Treatment with a targeted drug failed to improve survival in advanced esophageal cancer but did slow disease progression, according to a study reported here.
Overall survival was about 3.5 months whether patients received placebo or gefitinib (Iressa), an epidermal growth factor receptor (EGFR) inhibitor. Patients treated with gefitinib did have a significant, albeit numerically small, improvement in progression-free survival (P=0.017), said David Ferry, MD, at the European Society for Medical Oncology meeting.
The 8-week disease control rate (response plus stable disease) also favored the gefitinib arm, he added.
“The Cancer Oesophagus Gefitinib (COG) trial is the first large randomized trial in the second- and third-line setting in esophageal cancer,” said Ferry, of New Cross Hospital in Wolverhampton, U.K. “Although the primary overall survival (OS) endpoint was not achieved, there was significant PFS improvement and palliation.”
“Durable responses were seen in some patients, and the translational study is investigating the correlation of benefit with biomarkers,” he added. No systemic therapy has demonstrated a favorable effect on the natural history of metastatic esophageal cancer that has progressed after chemotherapy. Palliative treatment represents standard of care for most of the world, Ferry said. Elevated EGFR expression is associated with poor prognosis in esophageal cancer, providing a rationale to investigate EGFR inhibition as potential therapy for the disease. Several small studies and case series showed clinical responses in patients treated with EGFR inhibitors. A phase II clinical trial of gefitinib showed partial responses in 11% of patients, good tolerance, and a trend toward improved survival. The results were considered sufficiently promising to move on to a phase III trial, which Ferry reported at ESMO. Investigators at 51 centers throughout the U.K. recruited patients, from 2009 to 20011, with metastatic esophageal or types I/II junctional squamous-cell or adenocarcinoma that had progressed after prior chemotherapy. Patients with performance status (PS) 0 to 2 were eligible to participate. The trial accrued 450 patients who had a median age of 64, and 83% of the participants were men. Adenocarcinoma accounted for 76% of cases and esophageal involvement for 78%. A fourth of the patients had performance status 0, 54% had PS 1, and 21% had PS 2. Patients were randomized to gefitinib or placebo, and treatment continued until disease progression, as assessed by regular CT scans. The primary outcome was OS, and the trial had statistical power to detect an increase in 1-year OS from 10% to 18%. Secondary outcomes included PFS and health-related quality of life (QOL), focusing on dysphagia, eating, and odynophagia, or painful swallowing. When the trial ended, the gefitinib arm had a 1-week advantage in PFS (42 versus 35 days). Though small, the difference translated into a statistically significant 20% reduction in the progression hazard. As often occurs in trials of advanced cancer, the favorable effect on PFS did not carry over to a survival benefit, Ferry said. The gefitinib group had a median OS of 3.73 months compared with 3.60 months for the placebo group. Performance status strongly influenced the likelihood that a patient would benefit from gefitinib. Patients with PS 0 at enrollment had a median OS of 6.03 months, declining to 3.93 months in patients with PS 1, and to 1.97 months for the PS 2 subgroup (P<0.0001 for trend). Ferry suggested that future trials focus on patients with PS 0 to 1. Clinical benefit rate was another secondary endpoint. In the gefitinib arm, 25.5% of patients achieved partial responses or had stable disease for 8 weeks as compared with 16% in the placebo group (P=0.014). Some patients had dramatic and durable benefits from treatment with gefitinib. Ferry showed PET images demonstrating a partial response that brought about substantial symptomatic relief that lasted for 18 months in one patient. "A number of patients had significant symptom palliation, which is always an important benefit for this group of patients," he pointed out. Analysis of QOL outcomes showed significant improvement in odynophagia among patients in the gefitinib arm (P=0.004). A companion biomarker-based study is ongoing. Investigators are examining biopsy specimens from 300 patients with advanced esophageal cancer in hopes of identifying molecularly defined subgroups that are more likely to benefit from EGFR inhibition. ###