Zosia Chustecka

September 29, 2012

September 29, 2012 (Vienna, Austria) — No standard of care is available for the second-line treatment of esophageal cancer, but the first large phase 3 trial in this setting has raised some hope. A specific subgroup of patients who have progressed after chemotherapy may benefit from treatment with the targeted therapy gefitinib (Iressa, AstraZeneca), experts said here at the 2012 Congress of the European Society of Medical Oncology.

Conducted in the United Kingdom, the Cancer Oesophagus Gefitinib (COG) trial failed to meet its primary end point and showed no difference in overall survival between gefitinib and placebo.

However, the targeted drug improved many of the secondary end points and showed dramatic response in some patients, reported lead author David Ferry, MD, professor of medical oncology at New Cross Hospital in Wolverhampton, in the United Kingdom. He highlighted 1 patient who had a rapid and durable radiologic response, and who remained progression-free for 20 months, which he described as "remarkable." These patients usually have a poor prognosis, he added. Median survival in this trial was less than 4 months.

Work is now under way to analyze tumor samples from around 300 patients who took part in the trial, in an effort to identify a molecularly defined subgroup of patients who show the greatest benefit from the drug, Dr. Ferry said. Results from this further study, known as TRANSCOG, should be available next year, he added.

"If such a benefit can be identified, then given the good tolerance of gefitinib, it could potentially be used in relapsed esophageal cancer," Dr. Ferry commented.

One clinician said that he would consider using gefitinib off-label in some patients with relapsed esophageal cancer because it is well tolerated. Such patients may include young patients with a lot of symptoms who had previously responded to chemotherapy, commented Roberto Labiance, MD, professor of oncology from the Ospedali Riuniti di Bergamo, in Italy, who moderated the press conference at which the study results were highlighted.

Dr. Ferry emphasized that this treatment is not yet ready for clinical practice, and physicians interested in these results should enroll patients into clinical trials. His message to clinicians is, "There is not enough evidence yet to use gefitinib in unselected patients, no matter how tempted you might be on the basis of anecdotal results that you have heard."

Improvement in Secondary End Points

Enrolling the 450 patients who took part in the COG study took 29 months — longer than had been anticipated, Dr. Ferry said. About 80% of participants had esophageal cancer, and the remainder had type I and type II junction tumors: most (75%) were adenocarcinoma, and the remainder were squamous cell, with a few poorly differentiated tumors. All patients had progressed on chemotherapy (eg, cisplatin plus capecitabine) and were randomly assigned to receive placebo or gefitinib 500 mg/day.

Overall survival was not improved (3.73 months with gefitinib vs 3.60 months with placebo).

However, median progression-free survival was improved to 49 days with gefitinib vs 35 days with placebo (hazard ratio, 0.795; P = .017), as was the disease control rate at 8 weeks (25.5% gefitinib vs 16% placebo; P = .014). In addition, improvements in symptoms such as dysphagia, eating, and odynophagia were noted, Dr. Ferry reported.

No new safety concerns emerged. Adverse events seen with gefitinib included diarrhea and skin toxicity, he said.

Identifying Patients Who Will Benefit

"Do responding patients have activating EGFR [epidermal growth factor receptor] mutations like the super-responders in lung cancer? We don't know yet, but there would seem to be a dominant role for EGFR in a minority of esophageal cancer patients," Dr. Ferry commented in a statement.

In non–small cell lung cancer (NSCLC), patients who harbor an EGFR mutation derive significant benefit from treatment with targeted EGFR inhibitors such as gefitinib and erlotinib (Tarceva, Genentech/Astellas).

It may not be the same story in esophageal cancer, commented Arnuad Roth, MD, from Geneva University Hospital, in Switzerland, who acted as discussant for the article. Around 50% to 70% of esophageal cancers show overexpression of EGFR, but mutations are rare, and something else may be going on here. There may be some other abnormalities, he said.

Analysis of genetic expression profiles and proteomic studies should yield some data regarding which patients are responding, he noted.

"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," Dr. Roth stated, "and better knowledge will lead to better treatment."

"This is just the beginning of a spicy story," he added.

The COG study was funded by Cancer Research UK, and gefitinib was provided free of charge by AstraZeneca. Dr. Roth has reported no relevant financial relationships.

European Society of Medical Oncology 2012 Congress. Presented September 29, 2012: Abstract LBA20_PR.

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