No Survival Benefit of Erlotinib in EGFR-Unselected Patients With Nonprogressing Ovarian Cancer After Platinum Therapy
EGFR is overexpressed in the majority of advanced epithelial ovarian carcinomas, and there is evidence indicating that overexpression is associated with poorer prognosis. In a phase III European Organisation for Research and Treatment of Cancer (EORTC)-Gynaecological Cancer Group and Gynecologic Cancer Intergroup study reported in the Journal of Clinical Oncology, Vergote et al assessed the effects of the EGFR inhibitor erlotinib (Tarceva) vs observation in patients with ovarian carcinoma with no evidence of progression after first-line platinum-based therapy. No progression-free or overall survival benefit was observed with erlotinib treatment.
Study Details
In the trial, 835 patients with high-risk International Federation of Gynecology and Obstetrics (FIGO) stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer unselected for EGFR expression were randomly assigned between October 2005 and February 2008 to receive erlotinib 150 mg/d for 2 years or until disease progression (n = 420) or observation (n = 415).
All patients underwent first-line platinum-based chemotherapy and showed no signs of progression at the end of chemotherapy. Patients were stratified for FIGO stage, institution, age, clinical response to first-line therapy, and first-line therapy. Mutation analyses were performed in 318 patients (38%), and FISH (fluorescence in situ hybridization) and immunohistochemistry for EGFR were performed in 248 patients. The primary endpoint was progression-free survival.
The erlotinib and observation groups were generally balanced for age (median, 59 years in both), World Health Organization performance status (0 in 67% in both), primary tumor (ovarian in 93% and 89%), stage (III in 65% and 70%), days since last chemotherapy (median, 21.5 and 21), histology (serous in 66% and 58%), histologic grade (poorly differentiated in 46% and 47%), first-line chemotherapy (platinum doublet or triplet in 95.5% and 96%), surgery for ovarian cancer (primary in 58% and 64%), no residual disease after primary surgery (48.5% and 47%) or interval debulking surgery (66% and 60%), and serum cancer antigen 125 (median 12.0 and 11.0 U/mL).
No Differences in Survival
Median duration of erlotinib treatment was 244 days, and median follow-up in the study population was 51 months. Median progression-free survival was 12.7 months in the erlotinib group vs 12.4 months in the observation group (hazard ratio [HR] = 1.05, P = .525, after adjustment for stratification factors). Median overall survival was 50.8 vs 59.1 months (adjusted HR = 0.99, P = .903). There were no apparent differences between groups in progression-free or overall survival according to stratification subgroups, residual tumor after primary or interval debulking, subgroups according to immunohistochemistry or FISH for EGFR or mutations in EGFR pathway–related genes, or according to rash during erlotinib therapy. Overall, patients with a positive FISH EGFR score had worse overall survival (46.1 vs 67.0 months, HR = 1.56, P = .044) and progression-free survival (9.6 vs 16.1 months, HR = 1.57, P = .01) vs those with a negative FISH EGFR score.
Adverse Events
In the erlotinib group, 26% of patients stopped treatment due to adverse events (67% of these due to rash) and 50% required dose modification (primarily due to diarrhea or rash). Grade 3 and 4 rash occurred in 12% and 0.5% of patients. Other grade 3 or 4 adverse events occurred in <1% of patients, except for dry skin (1.7%), abdominal pain (2.4%), and increased gamma-glutamyl transpeptidase (3.4%). No deaths occurred as a result of toxicity.
Adherence was low for quality-of-life assessments. Assessment of global health/quality of life with the EORTC Quality of Life Questionnaire C30 showed a significant difference favoring the observation group during the first study year (P = .0102).
The investigators concluded: “Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.” They noted that new EGFR inhibitors designed to inhibit the kinase domain of mutant EGFR and spare wild-type EGFR may be more potent and less toxic to patients. “However, ovarian cancer is characterized by an extreme genomic destruction and an unparalleled amount of chromosome deletions that look dramatically different from those in other cancers…. In the future, it will be important to identify, in randomized phase II studies, new targeted drugs in subgroups of patients with ovarian cancer on the basis of histologic and molecular characteristics before embarking on phase III studies,” they wrote.
Ignace Vergote, MD, PhD, of University Hospital Leuven, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Vlaamse Liga Tegen Kanker through the EORTC Charitable Trust, Stichting Tegen Kanker of Belgium, and F. Hoffmann-La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.
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