66 years; 20% had BAC and 71% did not have BAC. The majority (70%) were current or former smokers and were previously untreated (99%). There were 56 patients in the target population and 75 in the nontarget population. There were no CRs in either population. In the target population, there was 1 (2%) PR and 14 (25%) patients had SD _>24 weeks. In the nontarget population, there was 1 (1%) PR and 28 (37%) patients had SD _>24 weeks. There were no responses in patients with ErbB1 mutations or those who harbored EGFR copy increases. There were no mutations in HER2, and 2 tumors harbored HER2 copy number increases. With a median treatment duration of 9.1 weeks, there were no notable differences in efficacy or toxicity in the once-daily versus the twice-daily regimen.

In this study, lapatinib's dual inhibition of EGFR and HER2 did not appear to be associated with any benefits in NSCLC. The prevalence of mutations in EGFR and HER2 in this population was lower than

has been reported in larger trials; therefore, it is not possible to determine lapatinib's activity in patients with these mutations.

Malignant Tumors of the Salivary Glands Agulnik et a148 evaluated patients with progressive,

recurrent, or metastatic adenoid cystic carcinoma (ACC) and non-ACC malignant salivary gland tumors in a multicenter, open-label, Phase II trial of oral lapatinib 1500 mg QD. There were no objective responses among the 36 evaluable patients, although SD >6 months was documented in 13 (36%) patients. Before initiating therapy, these patients had a mean TTP of 3 months. Over a median follow-up of 15.8 months, PFS was 3.4 months.

Results from correlative studies of EGFR or ErbB2 expression in this trial suggested greater therapeutic effect in patients with non-ACC when there was a high degree of marker expression, 48 but this requires further testing. Although there were no objective responses documented in the previous study, stabiliza- tion of disease in a group of patients with progressive disease at enrollment is clinically relevant, supporting the cytostatic activity of lapatinib in patients with malignant salivary gland tumors.

Biliary Tree and Hepatocellular Cancer Ramanathan et a149 presented the findings of a

multicenter, open-label, Phase II trial of oral lapatinib 1500 mg QD given continuously in patients with advanced biliary tree cancer (BTC) or hepatocellular carcinoma (HCC). This study, which employed a 2-stage design allowing for early termination at the first stage if treatment was not effective, enrolled 17 patients with BTC (5 gallbladder, 9 intrahepatic, and 3 extrahepatic tumors) and 37 patients with HCC. The median age of the population was 62 years, and the majority of patients were male (63%) and white (68 %), with an ECOG performance status of 0 (46%), 1 (42%), or 2 (12%). Patients had Child-Pugh class A hepatic impairment, and 65% and 43% of BTC and HCC patients, respectively, had received 1 previous drug therapy. Only 1 stage of BTC patients was ac- crued, as there were no PRs, and 5 (29%) patients had SD. In patients with BTC, PFS was 1.8 months (95% CI, 1.7-5.2), with an OS of 5.2 months. Among patients with HCC, there were 2 (5%) PRs and 13 (35%) patients with SD, which was associated with a median PFS of 2.3 months (95% CI, 1.7-5.6) and a

August 2008 1439


median OS of 6.2 months. Of the 2 PRs, 1 patient had received no previous therapy and 1 had received trans- catheter arterial chemoembolization. Skin rash of any grade occurred in 20 patients receiving lapatinib. Skin rash may have been correlated with efficacy, as the probability of PFS and OS was significantly correlated with the occurrence of rash, similar to reports from other trials involving EGFR inhibitors. 62 Pa- tients with rash had a PFS of 5 months, compared with 2 months in patients with no rash (P = 0.03); similarly, rash was associated with OS of 10 months, compared with 5 months in patients without rash (P = 0.004).

Although lapatinib was inactive in these patients with BTC and did not the meet study definition of a response in patients with HCC, its activity in HCC may be promising. However, evaluation of lapatinib in HCC is limited by the lack of available molecular markers that may be correlated with activity.

Squamous Cell Carcinoma of the Head and Neck Because EGFR inhibitors have reported activity in

patients with recurrent and metastatic squamous cell carcinoma of the head and neck, Abidoye et al 5° evaluated the effects of oral lapatinib 1500 nag QD in 2 groups, patients without previous exposure to an EGFR inhibitor (arm A) and patients with previous exposure (arm B). In the 42 evaluable patients, no objective responses were observed in either cohort. In an intent-to-treat analysis, SD was observed in 37% of patients in arm A and 20% of patients in arm B. Lapatinib appeared to have little clinical activity as a single agent in patients with squamous cell carcinoma of the head and neck who were EGFR-inhibitor naive or who had refractory disease.

Hormone-Sensitive Prostate Cancer In a multicenter, open-label, Phase II trial presented

by Sridhar et al, 51 23 patients with hormone-sensitive prostate cancer who had received no previous hormonal therapy, corticosteroid therapy, or chemotherapy were treated with oral lapatinib 1500 nag QD. Patients had a median age of 67 years and a median baseline prostate-specific antigen (PSA) level of 7.5 ng/mL; 96% had an ECOG performance status of 0. There were no PSA responses in the 17 patients who had completed treatment at the time of reporting; the median TTP was 4.6 months, with a 6-month PFS estimate of 49%. Although only preliminary data

were reported, lapatinib monotherapy did not appear to be effective in these patients with hormone-sensitive prostate cancer.

Gastric Cancer Iqbal et a152 presented the results of an open-label,

Phase II trial of oral lapatinib 1500 nag QD as first- line therapy in 46 patients with advanced or metastatic gastric cancer. Men accounted for 65% of ac- crued patients, and the median age was 68.7 years. There were 3 (7%) confirmed PRs and 2 (4%) uncon- firmed PRs; 9 (20%) patients had SD. The median TTP was 2 months, with an OS of 5 months. Given this modest activity in patients with gastric cancer, further investigation of combination regimens that include lapatinib is warranted.

Colorectal Cancer In a multicenter, open-label, Phase II trial in 86 pa-

tients with metastatic colorectal cancer that had progressed with first-line therapy consisting of 5-fluorouracil in combination with irinotecan or oxaliplatin, 53 patients received oral lapatinib 1250 mg QD as monotherapy. Tumor response (RECIST) was assessed by an independent review committee. ErbB expression was not required; however, 54.2% and 44.1% of patients had positive expression (1+, 2+, or 3+) of ErbB1 and ErbB2, respectively. Lapatinib had limited activity in this patient population, with a PR in 1 (1%) patient and minor responses in 5 other patients at week 8. The median TTP and OS were 8.0 and 42.9 weeks, respectively. Although overexpression of ErbB1 and ErbB2 was present, lapatinib had little activity in these patients with metastatic colorectal cancer, and there are no ongoing trials of lapatinib monotherapy or combination therapy for this indication.

Transitional Cell Carcinoma of the Urothelium In a European multicenter, open-label, Phase II

trial of second-line treatment with oral lapatinib 1250 nag QD in 59 patients with advanced or metastatic transitional cell carcinoma of the urothelial tract, 54 independent radiologic review found 1 (2%) confirmed PR and 18 (31%) patients with SD. Of the patients with SD, 6 and 3 had durable responses of 4 and 6 months, respectively. The median TTP was 8.6 weeks, and the median OS was 17.9 weeks. A clinical benefit (CR, PR, + SD for >16 weeks) of 12% was reported.



The TTP with lapatinib in this trial was similar to that associated with other second-line therapies. Fu- ture studies of lapatinib should include only patients with ErbB1 or ErbB2 overexpression and should ex- amine lapatinib in combination with other novel agents for the treatment of transitional cell carcinoma of the urothelium.

Advanced Renal Cell Carcinoma A European multicenter, randomized, open-label,

Phase III trial evaluated lapatinib in patients with advanced renal cell carcinoma that expressed EGFR and/or ErbB2. 55 Four hundred sixteen patients whose disease had progressed or had not responded to first- line cytokine therapy were randomized to receive either oral lapatinib 1250 mg QD or hormonal therapy (tamoxifen or megestrol acetate). Patients were strati- fied by Karnofsky performance status and number of metastatic sites. The groups were well balanced at baseline in terms of relevant prognostic factors, EGFR expression, and predominant site of metastatic disease (the lung). The results of the trial were negative for the primary end point of TTP in the overall population. There was no significant difference between lapatinib and hormone therapy in median TTP (15.3 and 15.4 weeks, respectively) or median OS (46.9 and 43.1 weeks). However, an exploratory biomarker analysis evaluated the correlation between response and EGFR status by IHC. On independent pathologist review, overexpression of ErbB1 that had moderate to strong complete membrane staining in >10% of tumor cells was scored 3+. In the subgroup of 241 patients with 3+ overexpression of ErbB1 by IHC, the median TTP was numerically increased in lapatinib recipients but did not reach statistical significance compared with hormonal therapy (15.1 vs 10.9 weeks). However, the median OS was significantly improved (46.0 vs 37.9 weeks; P = 0.02). This improved OS in patients with ErbB1 3+ tumors was validated by ret- rospective Cox regression analysis.

At the time this comparative trial of lapatinib and hormone therapy was initiated, there were limited treatment options for this patient population that had experienced disease progression while receiving cytokine therapy. However, studies are needed to com- pare lapatinib with current standard therapy, including sunitinib, sorafenib, and temsirolimus, to better define its role, if any, in patients with metastatic renal cell carcinoma.

Special Populations Pediatric Patients

Only 1 pharmacokinetic trial of lapatinib was identified that included children or adolescents. Thirty-four pediatric patients with refractory or recurrent CNS tumors were treated with lapatinib at doses ranging from 300 t o 1150 mg/m-). -)6 Response rates were not reported, and further study is needed in this population.

Elderly Patients Although no studies were identified that specifi-

cally enrolled elderly patients, 17% of patients in clinical trials of lapatinib + capecitabine in MBC were aged _>65 years, and 1% were aged _>75 years. 37 The effectiveness and tolerability of lapatinib did not appear to be affected by age, although increased sensitivity in some older individuals cannot be ruled out. s

Organ Dysfunction A review of the literature found no pharmacoki-

netic studies in patients with renal impairment or in those undergoing hemodialysis. However, because <2% of a lapatinib dose is eliminated by the kidneys, renal impairment is not likely to affect the clearance of lapatinib, s

In a small study in subjects with moderate or severe hepatic impairment (Child-Pugh classes B and C, respectively), systemic exposure (AUC) after a single oral dose of lapatinib 100 mg increased -14% and 63%, respectively, compared with healthy control subjects, s Therefore, increased lapatinib exposure may occur in patients with severe hepatic impairment. Dose reduction to 750 mg/d should be considered; this is predicted to adjust the AUC to within the normal range, although there are no clinical data to support this adjustment in patients with severe hepatic impairmenc 8

Pregnancy and Breastfeeding In rat and rabbit studies, malformations occurred

in rats exposed to lapatinib, and maternal toxicities and abortions occurred in rabbits, s Consequently, lapatinib is classified as pregnancy category D. Women should be advised not to become pregnant when taking lapatinib, and its use is not advised in pregnant or lactating women. 8

ADVERSE EVENTS Similar to other EGFR small-molecule TK inhibitors, lapatinib is well tolerated. The most common clinical

August 2008 1441


toxicities of all grades associated with lapatinib used in combination with capecitabine in the pivotal clinical trial were diarrhea (65%), hand-foot syndrome (53 %), nausea (44%), rash (29%), and fatigue (24%).39 In this trial, rates of discontinuation as a result of adverse events were 14% each in the combination and monotherapy groups, and dose interruptions and ad- justments due to adverse events were also similar between groups. In an analysis of the quality-adjusted time without symptoms or toxicity in the pivotal Phase III trial of lapatinib + capecitabine in MBC, 37 the longer TTP with combination therapy versus monotherapy (8.4 vs 4.4 months, respectively; HR = 0.49; 95% CI, 0.34-0.71; P < 0.001) was achieved without an increase in the time with serious adverse events, resulting in greater quality-adjusted survival. 63 Diar- rhea occurred in 65% of patients in the combination group, compared with 34% of patients receiving capecitabine alone. Rash occurred more frequently in the combination-therapy group than in the monotherapy group (29% vs 14%, respectively); however, the differences in both diarrhea and rash were the result of increases in grade 1 adverse events. > Grade 3 diarrhea occurred in 13% of the combination group and 10% of the capecitabine group, and grade 3 rash occurred in 2% and 1% of the respective groups.

Diarrhea in patients receiving lapatinib may be dose and schedule related. In a pooled analysis of diarrhea events in 9 completed Phase I, II, and III clinical trials in which lapatinib was administered at doses ranging from 1000 to 1500 mg QD as monotherapy or in combination with capecitabine or taxanes, Crown et a164 found that grade 3 diarrhea occurred in 10% to 17% of patients in trials of lapatinib 1500 mg QD, whereas 21% of patients reported diarrhea of grade 3 or higher with lapatinib 750 mg BID. In a trial of lapatinib 1500 mg QD + paclitaxel, 2s grade 3 diarrhea occurred in 18% of patients. Crown et al reported that diarrhea occurred in 55% of the 1417 lapatinib- treated patients and 24% of the 676 patients not treated with lapatinib. Diarrhea events with lapatinib were predominantly of grade 1 or 2 severity. There were no fatal lapatinib-related diarrhea events in any of the studies. Lapatinib-related diarrhea appeared to be an early event, occurring before day 6 in 42% of lapatinib recipients; among those not treated with lapatinib, the largest proportion of first diarrhea events (38 %) occurred after 28 days. The median duration of diarrhea with lapatinib was 5 days, with 85% of pa-

tients requiring no dose adjustment or interruption and only 2% discontinuing therapy due to diarrhea. The authors concluded that severe diarrhea did not occur with lapatinib-containing regimens when proac- tive monitoring and appropriate intervention were employed.

Dermatologic events, although of a low grade, are another frequently reported adverse event associated with lapatinib. Lacouture et a165 performed a review of dermatologic events occurring in 1419 patients enrolled in 9 clinical trials of lapatinib. A dermatologic event was defined as hand-foot syndrome (pal- mar plantar erythrodysesthesia), rash, hair disorder, dry skin, pruritus/urticaria, skin disorder, skin infec- tion, and nail disorder. In patients receiving lapatinib monotherapy, 55% experienced grade 1 or 2 dermatologic events; no grade 4 events were observed. Rash was the most common dermatologic event (43%) across all studies. Dermatologic events typically developed early (within days 1-14), lasted a median of 29 days, and did not require any intervention or lapatinib dose reduction, interruption, or discontinuation.

Because of the cardiac toxicity associated with trastuzumab, 66 which also targets HER2, there was initial concern about potential cardiotoxicity with lapatinib. However, in the pivotal Phase III trial in MBC in patients who had previously received trastuzumab, 37 there were no reported differences in mean left ven- tricular ejection fraction (LVEF) between the 2 treatment groups. To further analyze the cardiotoxicity potential of lapatinib, Perez et a167 analyzed data from 44 studies involving 3689 patients enrolled in Phase I-III trials of lapatinib monotherapy and combination therapy in breast cancer and other solid tumors. Car- diotoxicity was evaluated based on symptomatic events, defined as either grade 3 or 4 according to the National Cancer Institute Common Toxicity Criteria (NCI CTCAE) or asymptomatic decreases in LVEF >20% from baseline or below the institutional normal. A cardiac event was reported in 1.6% (n = 60) of patients; the event was not preceded by symptoms in 53 of these 60 patients. The decrease in LVEF resolved or improved in 88% (n = 35) of the 40 patients for whom the outcome was determined. The mean (standard deviation) absolute decrease in LVEF from baseline in all patients was 18.8% (5.2%). The mean time of the onset of LVEF decrease was 13 weeks, and the decrease was rarely severe (0.2%). Finally, unlike trastuzumab, there was no significant association of the



IIe655Val polymorphism and decreased LVEF with lapatinib. Because many patients who received lapatinib had not received previous cardiotoxic agents such as trastuzumab or an anthracycline (n = 2311), it was difficult to evaluate additive effects. The 1.3% reduction in LVEF with lapatinib was less than that associated with trastuzumab (3%-34%). 66 However, further studies are required to determine whether cardiac toxicity differs between these 2 agents.

To assess the cardiac tolerability of the combination of lapatinib + trastuzumab, Storniolo et a168 analyzed data from 4 trials involving 238 patients with HER2-positive MBC, 203 who received the combination of lapatinib + trastuzumab and 35 who received the combination with a taxane. Cardiac tolerability was assessed in a manner similar to that in the study by Perez et al. 67 No patient had a symptomatic cardiac event, 1.7% (n = 4) had a single asymptomatic decrease in LVEF, and 0.4% (n = 1) had 2 asymptomatic decreases. Two patients with a decrease in LVEF had received previous anthracyclines, and 2 patients had received previous anthracyclines and trastuzumab. These preliminary data indicated no incremental risk of cardiac toxicity with the combination of lapatinib + trastuzumab, although further studies of the cardiac tolerability of this combination are needed.

DOSING A N D A D M I N I S T R A T I O N Lapatinib is available in 250-mg tablets. The recommended oral lapatinib dose for patients with MBC whose tumors overexpresss HER2 (ErbB2) and who have received previous therapy including an anthracycline, a taxane, and trastuzumab is 1250 mg QD on days 1 to 21 in combination with capecitabine 2000 mg/m e daily administered in 2 divided doses on days 1 to 14 in a repeated 21-day cycle, s Treatment should be continued until disease progression or the occurrence of intolerable adverse effects. Lapatinib is to be taken as a single dose at least 1 hour before or after a meal. Dose adjustment of lapatinib is recommended based on tolerability and should be considered in patients receiving strong CYP3A4 inhibitors or inducers, s

Lapatinib should be discontinued in patients with an LVEF decrease of grade 2 or greater (NCI CTCAE) or whose LVEF decreases below the institution's lower limit of normal. Therapy may be restarted at 1000 mg QD after at least 2 weeks if the LVEF has returned to normal and the patient is asymptomatic, s

Based on lapatinib's route of metabolism and elimination, no dose adjustment is recommended in patients with renal insufficiency. However, dose adjustment is recommended in patients with severe hepatic impairment (Child-Pugh class C). A dose reduction to 750 mg/d in patients with severe hepatic impairment is predicted to adjust the AUC to within the normal range, s although there are no clinical data to support adjustment.

P H A R M A C O E C O N O M I C C O N S I D E R A T I O N S A literature search found no pharmacoeconomic analyses of lapatinib in the treatment of MBC. The average wholesale price for a month of lapatinib therapy is $3625, 69 and the manufacturer has an assistance program for uninsured and underinsured patients. 7°

C O N C L U S I O N S Lapatinib is a dual inhibitor of EGFR and HER2 that has proven activity in HER2-positive MBC. It has in vitro and in vivo activity as a single agent or as part of combination regimens in trastuzumab-resistant tumor models; in MBC that has progressed during treatment with trastuzumab; and in the first-line treatment of MBC. In Phase II trials in MBC, response rates ranged from 4.3% to 7.7% in trastuzumab-pretreated patients and were 24% in the first-line setting. Pre- liminary data suggest activity in other types of breast cancer, including IBC and breast cancer with CNS metastases. Phase III data from patients whose disease had progressed on an anthracycline, a taxane, and trastuzumab indicated a better response to the combination of lapatinib + capecitabine than to capecitabine alone (22% vs 14%, respectively; P = NS). The combination also was associated with significant 43 % and 45% risk reductions in TTP and PFS, respectively. No statistical difference in OS was seen in that trial.

The most common adverse events associated with use of lapatinib as a single agent were diarrhea, rash, nausea, hand-foot syndrome, and fatigue. These effects were generally mild, with few grade 3/4 toxicities. Lapatinib administered in combination with capecitabine was associated with grade 3/4 diarrhea (14%) and grade 3 rash (2%).

Although lapatanib has been associated with significant activity only in HER2-positive breast cancer, it has reported activity in other tumor types. No significant clinical activity as an EGFR inhibitor has been found, as the response in other tumors overex-

August 2008 1443


pressing EGFR has been limited. In advanced renal cell cancer, a Phase III trial of lapatinib monotherapy reported improved activity relative to hormonal therapy in the subgroup of patients whose tumors overexpressed ErbB1, although hormonal therapy would not be considered an appropriate comparative regimen as the standard of care for renal cell carcinoma in the second- line setting. Preliminary data from Phase I/lI trials in other tumor types are mixed, and trials are ongoing.

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Address correspondence to: Susan Goodin, PharmD, FCCP, BCOP, Director, Division of Pharmaceutical Sciences, The Cancer Institute of New Jersey, 195 Little Albany Street, Room 2040, New Brunswick, NJ 08901. E-mail: [email protected]

August 2008 1447

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