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Originally published as JCO Early Release 10.1200/JCO.2007.14.0590 on May 5 2008 © 2008 American Society of Clinical Oncology. Efficacy and Safety of Lapatinib As First-Line Therapy for ErbB2-Amplified Locally Advanced or Metastatic Breast Cancer
From the Instituto Nacional de Enfermedades Neoplásicas; Oncology, Hospital Alberto Sabogal, Lima, Peru; Rajiv Gandhi Cancer Institute and Research Centre, New Delhi; Jehangir Hospital and Medical Centre, Pune, India; National Cancer Centre, Singapore; Allama Iqbal Medical College, Lahore, Pakistan; University Malaya Medical Centre, Kuala Lumpur, Malaysia; University of Hong Kong and Queen Mary Hospital, Pokfulam, Hong Kong; Memorial Cancer Institute, Hollywood, FL; Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA; and Indiana University School of Medicine, Indianapolis, IN Corresponding author: Henry L. Gomez, MD, Instituto Nacional de Enfermedades, Neoplásicas, Avenida Angamos, Este 2520, Lima 34, Peru; e-mail: hgomez{at}inen.sld.pe
Purpose This study (EGF20009) assessed the efficacy and tolerability of two lapatinib administration schedules as first-line monotherapy in women with ErbB2-amplified locally advanced or metastatic breast cancer. Patients and Methods Patients with ErbB2-amplified, locally advanced or metastatic breast cancer previously untreated in the metastatic setting were randomly assigned to one of two lapatinib dose cohorts and received either 1,500 mg once daily or 500 mg twice daily. Clinical response was assessed at weeks 8 and 12 and every 12 weeks thereafter.
Results A total of 138 patients were treated with lapatinib for a median of 17.6 weeks. The overall response rate (complete response [CR] plus partial response [PR]) was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (CR, PR, or stable disease for Conclusion Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.
Breast cancer is the most frequently reported malignancy among women and is the primary cause of cancer mortality in women worldwide.1 The epidermal growth factor receptors ErbB1 and ErbB2 (also known as HER-1 and HER-2/neu) have both been shown to be overexpressed in approximately 25% of primary breast cancers.2-5 This overexpression is associated with poor prognosis,2-7 which is suggestive of an important role in tumor development and progression. The ErbB family of receptor tyrosine kinases dimerize on ligand binding, activating intracellular cascades that promote cellular survival and proliferation.8-10 Inhibition of ErbB1 using the small molecule gefitinib did not demonstrate significant clinical benefit for metastatic breast cancer in a study of predominantly ErbB1-positive patients.11 However, because an increased ErbB1 could cause resistance to ErbB2 inhibitors, it may be clinically advantageous to inhibit both ErbB1 and ErbB2 simultaneously in patients overexpressing ErbB2. Trastuzumab, a monoclonal antibody directed against the extracellular domain of ErbB2,12 has shown clinical benefit for women with metastatic and early-stage ErbB2-overexpressing breast cancer.13-18 Preclinical studies have shown that combined gefitinib/trastuzumab therapy causes greater apoptosis in breast cancer cell lines than either drug alone, suggesting that combined ErbB1 and ErbB2 inhibition could be clinically beneficial.19 Lapatinib (Tykerb/Tyverb; GlaxoSmithKline, Brentford, United Kingdom) is an oral, selective, reversible small-molecule dual tyrosine kinase inhibitor of both the ErbB1 and ErbB2 signaling pathways. In vitro studies have confirmed that lapatinib treatment inhibits growth20,21 and can lead to cell arrest or apoptosis20-22 in human tumor cells overexpressing ErbB1 or ErbB2. Furthermore, lapatinib treatment has been shown to inhibit the growth of ErbB2-overexpressing human breast cancer cells that do not respond to trastuzumab after long-term conditioning.22 It also reduced the volume of ErbB2-overexpressing human breast cancer xenografts in vivo.20,22 Promising evidence of clinical activity was demonstrated in a phase I study of lapatinib in advanced refractory solid tumors that expressed ErbB1 and/or overexpressed ErbB2.23 Pharmacokinetic data suggested that in vitro 90% inhibitory concentration for tumor cell growth would be exceeded by trough serum concentrations at 500 mg twice daily but not at 1,500 mg once daily. However, animal xenograft data suggested that intratumoral concentrations would exceed 90% inhibitory concentration after either regimen.24 Therefore, it was important to compare these dosing regimens for efficacy and safety. Previous investigations of lapatinib monotherapy were conducted in highly refractory metastatic breast cancer patients and showed modest cytoreduction and disease stabilization in a trastuzumab-refractory setting.25 Recently, lapatinib in combination with capecitabine was shown to be superior to capecitabine monotherapy for the treatment of women with ErbB2-positive advanced breast cancer who had experienced progression after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.26,27 These data support further investigation of lapatinib as first-line treatment for metastatic breast cancer. This trial was a randomized, open-label, parallel-group, multicenter study comparing the efficacy and tolerability of two lapatinib administration schedules, 1,500 mg once daily and 500 mg twice daily, as first-line treatment for ErbB2-amplified locally advanced or metastatic breast cancer patients.
Patient Eligibility Patients eligible for enrollment were women  18 years of age with a life expectancy of 12 weeks who had histologically confirmed stage IIIB, IIIC, or IV breast cancer at primary diagnosis or at relapse after curative-intent surgery. Patients were required to have measurable disease according to Response Evaluation Criteria in Solid Tumors,28 with the criteria modified to include lesions that were 15 to 19 mm in diameter to accommodate smaller ( 7 mm) spiral computed tomography construction intervals. Eligible patients consented to receiving lapatinib before other therapies (including trastuzumab where available) after being informed of their treatment options. Amplification of ErbB2 was documented by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue. Local laboratory results were used to determine eligibility, where available, and samples were also tested centrally. Patients were required to have a cardiac ejection fraction within the institutional range of normal as measured by echocardiogram or multigated acquisition scan. Patients with CNS metastases were eligible if they were clinically stable for 3 months after discontinuation of corticosteroid and anticonvulsant therapy. Patients were permitted to have received prior neoadjuvant or adjuvant therapy, provided it was discontinued 24 weeks before study entry. Prior adjuvant trastuzumab use was also permitted, provided it was discontinued 12 months before study entry. Patients were permitted to have received prior radiotherapy if the area treated was not the sole site of measurable disease and all radiotherapy-related toxicities had resolved before starting the study. Patients were excluded if they had received prior chemotherapy, immunotherapy, biologic therapy, or anti–ErbB1/ErbB2 therapy as primary treatment for their advanced or metastatic breast cancer. Surgery and/or hormonal therapy (eg, tamoxifen, raloxifene, or an aromatase inhibitor) within 4 weeks of starting study treatment were also prohibited. Patients were excluded if they had any of the following: inadequate renal or hepatic function; bilateral breast cancer; bone metastases as the only disease site; metastases to more than 30% of the hepatic parenchyma; active CNS metastases; a known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; a malabsorption syndrome; or any other concurrent medical condition that would preclude participation. Pregnant women and nursing mothers were also excluded, and women of childbearing potential were required to have a negative serum pregnancy test. Ethics approval was obtained from the relevant local ethics committees, and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided signed, informed consent before enrollment onto the study.
Study Treatments Patients received treatment until week 12, unless disease progression occurred or the patient withdrew from treatment for another reason. Patients benefiting clinically from lapatinib at week 12 (with a response assessment of complete response [CR], partial response [PR], or stable disease [SD]) were permitted to continue lapatinib until disease progression or withdrawal for another reason. Treatment delays lasting up to 2 weeks and dose reductions of 250 mg/d were permitted for the management of drug-related toxicity.
Safety Assessments
Evaluation of Clinical Activity
Statistical Analysis
Patient Population One hundred thirty-eight patients were recruited from 19 sites worldwide between July 2004 and January 2006; 69 patients were randomly allocated to each dose regimen. Patient groups were well balanced in terms of baseline demographics including disease stage, ER/PgR status, and prior anticancer therapy (Table 1). Local FISH results were available for 34 patients (25%); 104 patients (75%) were enrolled on the basis of central FISH results. Discordant FISH results were reported for three (9%) of 34 patients. No patients had received prior trastuzumab. Disease progression was the most common reason for lapatinib discontinuation (n = 97; 70%; Fig 1). Seven patients (5%) continued lapatinib at the time of analysis. Patients were treated for a median of 17.6 weeks (range, 1 to 92 weeks), and the treatment duration was similar between the treatment groups (1,500 mg once daily: median, 17.6 weeks; range, 1 to 70 weeks; 500 mg twice daily: median, 17.7 weeks; range, 2 to 92 weeks).
Clinical Activity The overall response rate (CR or PR) was 24% in the intent-to-treat population and was not significantly different between treatment groups (1,500 mg once daily, 22%; 500 mg twice daily, 26%; P = .691; Table 2). Nearly one third of patients derived clinical benefit (31% with CR or PR or SD 24 weeks), which was not significantly different between groups (1,500 mg once daily, 29%; 500 mg twice daily, 33%; P = .714). The median time to response was 7.9 weeks (1,500 mg once daily, 7.9 weeks; 500 mg twice daily, 7.9 weeks), and the median duration of response was 28.4 weeks (1,500 mg once daily, 27.6 weeks; 500 mg twice daily, 29 weeks). Most responses (22 of 33 responses, 67%) were reported by the first assessment at week 8. The progression-free survival rates at 4 and 6 months were 63% (1,500 mg once daily, 60%; 500 mg twice daily, 67%) and 43% (1,500 mg once daily, 41%; 500 mg twice daily, 45%), respectively (Fig 2). The median time to treatment failure was 16.1 weeks (1,500 mg once daily, 15.7 weeks; 500 mg twice daily, 17 weeks).
Six patients with stable CNS disease were enrolled onto the study (1,500 mg once daily, n = 3; 500 mg twice daily, n = 3). Of these patients, one had CNS relapse at the only site of disease, three patients had systemic relapse only, one subject died before objective documentation of progression, and one patient did not experience relapse at the time of discontinuation. Time to relapse or death for these patients ranged from 8 to 28.7 weeks.
Safety and Tolerability The incidence of AEs considered by investigators to be related to lapatinib was equal between the treatment regimens, affecting 71% of patients overall. These events were also mainly grade 1 or 2 in toxicity (60%); only 9%, less than 1%, and less than 1% of events were reported to be grade 3, 4, and 5, respectively. The most frequently reported AEs related to lapatinib were diarrhea (36%), rash (27%), pruritus (18%), and nausea (10%; Table 3). All other lapatinib-related AEs were experienced in less than 10% of patients.
Serious AEs were experienced by 24% of patients (1,500 mg once daily, n = 15; 500 mg twice daily, n = 18); urinary tract infection (2%) was the only SAE reported with an incidence rate more than 1%. Serious AEs that were considered to be related to lapatinib were reported by 7% of patients (1,500 mg once daily, n = 4; 500 mg twice daily, n = 5). Seven patients permanently withdrew from the study because of lapatinib-related AEs; four of these AEs were considered to be serious. These four withdrawals were a result of grade 3 abnormal hepatic function, grade 1 left ventricular dysfunction, grade 2 ejection fraction decrease, and grade 4 thrombocytopenia with grade 3 anemia in one patient each. There were six fatal AEs during the study, only one of which was considered to be related to lapatinib treatment. This was a case of hepatic failure and bacterial peritonitis, which began after 223 days of 500-mg twice daily lapatinib in a 73-year-old patient who had presented with extensive measurable and nonmeasurable liver metastases, chronic nonalcoholic hepatopathy, and grade 1 elevations in alkaline phosphatase, ALT, and AST levels before the first dose. The remaining five fatal AEs were caused by disease progression (n = 3), pneumonia, and multiple injuries sustained in a fall. Four patients (1,500 mg once daily, n = 1; 500 mg twice daily, n = 3) experienced asymptomatic reductions in left ventricular ejection fraction (LVEF) that met protocol-defined SAE criteria of more than 20% relative decrease from baseline and below the institutional lower limit of normal (Table 4). All patients who experienced cardiac events had previously received anthracyclines in the adjuvant setting. No symptomatic cardiac events or cases of congestive heart failure were reported. No cases of interstitial pneumonitis were reported.
This phase II study confirms the clinical activity of lapatinib administered as either 1,500 mg once daily or 500 mg twice daily. The study demonstrated no significant difference in efficacy (either clinical response or clinical benefit) between lapatinib 1,500 mg once daily and 500 mg twice daily dosing regimens as first-line therapy in this advanced-stage breast cancer patient population. However, because the study was powered at 90% to detect an increase of 30% in response rate in the 500-mg twice daily regimen, a larger sample size might have revealed potential smaller differences between the treatment groups. To minimize bias in response determination, the efficacy end points were based on disease assessments by independent, blinded reviewers. This is consistent with guidance provided by the US Food and Drug Administration.30 Although its use was permitted in the adjuvant setting, no patients in this study received trastuzumab before enrollment. The authors speculate that this may be because trastuzumab was not labeled for this indication during the study period and may not have been readily available through a clinical trial at participating sites. The overall response rate observed by the independent reviewers was 24%, and nearly one third of patients responded or were stable for 6 months, regardless of dosing regimen. Responses occurred rapidly, with most being reported by the first assessment at 8 weeks. Furthermore, the median duration of response exceeded 6 months, demonstrating that lapatinib treatment can produce a long-term benefit. Studies performed in similar populations using trastuzumab as first-line therapy have demonstrated broadly similar response rates in ErbB2-overexpressing patients.17,18 The level of efficacy observed in the current patient population supports the further study of lapatinib as first-line therapy. A gold standard of FISH was used for eligibility because HER-2 testing may not have been routine or standardized across study centers. Because interlaboratory variability was expected, patients with one positive FISH result were permitted to enroll onto the study. The level of discordant FISH results (9%) was consistent with previous findings.31-33 Because the primary focus of this study was to examine lapatinib in patients with ErbB2-amplified disease, ErbB1 overexpression was not analyzed. However, further characterization of the patients who benefited from lapatinib treatment could provide support for the use of biomarkers as predictors of clinical response. Lapatinib was well tolerated, with most related diarrhea and rash events reported as grade 1 or 2, which is largely consistent with previous findings.23,34 The rate and grade of AEs were consistent between the two dosing regimens. Pharmacokinetic data available at study inception suggested that the area under the curve in the 500-mg twice daily group would be greater than in the 1,500 mg once-daily group.35 Analysis of pharmacokinetic samples from this study is underway, but the clinical data reported here suggest that the hypothesized increase in area under the curve does not increase toxicity.
It has been suggested that cardiotoxicity may be associated with ErbB2-targeting agents.36,37 When trastuzumab is administered as monotherapy, the incidence of cardiac dysfunction has been calculated to be 7%, reaching 28% when administered in combination with an anthracycline and cyclophosphamide.38 In the current study, no symptomatic LVEF reductions were reported, although direct comparisons of data across the two studies should be avoided. Four patients (3%) experienced asymptomatic LVEF reductions that met protocol-defined SAE criteria, which is consistent with a meta-analysis of lapatinib cardiac safety data that demonstrated a low incidence (1.3%; n = 3,127) of LVEF decrease ( Lapatinib was recently approved by the US Food and Drug Administration and other authorities across the world for use in combination with capecitabine in patients with ErbB2-overexpressing advanced or metastatic breast cancer previously treated with taxanes, anthracyclines, and trastuzumab-based therapy. This followed positive results, including a 43% reduction in the risk of disease progression for lapatinib/capecitabine combination therapy compared with capecitabine monotherapy without an increase in serious toxic effects or symptomatic cardiac events.40 These results, combined with the clinical activity and safety of first-line lapatinib monotherapy demonstrated in the current study, suggest that further evaluation of lapatinib is warranted in the adjuvant and first-line settings for ErbB2-overexpressing early breast cancer. To date, the 500-mg twice daily dose schedule has not been evaluated in combination with other anticancer therapies. In conclusion, this study demonstrated the safety and efficacy of lapatinib monotherapy using schedules of 1,500 mg once daily and 500 mg twice daily as first-line treatment for advanced ErbB2-amplified breast cancer. Lapatinib was well tolerated, and no notable differences in either safety or efficacy were observed between the dosing schedules.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: Michael C. Arbushites, GlaxoSmithKline (C); Michelle A. Casey, GlaxoSmithKline (C); Steven H. Stein, GlaxoSmithKline (C) Consultant or Advisory Role: George W. Sledge, GlaxoSmithKline (C) Stock Ownership: Michael C. Arbushites, GlaxoSmithKline; Mark S. Berger, GlaxoSmithKline; Steven H. Stein, GlaxoSmithKline Honoraria: None Research Funding: Dinesh C. Doval, Eli Lilly, Roche, AstraZeneca; Shona Nag, GlaxoSmithKline; Sandra X. Franco, GlaxoSmithKline Expert Testimony: None Other Remuneration: Mark S. Berger, Employee of GlaxoSmithKline from 2002 - February 2007
Conception and design: Mark S. Berger Administrative support: Mark S. Berger Provision of study materials or patients: Henry L. Gomez, Dinesh C. Doval, Miguel A. Chavez, Peter C.-S. Ang, Zeba Aziz, Shona Nag, Christina Ng, Sandra X. Franco, Louis W.C. Chow Collection and assembly of data: Dinesh C. Doval, Miguel A. Chavez, Peter C.-S. Ang, Christina Ng, Sandra X. Franco, Louis W.C. Chow, Michael C. Arbushites Data analysis and interpretation: Dinesh C. Doval, Sandra X. Franco, Michael C. Arbushites, Michelle A. Casey, Mark S. Berger, Steven H. Stein, George W. Sledge Manuscript writing: Michael C. Arbushites, Michelle A. Casey, Mark S. Berger, Steven H. Stein, George W. Sledge Final approval of manuscript: Henry L. Gomez, Dinesh C. Doval, Miguel A. Chavez, Peter C.-S. Ang, Zeba Aziz, Shona Nag, Christina Ng, Sandra X. Franco, Louis W.C. Chow, Michael C. Arbushites, Michelle A. Casey, Mark S. Berger, Steven H. Stein, George W. Sledge
We thank the patients who volunteered for this study; the families, physicians, and research staff who cared for them; and the study team including Perceptive Informatics (lesion review) and D. Burrage, PhD (writing assistance).
published online ahead of print at www.jco.org on May 5, 2008. Supported by GlaxoSmithKline R&D Limited. Presented in part in posters at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; 12th European Congress of Clinical Oncology, October 29-November 1, 2005, Paris, France; 28th Annual San Antonio Breast Cancer Symposium, December 8-11, 2005, San Antonio, TX; 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX; and 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on www.JCO.org.
1. Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 55:74-108, 2005 2. Gullick WJ, Love SB, Wright C, et al: C-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63:434-438, 1991[Medline] 3. Nicholson S, Wright C, Sainsbury JR, et al: Epidermal growth factor receptor (EGFr) as a marker for poor prognosis in node-negative breast cancer patients: Neu and tamoxifen failure. J Steroid Biochem Mol Biol 37:811-814, 1990[CrossRef][Medline] 4. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 5. Tsutsui S, Ohno S, Murakami S, et al: Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer. Breast Cancer Res Treat 71:67-75, 2002[CrossRef][Medline] 6. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 7. Borg A, Tandon AK, Sigurdsson H, et al: HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 50:4332-4337, 1990 8. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127-137, 2001[CrossRef][Medline] 9. Jorissen RN, Walker F, Pouliot N, et al: Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp Cell Res 284:31-53, 2003[CrossRef][Medline] 10. Alroy I, Yarden Y: The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 410:83-86, 1997[CrossRef][Medline] 11. Baselga J, Albanell J, Ruiz A, et al: Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23:5323-5333, 2005 12. Carter P, Presta L, Gorman CM, et al: Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 89:4285-4289, 1992 13. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 14. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 15. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 16. 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 17. Baselga J, Carbonell X, Castaneda-Soto NJ, et al: Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 23:2162-2171, 2005 18. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 19. 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 20. Rusnak DW, Lackey K, Affleck K, et al: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85-94, 2001 21. 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] 22. Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66:1630-1639, 2006 23. Burris HA III, Hurwitz HI, Dees EC, et al: 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. J Clin Oncol 23:5305-5313, 2005 24. Clark KJ, Keith BR, Alligood K, et al: Pharmacokinetics and pharmacodynamics of GW572016 following oral administration to female BT474-bearing CB-17 SCID mice. 2002 Annual Meeting of the American Association of Pharmaceutical Scientists, Toronto, Canada, November 11-14, 2002 (abstr W5286) 25. Blackwell KL, Burstein H, Pegram M, et al: Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer. J Clin Oncol 23:193s, 2005 (suppl: abstr 3004) 26. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 27. GlaxoSmithKline: Tykerb prescribing information. http://www.tykerb.com 28. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 29. International Conference on Harmonisation: Guidance for industry: E6 Good Clinical Practice: Consolidated guidance. Rockville, MD, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 1996 30. Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research: Guidance for industry developing medical imaging drug and biological products—Part 3: Design, analysis, and interpretation of clinical studies. Rockville, MD, US Department of Health and Human Services Food and Drug Administration, 2004 31. Paik S, Bryant J, Tan-Chiu E, et al: Real-world performance of HER2 testing: National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 94:852-854, 2002 32. Roche PC, Suman VJ, Jenkins RB, et al: Concordance between local and central laboratory HER2 testing in the Breast Intergroup Trial N9831. J Natl Cancer Inst 94:855-857, 2002 33. Press MF, Sauter G, Bernstein L, et al: Diagnostic evaluation of HER-2 as a molecular target: An assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 11:6598-6607, 2005 34. Versola M, Burris HA, Jones S, et al: Clinical activity of GW572016 in EGF10003 in patients with solid tumors. J Clin Oncol 22:206s, 2004 (suppl, abstr 3047)[CrossRef] 35. 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 (suppl) 36. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002 37. Suter TM, Cook-Bruns N, Barton C: Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 13:173-183, 2004[CrossRef][Medline] 38. Genentech Inc: Herceptin trastuzumab anti-HER2 monoclonal antibody product information. http://www.herceptin.com/herceptin/patient/index.jsp 39. Perez EA, Byrne JA, Hammond IW, et al: Cardiac safety experience in 3127 patients (pts) treated with lapatinib. Ann Oncol 17:ix70, 2006 (suppl) 40. Geyer CE, Martin A, Newstat B, et al: Lapatinib (L) plus capecitabine (C) in HER2+ advanced breast cancer (ABC): Genomic and updated efficacy data. J Clin Oncol 25:40s, 2007 (suppl; abstr 1035) Submitted August 17, 2007; accepted February 6, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
