COG study: Addressing the need for second-line treatments in oesophageal cancer

Phase III, randomised, double-blind, placebo-controlled trial of gefitinib versus placebo in oesophageal cancer progressing after chemotherapy

The first phase III trial to address the need for second-line treatments in oesophageal cancer shows that gefitinib improves important quality-of-life measures and extends progression-free survival, researchers from Cancer Research UK reported at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

Each year, around 50,000 oesophageal cancer patients in the European Union relapse after first line chemotherapy. Yet currently, no treatments have been shown to prolong survival or improve quality of life in this second-line setting.

The COG study included 450 patients from 51 UK centres who had already progressed after first line treatment with up to two chemotherapy regimens, and were administered either placebo or the EGFR-inhibitor gefitinib. Median progression-free survival was 35 days for patients who received placebo, and 49 days for those administered gefitinib. Treatment with the drug also improved dysphagia and odynophagia, two important indicators of quality of life in this patient group.

In addition to the quality-of-life improvements and modest improvements in progression-free survival, some patients saw durable benefits from the treatment. A further study, TRANSCOG, is planned to analyse over 300 patients’ biopsies in an effort to identify a molecularly defined subgroup where the benefit is enriched, said study author Prof. David Ferry from New Cross Hospital in Wolverhampton, UK.

If such a benefit can be identified, then given the good tolerance of gefitinib it could potentially be used in relapsed oesophageal cancer, according to Prof Ferry. Do the responding patients have activating EGFR mutations like the super-responders in lung cancer? It is not known yet but there would seem to be a dominant role for EGFR in a minority of oesophageal patients.

This trial also shows that large randomised trials can be run in oesophageal cancer and rapidly recruit large numbers of patients. Performance status is a strong predictor of overall survival, and for patients with performance status 2, the median survival of 1.97 months was much worse than for those with performance status 1 or 0. Future studies should probably concentrate on patients with good performance status.

Commenting on the study, Prof. Jean-Yves Douillard, ICO Centre Rene Gauducheau, France, Chair of the ESMO Educational Committee, who was not involved in the study, said that this study is interesting and innovative. As stated by the author, there is no standard of care for such disease in second-line. However, more patients nowadays are eligible for second-line chemotherapy. The COG study showed that gefitinib at the high dose of 500 mg per day improves progression-free survival, the primary endpoint, with a significant reduction of 21% in the risk of progression, but a modest benefit of the median (2 weeks).

The improved progression-free survival may reflect a benefit in a subgroup of patients sensitive to gefitinib and the ancillary study TRANSCOG is looking at a predictive biomarker, possibly an EGFR mutation as seen in lung cancer. Hopefully a biomarker predicting efficacy will be identified to allow the use of gefitinib in this type of cancer in a personalised fashion. Considering the present practice however, future studies should have a more active treatment choice than placebo in the control arm, according to Prof. Douillard.