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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

From the University of Arizona Cancer Center, Tucson, AZ; Southwest Oncology Group Statistical Center; Puget Sound Oncology Consortium, Seattle, WA; University of California, Davis Cancer Center, Sacramento, CA; Fox Chase Cancer Center, Philadelphia, PA; and Cleveland Clinic Foundation, Cleveland, OH

Address reprint requests to Southwest Oncology Group (S0218), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

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.

Supported in part by the following Public Health Service Cooperative Agreement Grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA46441, CA20319, CA45808, CA58861, CA13612, CA45807, CA45377, CA11083, CA35431, CA37981, CA46368, CA27057, CA67575, CA45560, CA35090, CA35178, CA58882, CA42777, CA58416, CA12644, CA16385, CA46113, CA22433, and CA76462.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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