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Originally published as JCO Early Release 10.1200/JCO.2005.16.584 on June 13 2005 © 2005 American Society of Clinical Oncology. Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas
From the Sarah Cannon Research Institute, Nashville, TN; Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill; Duke University Medical Center, Durham; GlaxoSmithKline Inc, Research Triangle Park, NC; and Case Western Reserve University, Cleveland, OH Address reprint requests to Howard A. Burris III, The Sarah Cannon Research Institute, 250 25th Avenue N, Suite 110, Nashville, TN 37203; e-mail: hburris{at}tnonc.com.
PURPOSE: This study (EGF10004 assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.
RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer—two of whom were classified as having inflammatory breast cancer—had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.
In humans, the ErbB family of transmembrane tyrosine kinase receptors consists of four members: ErbB1 (epidermal growth factor receptor [EGFR]), ErbB2, ErbB3, and ErbB4.1,2 Expression of ErbB1 and/or overexpression of ErbB2 occur to varying degrees in epithelial malignancies, where they promote tumor cell growth/survival, and in certain tumors predict for a poor clinical outcome.3-6 Upon ligand binding, ErbB receptors form hetero- or homodimers resulting in the autophosphorylation of specific tyrosine residues within the conserved catalytic kinase domains of ErbB receptors.1,7 These phosphorylated tyrosine residues serve as docking sites for Src-homology 2 and phosphotyrosine-binding domain–containing proteins that link activated ErbB receptors to downstream cell proliferation (mitogen-activated protein kinase [MAPK]) and survival (phosphotidylinositol-3-kinase [PI3K]) pathways.1,2,7-12 The established role of ErbB1 and ErbB2 in promoting the growth and survival of various types of solid tumors makes them attractive therapeutic targets. Monoclonal antibodies such as cetuximab and trastuzumab targeting ErbB1 and ErbB2, respectively, as well as small-molecule tyrosine kinase inhibitors of ErbB1 (eg, gefitinib and erlotinib) have been shown to inhibit proliferation of ErbB1- or ErbB2-expressing cancer cells.13-17 Moreover, clinical studies have demonstrated the activity of these ErbB-targeted agents in patients with advanced stage malignancies.18-22 Lapatinib (GW572016) is an orally active small molecule that reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, leading to inhibition of MAPK and PI3K signaling in ErbB1-expressing and ErbB2-overexpressing tumor cell lines and xenografts.23,24 Lapatinib-treated tumor cells undergo apoptosis or growth arrest depending upon the cell type.23,24 ErbB2, the only member of the ErbB family without an exogenous ligand, is the preferred heterodimer partner for other ErbB receptors where it amplifies the biologic signal.1,7 Since ErbB2-containing heterodimers exert potent growth and survival effects, simultaneous inhibition of ErbB2 and ErbB1 is an appealing therapeutic strategy. In phase I studies in healthy volunteers, lapatinib was well tolerated at repeat doses up to the highest dose administered (175 mg/d).25 In the first phase I dose escalation study in cancer patients (EGF10003, lapatinib was well tolerated at doses up to the highest dose administered (1,800 mg once daily) with mild and transient diarrhea, nausea, rash, fatigue, anorexia, and vomiting as the predominant toxicities.26 Clinical activity was observed at doses of 650 mg/day and higher.26 Pharmacokinetic data from these studies indicated that serum lapatinib concentrations peak 4 hours after dosing, increase with increasing dose, accumulate approximately two-fold with daily dosing, and achieve steady state in 6 to 7 days, suggesting an effective half-life of 24 hours. This study (EGF10004 was designed to (1) assess the safety and tolerability of lapatinib after multiple dosing; (2) assess the pharmacokinetics of lapatinib; (3) evaluate the biologic effects of lapatinib in serial tumor biopsies; (4) determine a biologically active dose range for lapatinib; and (5) assess the clinical activity of lapatinib. The biologic effects of lapatinib on signaling pathways in tumor tissue obtained from a subset of 33 patients participating in this study who had sequential biopsies were recently reported.27 The safety/tolerability, pharmacokinetics, and clinical activity of lapatinib are reported here.
Eligibility Criteria Patients enrolled in this study were males or females age 18 years or older with a histologically-confirmed diagnosis of cancer; had an archived or fresh biopsy that demonstrated expression of ErbB1 (positive by immunohistochemistry [IHC]) and/or overexpression of ErbB2 (2+ or 3+ by IHC) or that displayed gene amplification of ErbB2 by fluorescence in situ hybridization; had a Karnofsky performance status  70%; had a life expectancy of at least 12 weeks; had a hemoglobin concentration 9 g/dL (5 mmol/L), an absolute granulocyte count 1,500/mm3 (1.5 x 109/L), a platelet count 100,000/mm3 (100 x 109/L); and were able to swallow and retain oral medication. Patients were excluded from the study if they were pregnant or lactating females; had malabsorption syndrome; received any chemotherapy within the previous 4 weeks or treatment with nitrosourea or mitomycin within the previous 6 weeks; received biologic, hormonal, or radiation therapy within the previous 4 weeks; were taking steroids; had a total bilirubin > 2 mg/dL; had AST or ALT > 3x the upper limit of normal; had a class III or IV heart failure as defined by the New York Heart Association functional classification system; or had a left ventricular ejection fraction (LVEF) < 40%. All patients provided a signed informed consent. The study protocol was approved by institutional review boards at the following institutions: TriStar Nashville Market, Nashville, TN; Duke University Health System, Durham; University of North Carolina School of Medicine, Chapel Hill, NC; and University Hospitals of Cleveland, Cleveland, OH. The study was conducted in accordance with the 1996 version of the Declaration of Helsinki.
Safety Assessments
Study Treatments
Pharmacokinetic Assessments
Evaluation of Clinical Activity
Patient Characteristics Sixty-seven patients were enrolled at four sites in the United States between March 2002 and May 2003. Patients were randomly assigned to one of five daily dose cohorts (500 mg [n = 13], 650 mg [n = 15], 900 mg [n = 11], 1,200 mg [n = 12], and 1,600 mg [n = 13]), with the later addition of a cohort at 1,000 mg daily (n = 3). Patient characteristics are shown in Table 1. The study population included patients with a variety of solid tumors, with breast cancer being the most common (n = 30). The patient population was heavily pretreated, with 66 patients (99%) having received previous chemotherapy. These patients received a median of five prior therapies with a range of one to 14.
Safety and Tolerability Forty-four (66%) of 67 patients experienced drug-related AEs. The most frequently reported drug-related AEs were diarrhea (42%) and rash (31%) (Table 2). Other drug-related AEs included nausea (13%) and fatigue (10%); all remaining drug-related AEs occurred with an incidence of 5% or less. Most drug-related AEs (135 of 140) were mild in intensity (grade 1 or 2). Five grade 3 AEs experienced by four patients were considered to be drug-related: one patient had grade 3 abdominal pain at the 650-mg dose level, one patient had grade 3 rash and grade 3 diarrhea at the 1,000-mg dose level that required a dose reduction to 500 mg; one patient had grade 3 diarrhea at the 1,200-mg dose level that required temporary interruption of lapatinib (the patient continued to experience grade 2 diarrhea at a reduced dose of 650 mg and was subsequently withdrawn); one patient who initially received 900 mg and subsequently received 1,600 mg lapatinib was withdrawn due to grade 3 gastroesophageal reflux disease. The gastrointestinal reflux was believed by the investigator to be related to the large pill burden. No grade 4 drug-related AEs were reported. No additional temporary treatment interruptions, dose-reductions, or withdrawals were associated with drug-related AEs.
Drug-related rash (rash, acne, dermatitis acneiform) was reported in 21 (31%) of 67 patients and was generally mild or moderate (grade 1 or 2) in intensity; only one grade 3 rash was reported (as described in the preceding paragraph). In most patients, the onset of rash occurred between days 2 and 66 and generally resolved without interrupting treatment. Five patients with one or more drug-related skin rash AEs received treatment with dermatologic medications without resolution. The rash remained unresolved at the time of study termination in three patients who did not receive dermatologic medications.
No significant drug-related reductions in LVEF or drug-related occurrences of interstitial pneumonitis were reported; one patient experienced an asymptomatic decrease in LVEF from 37% at baseline to 20% on day 140, which was reported to be related to underlying disease and cor pulmonale rather than lapatinib. The patient, who was granted a protocol exception at screening for LVEF Only one of 53 serious AEs (grade 2 diarrhea at the 650-mg dose level) was considered to be related to lapatinib. The remainder of the serious AEs were due to hospitalizations for events related to disease progression. There were seven deaths during the study, but none was considered drug-related.
Clinical Activity
Before discontinuing therapy, the protocol allowed investigator discretion for intrapatient dose escalation in patients who were assessed as having progressive disease. However, there was no instance in which this resulted in an objective clinical response. At the investigators' discretion, doses were increased after 1 to 3 months of treatment in four patients with SD who continued with SD for an additional 6 to 10 months.
Pharmacokinetics
Dose and Concentration Relationships With Response and Toxicity The frequency of clinical response, categorized as PR, SD > 6 months, or nonresponders, was examined in relation to drug exposure, in terms of dose, and steady-state AUC, Cmax, and Cmin. The relationship with dose (Fig 4) indicates that the majority of responders (PR and SD > 6 months) were receiving 1,200 mg daily (median dose in all responders). The relationship with Cmin (Fig 5), which demonstrated a right-skewed distribution, indicates that the majority of responders displayed a trough concentration in the 0.3 to 0.6 µg/mL range. The median dose in all patients, as well as responders only, which produced a Cmin in this range was 900 mg daily. Similar relationships were observed with AUC  and Cmax (data not shown).
Regression analysis suggested that the frequency of diarrhea was linearly related to dose (P < .03) over the 500 to 1,600 mg range. There was no apparent relationship of diarrhea to serum concentration. The incidence of rash showed no apparent relationship to dose or serum concentration, or to clinical response as described for other EGFR inhibitors. Figure 6 shows the incidence of clinical response in relation to lapatinib dose categorized by occurrence of rash. The number of responders (PR and SD > 6 months either alone or combined) was larger without rash compared to those with rash, demonstrating that rash is not an indicator of clinical response to lapatinib.
Lapatinib was well tolerated in this study at doses up to 1600 mg daily with clinical activity observed at doses ranging from 650 to 1,600 mg daily in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic solid tumors. At doses where clinical activity was observed, drug-related toxicity was primarily restricted to grade 1 and 2 diarrhea (42%) and skin rash (31%). No grade 4 toxicity was reported.
Four patients with advanced-stage breast cancer whose disease had progressed on prior trastuzumab and taxane- or anthracycline–based chemotherapy regimens, achieved a PR with lapatinib. All of these patients had tumors that overexpressed ErbB2, and with the one exception, co-expressed ErbB1.27 In addition, these four patients exhibited baseline expression of activated, phosphorylated ErbB2 that was increased compared with nonresponders (Fig 1).27 An additional 24 patients experienced disease stabilization. Twelve of 28 patients with either a PR or SD received lapatinib for Further evidence for the clinical activity of lapatinib in heavily pretreated patients with advanced solid tumors was presented in two studies.26,30 Minami et al30 reported that two patients had PR: one with breast cancer treated with lapatinib 1,600 mg once daily, and the other with squamous cell carcinoma of the lung treated with lapatinib 900 mg once daily. Twelve patients (NSCLC [n = 6], colorectal cancer [n = 3], breast cancer [n = 1], cervical cancer [n = 1], ovarian cancer [n = 1]) had SD and eight of 14 patients with clinical activity remained on lapatinib therapy for more than 3 months. Versola et al26 reported a CR in a patient with an ErbB1-overexpressing head and neck squamous cell carcinoma. Twenty-two patients with various tumors, most expressing either ErbB1 or ErbB2, experienced SD with a median duration of 4 months (range 1-13+ months).26 Together, these studies indicate the potential clinical activity of lapatinib in patients with a variety of solid tumors. The pharmacokinetics of lapatinib upon repeated dosing display a time-dependent increase in systemic exposure as described previously.25 For this reason, half-lives and areas under the curve (AUCs) after a single or first dose do not predict accumulation or steady-state concentration, which represents the therapeutically relevant systemic exposure for this chronic therapy. The pharmacokinetics of lapatinib in this study were, on average, similar, but exhibited greater variability than in previous studies of either healthy volunteers or cancer patients.25,31 This difference may be secondary to allowing consumption of food with the doses on days 2 through 19 or the effect of concurrent medications required by patients that could alter the absorption and/or metabolism of lapatinib. Absorption of lapatinib is restricted by low solubility and first-pass metabolism by CYP3A4/5, which likely contribute to the variability in systemic exposure. Transporters may also be involved, although lapatinib does not appear to be a substrate for P-glycoprotein (ABCB1). Clinical responses were generally associated with doses in the middle of the range examined in this study. In terms of either the administered dose or the resulting serum concentration, clinical response was more often associated with doses of 900 to 1,200 mg daily. However, due to the limited response data, it was not possible to adequately characterize the relationship between clinical response and drug exposure. In addition, there was no clear distinction between responders (PR and SD > 6 months) and nonresponders related to drug exposure, suggesting that the distinction between responders and nonresponders may lie in the inherent biologic profile of the tumor, specifically, which signaling pathways are operative, and which pathways are directly involved in regulating tumor cell growth and survival. If tumor cell survival is dependent upon pathways that can be abrogated by lapatinib, then those tumors might be more likely to respond to therapy. If tumors have developed mechanisms to evade apoptosis, and lapatinib exerts its anti-tumor effects through activation of apoptosis,23,24 then those tumors might be resistant to lapatinib therapy.27 Current efforts are focused on identifying a tumor profile that will predict for response to lapatinib therapy. There has been considerable discussion regarding whether skin rash is requisite to achieve clinical response with ErbB1 inhibitors. In this study, the incidence and severity of skin rash was not associated with clinical response (Fig 5) as reported for other small-molecule ErbB inhibitors (eg, gefitinib, erlotinib). This distinction, along with other differences in biochemical and biologic activity, may relate to the unique 4-anilinoquinazoline structure of lapatinib in contrast to either gefitinib or erlotinib, which are quinazolines.32 Lapatanib was well tolerated at doses ranging from 500 to 1,600 mg once daily with grade 1 and 2 diarrhea and rash as the most common drug-related toxicities. The association between diarrhea and dose but not concentration suggests that this toxicity evolves from a local effect on the gut epithelium. Similar and more severe toxicities have been reported in studies of other small-molecule ErbB1 tyrosine kinase inhibitors. In phase I studies of gefitinib and erlotinib, both reversible inhibitors of ErbB1, the most frequently reported AEs were nausea, vomiting, acneiform rash, and diarrhea in patients treated with gefitinib,33 and diarrhea, rash, nausea, headache, emesis, and fatigue in patients with treated with erlotinib.34 Dose-limiting toxicities of PKI166, a ErbB1 and ErbB2 tyrosine kinase inhibitor, included grade 3 transaminase elevations, skin rash, and diarrhea.35-37 Clinical studies of CI-1033, an irreversible pan-ErbB inhibitor, have shown that the most frequently reported AEs were grade 1 to 2 nausea, emesis, diarrhea, acneiform rash, stomatitis,38 and asthenia.39 In addition, reversible dose-limiting hypersensitivity reactions,38 grade 3 thrombocytopenia,40 and dose-limiting grade 3 stomatitis have also been reported with CI-1033.41 Treatment with trastuzumab has been reported to be associated with an increased incidence of reversible cardiomyopathy. However, it is not known whether this effect is specific to trastuzumab, or a class effect associated with ErbB2 inhibition.42,43 No evidence of drug-related cardiac dysfunction was observed in this study. Clinical activity was observed at lapatinib daily doses ranging from 500 to 1,600 mg, and most frequently at 900 to 1,200 mg, in heavily pretreated patients with metastatic carcinomas overexpressing ErbB2 and/or expressing ErbB1. Because drug exposure does not appear to distinguish between responders and nonresponders, identification of a tumor profile, based on biologic features, that predicts for response to lapatinib is currently being investigated.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C)
We thank the patients who participated in this study and their families. We thank Terry Paul for his assistance in the preparation of the manuscript, and Lini Pandite and Elaine Paul for their critical review of the manuscript. We also thank the staff at the study centers, in particular, Elizabeth Humes, Henry Bell, Roxanne Williams-Truax, Shawna Savage, Noel Willcutt, Sharon Calvert, and Leslie Kosco, for their diligence in identifying and caring for the patients who participated in the study.
Supported by a grant from GlaxoSmithKline. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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7. Olayioye MA, Graus-Porta D, Beerli RR, et al: ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 18:5042-5051, 1998 8. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-212, 1990[CrossRef][Medline]
9. Fukazawa T, Miyake S, Band V, et al: Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation and its association with EGF receptor and downstream signaling proteins. J Biol Chem 271:14554-14559, 1996 10. Hackel PO, Zwick E, Prenzel N, et al: Epidermal growth factor receptors: Critical mediators of multiple receptor pathways. Curr Opin Cell Biol 11:184-189, 1999[CrossRef][Medline] 11. Tzahar E, Waterman H, Chen X, et al: A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276-5287, 1996[Abstract]
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14. Moasser MM, Basso A, Averbuch SD, et al: The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184-7188, 2001
15. Hudziak RM, Lewis GD, Winget M, et al: A p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9:1165-1172, 1989
16. Moulder SL, Yakes FM, Muthuswamy SK, et al: Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 61:8887-8895, 2001
17. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000
18. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-Her2 monoclonal antibody in women who have Her2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 19. Mendelsohn J, Baselga J: The EGF receptor as targets for cancer therapy. Oncogene 19:6550-6565, 2000[CrossRef][Medline] 20. Hecht JR, Patnaik A, Malik I, et al: ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis. Proc Am Soc Clin Oncol 23:248, 2004 (abstr 3511)
21. Vanhoefer U, Tewes M, Rojo F, et al: Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 22:175-184, 2004 22. Trigo J, Hitt R, Koralewski P, et al: Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study, Proc Am Soc Clin Oncol 23:487, 2004 (abstr 5502) 23. Xia W, Mullin RJ, Keith BR, et al: Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255-6263, 2002[CrossRef][Medline]
24. Rusnak DW, Lackey K, Affleck K, et al: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW572016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85-94, 2001 25. Bence AK, Anderson EB, Doukas MA, et al: Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects. Invest New Drugs 23:39-49, 2005[CrossRef][Medline] 26. Versola M, Burris HA, Jones S, et al: Clinical activity of GW572016 in EGF10003 in patients with solid tumors. Proc Am Soc Clin Oncol 23: 2004 (abstr 3047)
27. Spector NL, Xia W, Burris H, III, et al: Study of the biological effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol 23:1-11, 2005 28. Hsieh S, Tobien T, Koch K, et al: Increasing throughput of parallel on-line extraction liquid chromatography/electrospray ionization tandem mass spectrometry system for GLP quantitative bioanalysis in drug development. Rapid Commun Mass Spectrom 18:285-292, 2004[CrossRef][Medline]
29. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 30. Minami H, Nakagawa K, Kawada K, et al: A phase I study of GW572016 in patients with solid tumors. Proc Am Soc Clin Oncol 22:14S, 2004 (abstr 3048) 31. Koch KM, Lee D, Jones S, et al: Pharmacokinetics of GW572016 in an ascending dose tolerability study of phase I cancer patients. Eur J Cancer 1:S169, 2003 (poster 559)
32. Wood ER, Truesdale AT, McDonald OB, et al: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): Relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652-6659, 2004
33. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected tumor types. J Clin Oncol 20:4292-4302, 2002
34. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI- 774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 35. Hoekstra R, Dumez H, van Oosterom AT, et al: A phase I and pharmacological study of PKI166, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally in a two weeks on, two weeks off scheme to patients with advanced cancer. Proc Am Soc Clin Oncol 21, 2002 (abstr 340) 36. Dumez H, Hoekstra R, Eskens F, et al: A phase I and pharmacological study of PKI166, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, administered orally 3 times a week to patients with advanced cancer. Proc Am Soc Clin Oncol 21, 2002 (abstr 341) 37. Murren JR, Papadimitrakopoulou VA, Sizer KC, et al: A phase I dose-escalating study to evaluate the biological activity and pharmacokinetics of PKI166, a novel tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 21, 2002 (abstr 377) 38. Garrison MA, Tolcher A, McCreery H, et al: A phase I and pharmacokinetic study of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, given orally on days 1, 8, and 15 every 28 days to patients with solid tumors. Proc Am Soc Clin Oncol 20:72a, 2001 (abstr 283) 39. Nemunaitis JJ, Eiseman C, Cunningham C, et al: A phase I trial of CI-1033, a pan-erbB tyrosine kinase inhibitor, given daily for 14 days every 3 weeks, in patients with solid advanced tumors. Proc Am Soc Clin Oncol 22:243, 2003 (abstr 974) 40. Rinehart JJ, Wilding G, Willson J, et al: A phase I clinical and pharmacokinetic study of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 21:11a, 2002 (abstr 41) 41. Shin DM, Nemunaitis JJ, Zinner RG, et al: A phase I biomarker study of CI-1033, a novel pan-erbB tyrosine kinase inhibitor in patients with solid tumors. Proc Am Soc Clin Oncol 20:82a, 2001 (abstr 324)
42. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002 43. Suter TM, Cook-Burns N, Barton C: Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 13:173-183, 2004[CrossRef][Medline] Submitted February 22, 2005; accepted April 25, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40%, continued treatment without interruption until disease progression. The LVEF value returned to near baseline by the time of study termination. Few changes in clinical laboratory values were reported as AEs during the study, and most of these laboratory changes were not related to lapatinib. Three patients had grade 1 anemia at the 500-, 900-, and 1,600-mg dose levels that was considered to be drug-related. Grade 1 anemia resolved on the same day as onset in one patient (900 mg), 5 days after onset in the second patient (500 mg), and remained unresolved in the third patient (1,600 mg). No clinically significant changes in vital sign measurements or ECG results were observed at any dose level, and no patient had ophthalmologic abnormalities. 
