Phase II study of erlotinib in patients with malignant pleural mesothelioma: a Southwest Oncology Group Study.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Garland
Linda L
LL
University of Arizona Cancer Center, Tucson, AZ, USA.
Rankin
Cathryn
C
Gandara
David R
DR
Rivkin
Saul E
SE
Scott
Katherine M
KM
Nagle
Raymond B
RB
Klein-Szanto
Andres J P
AJ
Testa
Joseph R
JR
Altomare
Deborah A
DA
Borden
Ernest C
EC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt