Clinical summary of 67 heavily pre-treated patients with metastatic carcinomas treated with GW572016 in a phase Ib study

Dees, E. Claire; Burris, H.; Hurwitz, H.; Dowlati, Afshin; Smith, D.; Koch, Kristina; Stead, Andrew G.; Mangum, Stacey; Harris, J. Ieuan; Spector, Nelson

doi:10.1200/jco.2004.22.90140.3188

Cited by 13 publications

(10 citation statements)

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“…Dose-limiting toxicities including mucositis, anorexia, rash, diarrhea, fatigue, and bleeding stomatitis, resulted in an optimally tolerated regimen of lapatinib 1250 mg plus capecitabine 2000 mg/m 2 . In agreement with previous studies (Dees et al 2004) it was reported that no clear relationship exists between peak plasma concentrations and toxicity. Grade 1-2 diarrhea, nausea, rash, and fatigue were the common nonhematologic toxicities experienced in cancer patients (n=36) treated with the optimally tolerated regimen of lapatinib (1500 mg/day) plus letrozole (2.5 mg/day) (Chu et al 2005).…”

Section: Safety and Tolerabilitysupporting

confidence: 93%

“…Outcomes measured in this study include clinical response at 8 weeks and expression of biomarkers (Dees et al 2004;Burris et al 2005;Spector et al 2005). In this study, lapatinib 500-1600 mg/day was administered to 67 patients with a variety of metastatic carcinomas overexpressing ErbB1 and/or ErbB2.…”

Section: Monotherapymentioning

confidence: 99%

“…The incidence of adverse events was reported for 67 patients with metastatic carcinomas treated with daily doses of lapatinib 500-1600 mg (Dees et al 2004;Burris et al 2005). Five grade 3 drug-related toxicities (gastrointestinal and rash) were reported in four patients.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

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Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

Thomson¹

2005

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Section: Safety and Tolerabilitysupporting

confidence: 93%

Section: Monotherapymentioning

confidence: 99%

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Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

Thomson¹

2005

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“…4 Lapatinib, a reversible dual kinase inhibitor against EGFR and HER2, 5 has activity in patients with HER2 overexpression when given either as first-line therapy or after treatment failure with trastuzumab [6][7][8] and has been approved in combination…”

Section: Introductionmentioning

confidence: 99%

Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

Dave

Migliaccio

Gutierrez

et al. 2011

JCO

216

167

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Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

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“…96 The final results are available from a Phase Ib study (EGF10004) of lapatinib in heavily pretreated patients with metastatic disease (n ϭ 67 patients). 97 Inclusion criteria for that study were EGFR or HER-2 overexpression on IHC, HER-2 gene amplification, or evidence of activated EGFR or HER-2 receptors demonstrated by IHC. Four PRs were observed in patients with breast carcinoma; and 23 patients with other tumor types, including colon, demonstrated disease stabilization for 8 -41 weeks.…”

Section: Other Tkismentioning

confidence: 99%

Epidermal growth factor receptor‐targeted treatment for advanced colorectal carcinoma

Venook

2005

Cancer

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Substantial effort has focused on the development of novel targeted agents for treating patients with late-stage colorectal carcinoma. These agents are designed specifically to inhibit biochemical processes associated with pathogenesis. Numerous molecules targeting the epidermal growth factor receptor have been investigated as therapeutic agents and appear to herald a shift in the treatment paradigm for colorectal carcinoma. Cancer 2005;103:2435-46.

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Clinical summary of 67 heavily pre-treated patients with metastatic carcinomas treated with GW572016 in a phase Ib study

Cited by 13 publications

References 0 publications

Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

Epidermal growth factor receptor‐targeted treatment for advanced colorectal carcinoma

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