Phase II study of erlotinib in patients with malignant pleural mesothelioma

A Southwest Oncology Group study

Linda L Garland, Cathryn Rankin, David R. Gandara, Saul E. Rivkin, Katherine M. Scott, Raymond B Nagle, Andres J P Klein-Szanto, Joseph R. Testa, Deborah A. Altomare, Ernest C. Borden

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

Purpose: Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM. Patients and Methods: Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho-extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway. Results: Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho-mammalian target of rapamycin (74%), and phospho-forkhead (74%). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42%) had stable disease, 15 patients (45%) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51%), dermatologic (82%), and GI (52%); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months; 1-year survival rate was 43%; and median progression-free survival time was 2 months. Conclusion: Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.

Original languageEnglish (US)
Pages (from-to)2406-2413
Number of pages8
JournalJournal of Clinical Oncology
Volume25
Issue number17
DOIs
StatePublished - Jun 10 2007
Externally publishedYes

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Epidermal Growth Factor Receptor
Phosphatidylinositol 3-Kinase
Extracellular Signal-Regulated MAP Kinases
Protein-Tyrosine Kinases
Phosphoric Monoester Hydrolases
Malignant Mesothelioma
Erlotinib Hydrochloride
Sirolimus
Dyspnea
Disease-Free Survival
Disease Progression
Neoplasms
Survival Rate
Phosphorylation
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase II study of erlotinib in patients with malignant pleural mesothelioma : A Southwest Oncology Group study. / Garland, Linda L; Rankin, Cathryn; Gandara, David R.; Rivkin, Saul E.; Scott, Katherine M.; Nagle, Raymond B; Klein-Szanto, Andres J P; Testa, Joseph R.; Altomare, Deborah A.; Borden, Ernest C.

In: Journal of Clinical Oncology, Vol. 25, No. 17, 10.06.2007, p. 2406-2413.

Research output: Contribution to journalArticle

Garland, LL, Rankin, C, Gandara, DR, Rivkin, SE, Scott, KM, Nagle, RB, Klein-Szanto, AJP, Testa, JR, Altomare, DA & Borden, EC 2007, 'Phase II study of erlotinib in patients with malignant pleural mesothelioma: A Southwest Oncology Group study', Journal of Clinical Oncology, vol. 25, no. 17, pp. 2406-2413. https://doi.org/10.1200/JCO.2006.09.7634
Garland, Linda L ; Rankin, Cathryn ; Gandara, David R. ; Rivkin, Saul E. ; Scott, Katherine M. ; Nagle, Raymond B ; Klein-Szanto, Andres J P ; Testa, Joseph R. ; Altomare, Deborah A. ; Borden, Ernest C. / Phase II study of erlotinib in patients with malignant pleural mesothelioma : A Southwest Oncology Group study. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 17. pp. 2406-2413.
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abstract = "Purpose: Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM. Patients and Methods: Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho-extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway. Results: Sixty-three patients were treated on the study. EGFR was highly expressed in 75{\%} of patient tumors, as was phospho-ERK (82{\%}), phospho-Akt (84{\%}), phospho-mammalian target of rapamycin (74{\%}), and phospho-forkhead (74{\%}). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42{\%}) had stable disease, 15 patients (45{\%}) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51{\%}), dermatologic (82{\%}), and GI (52{\%}); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months; 1-year survival rate was 43{\%}; and median progression-free survival time was 2 months. Conclusion: Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.",
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T1 - Phase II study of erlotinib in patients with malignant pleural mesothelioma

T2 - A Southwest Oncology Group study

AU - Garland, Linda L

AU - Rankin, Cathryn

AU - Gandara, David R.

AU - Rivkin, Saul E.

AU - Scott, Katherine M.

AU - Nagle, Raymond B

AU - Klein-Szanto, Andres J P

AU - Testa, Joseph R.

AU - Altomare, Deborah A.

AU - Borden, Ernest C.

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N2 - Purpose: Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM. Patients and Methods: Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho-extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway. Results: Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho-mammalian target of rapamycin (74%), and phospho-forkhead (74%). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42%) had stable disease, 15 patients (45%) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51%), dermatologic (82%), and GI (52%); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months; 1-year survival rate was 43%; and median progression-free survival time was 2 months. Conclusion: Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.

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