Gefitinib: Small Benefit as Second-Line Therapy in Esophageal Cancer

Gefitinib improved progression-free survival (PFS) and some quality of life measures when used as second-line therapy for esophageal cancer. However, the PFS benefit did not extend to improved overall survival (OS), the primary endpoint of the trial. These were the findings of the first randomized controlled trial to address a second-line treatment for esophageal cancer. The study was presented by David Ferry, MD, New Cross Hospital, Wolverhampton, UK, at the 2012 ESMO Congress in Vienna.

“At the moment, there is no therapy for esophageal cancer that has progressed on first-line therapy. The standard of care after progression is palliative therapy,” Ferry told listeners at an official ESMO press conference September 29.

The Phase III, multicenter, double-blind, study was conducted at 51 centers in the UK. Participants were 450 patients with esophageal cancer or cancer of the esophageal junction who progressed on first-line treatment with up to two previous chemotherapy regimens; they were randomized to the epidermal growth factor receptor (EGFR)-inhibitor gefitinib 500 mg/day versus placebo and treated until disease progression, as documented on regular CT scans.

At baseline, median age was 64 years and 83% were male; 76% had adenocarcinoma, and 78% had esophageal cancer. Twenty-five percent were performance status (PS) 0; 54% were PS 1, and 21% were PS 2.

A small but statistically significant difference in PFS was observed in favor of gefitinib: median PFS was 49 days on gefitinib versus 35 days for placebo (P = .017).

“The improved PFS on gefitinib did not translate to an overall survival benefit. But these patients treated second-line have a very dire prognosis with an overall survival of 2 months,” Ferry said. “We saw durable responses.”

At 8 weeks, disease control was observed in 25.5% of gefitinib-treated patients versus 16% of the placebo group (P = .014).

The investigators found that PS was a prognostic marker for survival in this trial. Patients with PS 0 had a median OS of 6.03 months; those with PS 1 had median OS of 3.93 months; and those with PS 2 had a median OS of 1.97 months.

Both dysphagia (difficulty swallowing) and odynophagia (pain while swallowing) were significantly improved for patients taking gefitinib versus placebo (P = .004). Ferry said that these two symptoms are important indicators of quality of life in patients with esophageal cancer.

The UK investigators are planning an associated study called TRANSCOG to analyze biopsies of more than 300 patients enrolled in the trial to identify molecular characteristics associated with enriched benefit of gefitinib.

When questioned as to why OS was selected as the primary endpoint of the trial, Ferry said, “A drug that doesn’t produce an overall survival benefit is unlikely to get approved. We need to put our new drugs through these tough tests [i.e., overall survival]. Otherwise, no new drugs will be approved for out patients for our patients.

At present, gefitinib should not be used outside of a clinical trial setting. Ferry said: “There is not sufficient benefit of gefitinib in unselected patients. That’s why will do the TRANSCOG translational study to identify biomarkers.”

He and his colleagues are planning a new placebo-controlled trial “with another active drug” using biomarkers for selection. Ferry did not name the new drug to be studied.

“That would be telling a secret,” he commented.

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