Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852

Roman Perez-Soler, Nicholas J. Donato, Dong M. Shin, Michael G. Rosenblum, Hua Zhong Zhang, Carmen Tornos, Hanna Brewer, James C. Chan, Jin Soo Lee, Waun K. Hong, James L. Murray

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Abstract

Purpose: Tumor tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) and localization of anti-EGFR monoclonal antibody RG 83852 were studied in patients with non-small-cell lung cancer (NSCLC) and head and neck cancer. Patients and Methods: Fifteen patients were treated with escalating doses of RG 83852 by continuous intravenous infusion for 5 days. Fresh tumor specimens were obtained 24 hours after therapy in 10 patients (of whom five had a pretherapy sample taken). Tumor EGFR tyrosine kinase activity was determined in fresh tumor samples by autophosphorylation of EGFR isolated in immunocomplexes with RG 83852. Tumor EGFR saturation with RG 83852 was assessed semiquantitatively by comparing the EGFR tyrosine kinase activity in immunocomplexes of tumor specimens obtained after therapy with total EGFR tyrosine kinase activity assessed by exogenous addition of RG 83852 to tumor lysates. Modulation of EGFR tyrosine kinase activity after the administration of RG 83852 was assessed by comparing EGFR tyrosine kinase activity from the same malignant lesion obtained before and after therapy. Tumor localization of RG 83852 and EGFR saturation were also assessed by immunohistochemistry. Results: No significant side effects were observed up to a total dose of 600 mg/m2. Based on tyrosine kinase activity, a high degree of EGFR saturation (≥ 50%) was observed at doses ≥ 200 mg/m2, and EGFR saturation was estimated to be 100% at a dose level of 600 mg/m2 both in tumor tissue and skin used as surrogate EGFR-positive tissue. Immunohistochemistry studies showed that RG 83852 localized in tumor tissue and skin, but not in stroma, at doses ≥ 400 mg/m2, and high EGFR saturation was observed at 600 mg/m2. Tumor EGFR tyrosine kinase activity was studied in five patients (four with EGFR-positive tumors) before and 24 hours post-therapy; a threefold to fourfold upregulation of EGFR tyrosine kinase activity in posttherapy specimens was observed in two patients. Moderate upregulation of EGFR itself was suggested in both of these patients and in two additional patients by immunohistochemistry. Conclusion: RG 83852 causes no toxic effects at doses that result in high tumor EGFR saturation. Treatment with RG 83852 may enhance EGFR tyrosine kinase activity and/or EGFR expression. Because high EGFR expression by tumors has been associated with increased sensitivity to cytotoxic therapy, the suggestion of antibody-mediated upregulation of EGFR by agents such as RG 83852 may prove useful in enhancing chemotherapeutic efficacy. J Clin Oncol 12:730-739.

Original languageEnglish (US)
Pages (from-to)730-739
Number of pages10
JournalJournal of Clinical Oncology
Volume12
Issue number4
StatePublished - Apr 1994
Externally publishedYes

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Head and Neck Neoplasms
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Neoplasms
Protein-Tyrosine Kinases
RG 83852 monoclonal antibody
Up-Regulation
Immunohistochemistry
Therapeutics
Skin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852. / Perez-Soler, Roman; Donato, Nicholas J.; Shin, Dong M.; Rosenblum, Michael G.; Zhang, Hua Zhong; Tornos, Carmen; Brewer, Hanna; Chan, James C.; Lee, Jin Soo; Hong, Waun K.; Murray, James L.

In: Journal of Clinical Oncology, Vol. 12, No. 4, 04.1994, p. 730-739.

Research output: Contribution to journalArticle

Perez-Soler, R, Donato, NJ, Shin, DM, Rosenblum, MG, Zhang, HZ, Tornos, C, Brewer, H, Chan, JC, Lee, JS, Hong, WK & Murray, JL 1994, 'Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852', Journal of Clinical Oncology, vol. 12, no. 4, pp. 730-739.
Perez-Soler, Roman ; Donato, Nicholas J. ; Shin, Dong M. ; Rosenblum, Michael G. ; Zhang, Hua Zhong ; Tornos, Carmen ; Brewer, Hanna ; Chan, James C. ; Lee, Jin Soo ; Hong, Waun K. ; Murray, James L. / Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852. In: Journal of Clinical Oncology. 1994 ; Vol. 12, No. 4. pp. 730-739.
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title = "Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852",
abstract = "Purpose: Tumor tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) and localization of anti-EGFR monoclonal antibody RG 83852 were studied in patients with non-small-cell lung cancer (NSCLC) and head and neck cancer. Patients and Methods: Fifteen patients were treated with escalating doses of RG 83852 by continuous intravenous infusion for 5 days. Fresh tumor specimens were obtained 24 hours after therapy in 10 patients (of whom five had a pretherapy sample taken). Tumor EGFR tyrosine kinase activity was determined in fresh tumor samples by autophosphorylation of EGFR isolated in immunocomplexes with RG 83852. Tumor EGFR saturation with RG 83852 was assessed semiquantitatively by comparing the EGFR tyrosine kinase activity in immunocomplexes of tumor specimens obtained after therapy with total EGFR tyrosine kinase activity assessed by exogenous addition of RG 83852 to tumor lysates. Modulation of EGFR tyrosine kinase activity after the administration of RG 83852 was assessed by comparing EGFR tyrosine kinase activity from the same malignant lesion obtained before and after therapy. Tumor localization of RG 83852 and EGFR saturation were also assessed by immunohistochemistry. Results: No significant side effects were observed up to a total dose of 600 mg/m2. Based on tyrosine kinase activity, a high degree of EGFR saturation (≥ 50{\%}) was observed at doses ≥ 200 mg/m2, and EGFR saturation was estimated to be 100{\%} at a dose level of 600 mg/m2 both in tumor tissue and skin used as surrogate EGFR-positive tissue. Immunohistochemistry studies showed that RG 83852 localized in tumor tissue and skin, but not in stroma, at doses ≥ 400 mg/m2, and high EGFR saturation was observed at 600 mg/m2. Tumor EGFR tyrosine kinase activity was studied in five patients (four with EGFR-positive tumors) before and 24 hours post-therapy; a threefold to fourfold upregulation of EGFR tyrosine kinase activity in posttherapy specimens was observed in two patients. Moderate upregulation of EGFR itself was suggested in both of these patients and in two additional patients by immunohistochemistry. Conclusion: RG 83852 causes no toxic effects at doses that result in high tumor EGFR saturation. Treatment with RG 83852 may enhance EGFR tyrosine kinase activity and/or EGFR expression. Because high EGFR expression by tumors has been associated with increased sensitivity to cytotoxic therapy, the suggestion of antibody-mediated upregulation of EGFR by agents such as RG 83852 may prove useful in enhancing chemotherapeutic efficacy. J Clin Oncol 12:730-739.",
author = "Roman Perez-Soler and Donato, {Nicholas J.} and Shin, {Dong M.} and Rosenblum, {Michael G.} and Zhang, {Hua Zhong} and Carmen Tornos and Hanna Brewer and Chan, {James C.} and Lee, {Jin Soo} and Hong, {Waun K.} and Murray, {James L.}",
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T1 - Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852

AU - Perez-Soler, Roman

AU - Donato, Nicholas J.

AU - Shin, Dong M.

AU - Rosenblum, Michael G.

AU - Zhang, Hua Zhong

AU - Tornos, Carmen

AU - Brewer, Hanna

AU - Chan, James C.

AU - Lee, Jin Soo

AU - Hong, Waun K.

AU - Murray, James L.

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N2 - Purpose: Tumor tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) and localization of anti-EGFR monoclonal antibody RG 83852 were studied in patients with non-small-cell lung cancer (NSCLC) and head and neck cancer. Patients and Methods: Fifteen patients were treated with escalating doses of RG 83852 by continuous intravenous infusion for 5 days. Fresh tumor specimens were obtained 24 hours after therapy in 10 patients (of whom five had a pretherapy sample taken). Tumor EGFR tyrosine kinase activity was determined in fresh tumor samples by autophosphorylation of EGFR isolated in immunocomplexes with RG 83852. Tumor EGFR saturation with RG 83852 was assessed semiquantitatively by comparing the EGFR tyrosine kinase activity in immunocomplexes of tumor specimens obtained after therapy with total EGFR tyrosine kinase activity assessed by exogenous addition of RG 83852 to tumor lysates. Modulation of EGFR tyrosine kinase activity after the administration of RG 83852 was assessed by comparing EGFR tyrosine kinase activity from the same malignant lesion obtained before and after therapy. Tumor localization of RG 83852 and EGFR saturation were also assessed by immunohistochemistry. Results: No significant side effects were observed up to a total dose of 600 mg/m2. Based on tyrosine kinase activity, a high degree of EGFR saturation (≥ 50%) was observed at doses ≥ 200 mg/m2, and EGFR saturation was estimated to be 100% at a dose level of 600 mg/m2 both in tumor tissue and skin used as surrogate EGFR-positive tissue. Immunohistochemistry studies showed that RG 83852 localized in tumor tissue and skin, but not in stroma, at doses ≥ 400 mg/m2, and high EGFR saturation was observed at 600 mg/m2. Tumor EGFR tyrosine kinase activity was studied in five patients (four with EGFR-positive tumors) before and 24 hours post-therapy; a threefold to fourfold upregulation of EGFR tyrosine kinase activity in posttherapy specimens was observed in two patients. Moderate upregulation of EGFR itself was suggested in both of these patients and in two additional patients by immunohistochemistry. Conclusion: RG 83852 causes no toxic effects at doses that result in high tumor EGFR saturation. Treatment with RG 83852 may enhance EGFR tyrosine kinase activity and/or EGFR expression. Because high EGFR expression by tumors has been associated with increased sensitivity to cytotoxic therapy, the suggestion of antibody-mediated upregulation of EGFR by agents such as RG 83852 may prove useful in enhancing chemotherapeutic efficacy. J Clin Oncol 12:730-739.

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