VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.

Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.

In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor (EGFR) inhibitor.

Median overall survival increased significantly from 1.97 months in patients with a performance status of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).

"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.

The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.

"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing.

He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."

More Study Details

COG was prompted by a round of promising single-agent phase II trials involving the EGFR inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress EGFR.

At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.

Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression. Patients with stable brain metastases who had received prior cranial irradiation were not excluded.

Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments. Performance status (PS) was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.

Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.

Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.

This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).

At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.

Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.

Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.

There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.

Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.

"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth.

Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.

Gefitinib Offers Palliative Care in Advanced Esophageal Cancer