Advanced Esophageal Cancer Patients Offered New Hope

Liam Davenport

November 18, 2014

Patients with advanced esophageal cancer have benefited from the targeted drug gefitinib (Iressa, AstraZeneca Pharmaceuticals LP), and patients who are likely to respond can be identified by a simple diagnostic-grade test, potentially increasing disease control and survival, conclude UK investigators.

The TRANS COG study, a subgroup analysis of a larger trial, found that esophageal cancer patients for whom other treatments had failed responded to gefitinib, which acts as an inhibitor at the epidermal growth factor receptor (EGFR). Furthermore, patients were more likely to respond if they were found to have increased expression of the EGFR gene. "These patients were resistant to chemotherapy and often quite near the end of their life, unfortunately," lead researcher Russell Petty, MD, Medical and Experimental Oncology Group, University of Aberdeen, told Medscape Medical News.

"Having seen this signal, it would be of interest to see if it translate forward into the first-line treatment setting and maybe into the adjuvant, postoperative setting, where, potentially, if the same holds true, it would be much more effective," Dr Petty commented.

The study was presented at the National Cancer Research Institute (NCRI) Cancer Conference 2014, in Liverpool, United Kingdom.

Gefinib is currently used in the treatment of EGFR-positive lung cancer in many parts of the world, but the drug is not available in the United States. There are, however, several other EGFR inhibitor–targeted agents on the market, including erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc).

Signal in Initial Study

The original Cancer Oesophagus Gefitinib (COG) study was a phase III, parallel, randomized, placebo-controlled trial in which 450 patients from 48 centers across the United Kingdom were randomly assigned to receive either gefitinib 500 mg or matching placebo.

Patients had either advanced esophageal cancer or type I/II Siewert junctional tumors, histologically confirmed squamous cell carcinoma, or adenocarcinoma that had progressed after chemotherapy.

There was no difference in overall survival between patients given gefitinib and those assigned to placebo, at a hazard ratio (HR) of 0.90 (P = .29), and there were no significant differences in global quality life (P = .293), dysphagia (P = .228), and eating (P = .168).

However, there were some interesting signals from the results. "What came out of that was that it did appear there was a minority subgroup, perhaps 1 in 10 patients, that had rapid and durable responses to gefitinib," commented Dr Petty. "These were patients who would otherwise be expected to be in the terminal phase of their illness ― if you like, within a few months of death."

He added that the patients who responded did so "very dramatically, with improved symptoms within several weeks of starting treatment." He observed that the patients often returned to normal levels of activity, in some cases for many months, and even up to 2 years.

Dr Petty continued: "We were encouraged by that, but we realized that in order to make this an effective treatment, we would have to find a biomarker test to identify those patients that were responding."

For the current investigation, the team selected biopsy specimens from 295 patients in the original COG trial and carried out a series of biomarker tests to determine whether patients who responded to treatment could be identified.

Test to Identify Responders

Specifically, the researchers performed a fluorescent in situ hybridization (FISH) test, looking for increased copy numbers of the EGFR gene. "Scientifically, we felt that this was most likely to be the test that would identify those that would respond, and we hypothesized that those that had increased numbers of EGFR...would be the ones that would be sensitive," explained Dr Petty.

Analysis revealed that 16.3% of patients were positive for EGFR copy number gain (CNG). Patients positive for EGFR CNG had significantly improved overall survival when treated with gefitinib compared with placebo (HR = 0.52, P = .033), with improvements seen at 3, 6, 9, and 12 months.

Patients who were positive for EGFR CNG also experienced improvements with gefitinib in comparison with placebo in terms of progression-free survival (HR = 0.55, P = .051) and disease control rates (39% vs 14%, P = .054).

No improvements in any measures of survival or disease control with gefitinib therapy were observed in patients who tested negative for EGFR CNG.

Dr Petty commented: "There was a clear signal that EGFR copy number gain was able to identify the subgroup of patients that have the rapid and durable responses."

He added: "It's the first time that a targeted therapy, as opposed to chemotherapy or radiotherapy, has been shown to be effective in the disease. And it's also the first time that there's been a personalized treatment strategy that's been effective ― in other words, using a biomarker to decide who gets the treatment."

"That's why we're quite excited about these results, because we feel it's been a key advance," Dr Perry commented.

Need More Data

Approached for comment, Alok A. Khorana, MD, associate professor and vice-chief of hematology-oncology, University of Rochester, in New York, said to Medscape Medical News: "It's obviously very interesting."

"Researchers have been trying to use anti-EGFR agents in this setting for a long time, and in other settings we have a better idea of which patients will benefit."

He observed: "For esophegeal cancer, in the past we have not had such biomarkers, and certainly this is very interesting and raises very important questions about how best we can identify patients who potentially benefit from what's really a very well-tolerated and generally nontoxic treatment."

Nevertheless, Dr Khorana commented: "Having said that, it is one study, and we would want this to be confirmed before we start using it in general practice. But it certainly offers a way to identify at least a small subgroup of patients who could potentially benefit from anti-EGFR therapy."

Dr Petty believes, however, that gefitinib could already be used in the clinic for the treatment of esophageal cancer. "It is possible to prescribe and use gefitinib in an off-label fashion," he said. "At the moment, it's licensed and approved for use in lung cancer."

He noted that patients could be chosen on the basis of the EGFR FISH test, which his team developed as a diagnostic-grade test to be robust and reliable. He said: "If patients are positive for EGFR copy number gain, by a FISH test by our criteria, then I think that there is a valid reason to prescribe gefitinib in an off-label fashion."

"The ball is now in the court of patients, I suppose, and their oncologist to decide upon that and decide whether it's something that they wish to pursue," Dr Perry commented.

One stumbling block is that the manufacturer, AstraZeneca, would have to apply for a license and regulatory approval for use of gefitinib in esophageal cancer. "They are aware of the data, and as far as I am aware, they are considering it, but they haven't confirmed or otherwise that they are going to get that license," said Dr Petty.

The finding also opens up this therapeutic area for other manuafcturers of EGFR inhibitors to explore.

Proof of Principle Established

What Dr Petty believes is particularly important about the findings, however, is that they establish the proof of principle that a biomarker can be found in esophageal cancer and that a targeted therapy will work.

"We are now looking to use next-generation DNA sequencing to characterize all the patients from the study, from all the samples we have, in a lot of detail," he said. "The aims of that are to see if we can get an even better biomarker for gefitinib with even greater accuracy, and the other reason is to try and find markers for the other 85% of patients that don't respond to gefitinib."

"I think it is likely, extrapolating this research, that there will be other targets, and we can find markers for them that will allow us to treat these other patients with a personalized treatment approach."

I suppose it is a watershed moment in that regard in esophageal cancer. Dr Russell Petty

Dr Petty concluded: "I suppose it is a watershed moment in that regard in esophageal cancer because it's shown that the same personalized treatment approaches can work in this disease as has been shown to work in breast cancer and renal cancer and melanoma and all the other examples which are very promising."

"I suppose that wasn't always thought to be the case, given the lack of progress that we've seen in esophageal cancer," he added.

The TRANS-COG trial was funded by the Scottish Government's Chief Scientist Office, the Cameron Clinical Academic Fellowship, and the Grampian Gastro-oesophageal Cancer Research Fund (GASTROCAN). The researchers have reported no relevant financial relationships.

National Cancer Research Institute (NCRI) Cancer Conference 2014, November 2-5, Liverpool, United Kingdom. Presented November 4, 2014.


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