VIENNA—Targeted therapy with gefitinib significantly improved the progression-free survival rate when given as second- or third-line treatment for advanced esophageal cancer, according to results of the Cancer Oesophagus Gefitinib (COG) trial.
However, the improvement in the time to progression was small—only about two weeks—and the drug failed to improve the overall survival rate, the study's primary endpoint, reported the principal investigator, David R. Ferry, MD, Professor of Medical Oncology at New Cross Hospital in Wolverhampton, UK, speaking here at the European Society for Medical Oncology Congress.
He said he still considers the study (Abstract LBA20) a success, though, in that “a number of patients had significant symptom palliation, which is always an important benefit for this group of patients. Additionally, durable responses were seen in some patients. This is the first-ever Phase III trial of second-line treatment after chemotherapy in this ‘Cinderella’ malignancy. The standard of care across the world is palliative care once cancer has progressed on first-line therapy.”
Yet second-line treatments are desperately needed, given that at presentation, most cases of esophageal cancer are inoperable and that about 50 percent of patients have disease progression on first-line chemotherapy, he said in response to a question from OT at a news briefing held prior to the presentation. “And by six months later, cancer starts to come back in the rest, so in a sense, all the patients eventually progress,” he said.
Epidermal growth factor receptor (EGFR) is almost universally expressed in adenocarcinoma of the esophagus and is a negative prognostic factor, providing a rationale to investigate treatment with an EGFR inhibitor such as gefitinib as treatment for the disease, Ferry noted, saying that several “promising” Phase II studies showed improved response rates in patients treated with EGFR inhibitors. One such trial, which he headed, showed a disease control rate (partial response plus stable disease) of 37 percent and “good tolerance” in 27 patients treated with gefitinib (Clin Cancer Res 2007;13:5869-5874 ).
Together, the mid-stage studies warranted a Phase III trial of gefitinib against placebo in patients progressing after chemotherapy—a study which Ferry stressed was not funded by a drug company. Cancer Research UK funded the study, with AstraZeneca providing the drug for free.
Included were 450 patients with histologically confirmed esophageal cancer or gastroesophageal junction tumor including the following subtypes: adenocarcinoma, squamous cell cancer, poorly differentiated epithelial malignancy, or gastroesophageal junction with Siewert Type I or II tumors. All patients had metastatic disease, which had progressed after no more than two prior chemotherapy regimens and one course of chemoradiation.
Twenty-five percent of the patients had a Performance Status (PS) of 0, 54 percent had a PS of 1, and 21 percent had a PS of 2.
Patients were randomized in a 1:1 fashion to receive oral gefitinib (500 mg) or oral placebo once daily. Treatment continued until disease progression, as measured by regular CT scans, or unacceptable toxicity.
The primary endpoint was overall survival, with the trial powered to detect an increase in the one-year survival rate from 10 to 18 percent.
Secondary endpoints were progression-free survival; toxicity and safety; quality of life; and health-related quality of life as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, with particular attention paid to questions on eating and swallowing, Ferry said.
Results showed a similar median overall survival time: 3.6 months in the placebo arm and 3.7 months in the gefitinib arm.
The progression-free survival time was 1.6 months in the gefitinib arm vs. 1.2 months in the placebo arm. “While the difference may seem small, please keep in mind the very dire progression of these patients' disease, with an overall survival of just 3.6 months in the placebo arm,” he said.
Gefitinib-treated patients also had a significantly better rate of disease control: At eight weeks, disease control was observed in 25.5 percent of those patients vs. 16.0 percent of the placebo group.
Performance status strongly predicted the response to gefitinib. Patients with PS 0 at baseline had a median overall survival time of about six months, compared with about four months in patients with PS 1, and about two months for patients with PS 2. “We need to define which patients benefit, as some patients benefit a little and some benefit a lot,” Ferry said, explaining why he thought future trials should include PS 0 or PS 1 as inclusion criteria.
To illustrate the “rapid durable radiological and palliative response” experienced by some patients, he showed CT images of one patient that clearly demonstrated significant tumor shrinkage on Day 21 of treatment. The partial response was accompanied by a decrease in morphine dose. At 18 months, however, the scan showed regrowth of the tumor, and the patient reported return of baseline-level pain.
As for quality of life, there was a significant improvement in dysphagia and odynophagia among patients in the gefitinib arm, Ferry said. “A number of patients had significant symptom palliation, which is an important benefit for this group.”
Adverse events were consistent with those seen in the Phase II trials, with generally mild, but also Grade 3, diarrhea and rash being most frequent, he said.
Companion Biomarker Study
In a companion biomarker study, the TRANSlational Cancer Oesophagus Gefitinib (TRANS-COG) study, the researchers are performing molecular analysis of tumor samples from some 300 patients in an effort to correlate biomarkers with benefit from EGFR inhibition, Ferry said.
Asked why overall survival was selected as the primary endpoint of the current trial, he said that drugs that don't produce an overall survival benefit are unlikely to be approved.
For now, gefitinib should be given only to patients with esophageal cancer who are participating in a clinical trial, he said. “There is not sufficient benefit of gefitinib in unselected patients. That's why we will do the TRANS-COG translational study to identify biomarkers.”
‘Proof of Concept’
Asked to comment on the findings, Roberto Labianca, MD, Chair of Medical Oncology at Ospedali Riuniti di Bergamo in Bergamo, Italy, and a specialist in GI cancers, said he is so impressed by the improvement in quality of life that he recommends off-label use of gefitinib for selected patients.
The trial provides “proof of concept that targeted therapy with an EGFR inhibitor can benefit patients who progress after first-line chemotherapy,” he said.
And while the “modest improvement in PFS of two weeks is not relevant from a clinical point of view, the fact that the drug can not only slow the cancer but improve the symptoms of painful and difficult swallowing is very important to patients' quality of life. From my point of view, I would use gefitinib off-label in patients with good performance status and a lot of symptoms. Also, in younger patients as they tend [to comply with medication instructions].
“Still, [the treatment] is not water,” he continued, meaning that the drug does carry a risk of adverse events. “So I would only use it as second-line treatment in patients who initially responded well to first-line chemotherapy. In my opinion, they have a better chance of responding.”