Originally published as JCO Early Release 10.1200/JCO.2005.16.584 on June 13 2005
Journal of Clinical Oncology, Vol 23, No 23 (August 10), 2005: pp. 5305-5313
© 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
Howard A. Burris, III,
Herbert I. Hurwitz,
E. Claire Dees,
Afshin Dowlati,
Kimberly L. Blackwell,
Bert O'Neil,
Paul K. Marcom,
Matthew J. Ellis,
Beth Overmoyer,
Suzanne F. Jones,
Jennifer L. Harris,
Deborah A. Smith,
Kevin M. Koch,
Andrew Stead,
Steve Mangum,
Neil L. Spector
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  6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.
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.
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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Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice
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297(1):
H65 - H75.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. Blackwell, M. D. Pegram, E. Tan-Chiu, L. S. Schwartzberg, M. C. Arbushites, J. D. Maltzman, J. K. Forster, S. D. Rubin, S. H. Stein, and H. J. Burstein
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Ann. Onc.,
June 1, 2009;
20(6):
1026 - 1031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Dokmanovic, D. S. Hirsch, Y. Shen, and W. J. Wu
Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
Mol. Cancer Ther.,
June 1, 2009;
8(6):
1557 - 1569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Koch, N. J. Reddy, R. B. Cohen, N. L. Lewis, B. Whitehead, K. Mackay, A. Stead, A. P. Beelen, and L. D. Lewis
Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients
J. Clin. Oncol.,
March 10, 2009;
27(8):
1191 - 1196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Harrington, I. A. El-Hariry, C. S. Holford, A. Lusinchi, C. M. Nutting, D. Rosine, M. Tanay, E. Deutsch, J. Matthews, C. D'Ambrosio, et al.
Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
J. Clin. Oncol.,
March 1, 2009;
27(7):
1100 - 1107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nakagawa, H. Minami, M. Kanezaki, A. Mukaiyama, Y. Minamide, H. Uejima, T. Kurata, T. Nogami, K. Kawada, H. Mukai, et al.
Phase I Dose-escalation and Pharmacokinetic Trial of Lapatinib (GW572016), a Selective Oral Dual Inhibitor of ErbB-1 and -2 Tyrosine Kinases, in Japanese Patients with Solid Tumors
Jpn. J. Clin. Oncol.,
February 1, 2009;
39(2):
116 - 123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. Strecker, Q. Shen, Y. Zhang, J. L. Hill, Y. Li, C. Wang, H.-T. Kim, T. M. Gilmer, K. R. Sexton, S. G. Hilsenbeck, et al.
Effect of Lapatinib on the Development of Estrogen Receptor-Negative Mammary Tumors in Mice
J Natl Cancer Inst,
January 21, 2009;
101(2):
107 - 113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ciccarese and V. Lorusso
How Should We Prescribe Lapatinib to Our Patients: Once Daily or Twice Daily, and at What Dose?
J. Clin. Oncol.,
January 10, 2009;
27(2):
314 - 315.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Castaneda and H. L. Gomez
In Reply
J. Clin. Oncol.,
January 10, 2009;
27(2):
315 - 316.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J.A. Eichhorn, M. Gili, M. Scaltriti, V. Serra, M. Guzman, W. Nijkamp, R. L. Beijersbergen, V. Valero, J. Seoane, R. Bernards, et al.
Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235
Cancer Res.,
November 15, 2008;
68(22):
9221 - 9230.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. L. Chen, W. Xia, and N. L. Spector
Acquired Resistance to Small Molecule ErbB2 Tyrosine Kinase Inhibitors
Clin. Cancer Res.,
November 1, 2008;
14(21):
6730 - 6734.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-l. Dai, A. K. Tiwari, C.-P. Wu, X.-d. Su, S.-R. Wang, D.-g. Liu, C. R. Ashby Jr., Y. Huang, R. W. Robey, Y.-j. Liang, et al.
Lapatinib (Tykerb, GW572016) Reverses Multidrug Resistance in Cancer Cells by Inhibiting the Activity of ATP-Binding Cassette Subfamily B Member 1 and G Member 2
Cancer Res.,
October 1, 2008;
68(19):
7905 - 7914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Paul, J. A. Trovato, and J. Thompson
Lapatinib: A dual tyrosine kinase inhibitor for metastatic breast cancer
Am. J. Health Syst. Pharm.,
September 15, 2008;
65(18):
1703 - 1710.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Laheru, G. Croghan, R. Bukowski, M. Rudek, W. Messersmith, C. Erlichman, R. Pelley, A. Jimeno, R. Donehower, J. Boni, et al.
A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer
Clin. Cancer Res.,
September 1, 2008;
14(17):
5602 - 5609.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Gril, D. Palmieri, J. L. Bronder, J. M. Herring, E. Vega-Valle, L. Feigenbaum, D. J. Liewehr, S. M. Steinberg, M. J. Merino, S. D. Rubin, et al.
Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain
J Natl Cancer Inst,
August 6, 2008;
100(15):
1092 - 1103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. S.C. Chu, M. E. Cianfrocca, L. J. Goldstein, M. Gale, N. Murray, J. Loftiss, N. Arya, K. M. Koch, L. Pandite, R. A. Fleming, et al.
A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer
Clin. Cancer Res.,
July 15, 2008;
14(14):
4484 - 4490.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. P. Shah, H. M. Kantarjian, D.-W. Kim, D. Rea, P. E. Dorlhiac-Llacer, J. H. Milone, J. Vela-Ojeda, R. T. Silver, H. J. Khoury, A. Charbonnier, et al.
Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia
J. Clin. Oncol.,
July 1, 2008;
26(19):
3204 - 3212.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Zhang, A. Pal, W. G. Bornmann, F. Yamasaki, F. J. Esteva, G. N. Hortobagyi, C. Bartholomeusz, and N. T. Ueno
Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells
Mol. Cancer Ther.,
July 1, 2008;
7(7):
1846 - 1850.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. LoRusso, S. F. Jones, K. M. Koch, N. Arya, R. A. Fleming, J. Loftiss, L. Pandite, S. Gadgeel, B. L. Weber, and H. A. Burris III
Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer
J. Clin. Oncol.,
June 20, 2008;
26(18):
3051 - 3056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. L. Gomez, D. C. Doval, M. A. Chavez, P. C.-S. Ang, Z. Aziz, S. Nag, C. Ng, S. X. Franco, L. W.C. Chow, M. C. Arbushites, et al.
Efficacy and Safety of Lapatinib As First-Line Therapy for ErbB2-Amplified Locally Advanced or Metastatic Breast Cancer
J. Clin. Oncol.,
June 20, 2008;
26(18):
2999 - 3005.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Seruga and I. F. Tannock
Mathematics in the Realm of Lapatinib: 500 + 500 = 1,500?
J. Clin. Oncol.,
June 20, 2008;
26(18):
2940 - 2942.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. E Hynes
ErbB Receptors in Cancer: HER2/ErbB2 as a Therapeutic Target
Am. Assoc. Cancer Res. Educ. Book,
April 12, 2008;
2008(1):
123 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Frei and S. A. Soefje
A Review of the Cardiovascular Effects of Oncology Agents
Journal of Pharmacy Practice,
April 1, 2008;
21(2):
146 - 158.
[Abstract]
[PDF]
|
|
|
|
|
|
|
G. Arpino, L. Wiechmann, C. K. Osborne, and R. Schiff
Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance
Endocr. Rev.,
April 1, 2008;
29(2):
217 - 233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Johnston, M. Trudeau, B. Kaufman, H. Boussen, K. Blackwell, P. LoRusso, D. P. Lombardi, S. Ben Ahmed, D. L. Citrin, M. L. DeSilvio, et al.
Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy
J. Clin. Oncol.,
March 1, 2008;
26(7):
1066 - 1072.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ocana and A. Pandiella
Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options
Clin. Cancer Res.,
February 15, 2008;
14(4):
961 - 970.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Aird, X. Ding, A. Baras, J. Wei, M. A. Morse, T. Clay, H. K. Lyerly, and G. R. Devi
Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression
Mol. Cancer Ther.,
January 1, 2008;
7(1):
38 - 47.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Rixe and T. Fojo
Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient?
Clin. Cancer Res.,
December 15, 2007;
13(24):
7280 - 7287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Lu, S. L. Wyszomierski, L.-M. Tseng, M.-H. Sun, K.-H. Lan, C. L. Neal, G. B. Mills, G. N. Hortobagyi, F. J. Esteva, and D. Yu
Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency
Clin. Cancer Res.,
October 1, 2007;
13(19):
5883 - 5888.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Harari, G. W. Allen, and J. A. Bonner
Biology of Interactions: Antiepidermal Growth Factor Receptor Agents
J. Clin. Oncol.,
September 10, 2007;
25(26):
4057 - 4065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. S.C. Chu, G. Schwartz, J. de Bono, D. A. Smith, K. M. Koch, M. J. Versola, L. Pandite, N. Arya, J. Curtright, R. A. Fleming, et al.
Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies
J. Clin. Oncol.,
August 20, 2007;
25(24):
3753 - 3758.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Ratain and E. E. Cohen
The Value Meal: How to Save $1,700 Per Month or More on Lapatinib
J. Clin. Oncol.,
August 10, 2007;
25(23):
3397 - 3398.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. S. Siegel-Lakhai, J. H. Beijnen, W. L. Vervenne, H. Boot, M. Keessen, M. Versola, K. M. Koch, D. A. Smith, L. Pandite, D. J. Richel, et al.
Phase I Pharmacokinetic Study of the Safety and Tolerability of Lapatinib (GW572016) in Combination with Oxaliplatin/Fluorouracil/Leucovorin (FOLFOX4) in Patients with Solid Tumors
Clin. Cancer Res.,
August 1, 2007;
13(15):
4495 - 4502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Hegde, D. Rusnak, M. Bertiaux, K. Alligood, J. Strum, R. Gagnon, and T. M. Gilmer
Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles
Mol. Cancer Ther.,
May 1, 2007;
6(5):
1629 - 1640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Goodin
Oral chemotherapeutic agents: Understanding mechanisms of action and drug interactions
Am. J. Health Syst. Pharm.,
May 1, 2007;
64(9_Supplement_5):
S15 - S24.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Scaltriti, F. Rojo, A. Ocana, J. Anido, M. Guzman, J. Cortes, S. Di Cosimo, X. Matias-Guiu, S. Ramon y Cajal, J. Arribas, et al.
Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer
J Natl Cancer Inst,
April 18, 2007;
99(8):
628 - 638.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Patel and M. P. Mehta
Targeted Therapy for Brain Metastases: Improving the Therapeutic Ratio
Clin. Cancer Res.,
March 15, 2007;
13(6):
1675 - 1683.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. N. Munster, C. D. Britten, M. Mita, K. Gelmon, S. E. Minton, S. Moulder, D. J. Slamon, F. Guo, S. P. Letrent, L. Denis, et al.
First Study of the Safety, Tolerability, and Pharmacokinetics of CP-724,714 in Patients with Advanced Malignant Solid HER2-Expressing Tumors
Clin. Cancer Res.,
February 15, 2007;
13(4):
1238 - 1245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Steeghs, J. W. R. Nortier, and H. Gelderblom
Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments
Ann. Surg. Oncol.,
February 1, 2007;
14(2):
942 - 953.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Xia, I. Husain, L. Liu, S. Bacus, S. Saini, J. Spohn, K. Pry, R. Westlund, S. H. Stein, and N. L. Spector
Lapatinib Antitumor Activity Is Not Dependent upon Phosphatase and Tensin Homologue Deleted on Chromosome 10 in ErbB2-Overexpressing Breast Cancers
Cancer Res.,
February 1, 2007;
67(3):
1170 - 1175.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Beslija, J Bonneterre, H Burstein, V Cocquyt, M Gnant, P Goodwin, V Heinemann, J Jassem, W. Kostler, M Krainer, et al.
Second consensus on medical treatment of metastatic breast cancer
Ann. Onc.,
February 1, 2007;
18(2):
215 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kawada, K. Murakami, T. Sato, Y. Kojima, H. Ebi, H. Mukai, M. Tahara, K. Shimokata, and H. Minami
Prospective Study of Positron Emission Tomography for Evaluation of the Activity of Lapatinib, a Dual Inhibitor of the ErbB1 and ErbB2 Tyrosine Kinases, in Patients with Advanced Tumors
Jpn. J. Clin. Oncol.,
January 1, 2007;
37(1):
44 - 48.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Meric-Bernstam and M.-C. Hung
Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy.
Clin. Cancer Res.,
November 1, 2006;
12(21):
6326 - 6330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Moy and P. E. Goss
Lapatinib: Current Status and Future Directions in Breast Cancer
Oncologist,
November 1, 2006;
11(10):
1047 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. W. Wong, F. Y. Lee, C. Yu, F. R. Luo, S. Oppenheimer, H. Zhang, R. A. Smykla, H. Mastalerz, B. E. Fink, J. T. Hunt, et al.
Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling.
Clin. Cancer Res.,
October 15, 2006;
12(20):
6186 - 6193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Garland, M. Hidalgo, D. S. Mendelson, D. P. Ryan, B. K. Arun, J. L. Lovalvo, I. A. Eiseman, S. C. Olson, P. F. Lenehan, and J. P. Eder
A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors.
Clin. Cancer Res.,
July 15, 2006;
12(14):
4274 - 4282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. V. Heymach, M. Nilsson, G. Blumenschein, V. Papadimitrakopoulou, and R. Herbst
Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer.
Clin. Cancer Res.,
July 15, 2006;
12(14):
4441s - 4445s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Baselga
Targeting Tyrosine Kinases in Cancer: The Second Wave.
Science,
May 26, 2006;
312(5777):
1175 - 1178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Xia, S. Bacus, P. Hegde, I. Husain, J. Strum, L. Liu, G. Paulazzo, L. Lyass, P. Trusk, J. Hill, et al.
A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer
PNAS,
May 16, 2006;
103(20):
7795 - 7800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H Nelson and C. R Dolder
Lapatinib: A Novel Dual Tyrosine Kinase Inhibitor with Activity in Solid Tumors
Ann. Pharmacother.,
February 1, 2006;
40(2):
261 - 269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
