Cell Mutation Identifies Patients Who Benefit From New Lung Cancer Drug

By Rachael Myers Lowe, cancerpage.com

(April 29, 2004) – Japanese and American scientists have discovered why 10% of lung cancer patients are likely to respond dramatically to the drug gefitinib (Iressa) while the majority of patients do not.

Patients with non-small-cell lung cancer whose tumor had a mutation in the epidermal growth factor receptor (EGFR) responded to the drug while patients whose tumors did not have this mutation did not.

“We now have discovered a rational basis for determining who should get the drug,” Dr. Daniel Haber of Massachusetts General Hospital Cancer Center told cancerpage.com.

Haber was a member of a team reporting its work in the May 20^th issue of the New England Journal of Medicine. The research was released early to coincide with the publication this week in the journal Science of another team’s work on the same subject.

Gefitinib is one of a number of new “smart bomb” cancer drugs on the market that target specific vulnerabilities in cancer cells.  Known as an epidermal growth factor receptor inhibitor, gefitinib attaches itself to an epidermal growth factor receptor on a cancer cell’s surface, preventing a working epidermal growth factor protein from attaching there to do its cell division work.

Conventional chemotherapy attacks both cancer and normal cells leading to many of the side effects associated with cancer therapies such as nausea, hair loss, and a compromised immune system. But because gefitinib zeros in on mutated EGF receptors it targets cancer cells only. As a result fewer side effects are associated with its use.  Patients are warned about the possibility of rashes, acne, diarrhea, loss of appetite and some nausea. In a small percentage of cases, more serious complications leading to pneumonia and death have been reported.

Clinical trials for gefitinib and other drugs like it have been disappointing because of the low number of patients who respond. Yet, when a patient does respond, the response is often quick and dramatic. Identifying the patients who will benefit has been a major challenge.

The test to identify the mutation is not generally available though Haber says “it’s a relatively easy test to do and if licensed quickly, it could be available in a couple of months.”

The studies identified certain patients were more likely to carry this beneficial mutation than others. The most prevalent cell type in non-small-cell lung cancer is adenocarcinoma. About one in five adenocarcinomas examined carried the mutation. It was most likely to be seen in a type of adenocarcinoma not associated with cigarette smoking, broncoalveolar tumors. The mutation was more likely in female patients (20%) than in male patients (9%) and more frequent in patients from Japan (26%) than in patients from the US (2%.)

In an accompanying editorial in the New England Journal of Medicine, Dr. Mark Green of the Medical University of South Carolina contends that this work, if confirmed in additional studies, “will fundamentally change targeted therapy for solid tumors.”

Green says oncologists face a “conundrum of when to offer an approved, highly publicized, expensive, and somewhat toxic therapy and when to select another option.”

Taken once a day, gefitinib can cost between $1,500 and $2,000 a month depending on dosage and where you buy it. Being able to identify patients who will benefit “has the potential to lift this burden from patients and physicians,” Green writes. Clinical Trials Seek More Uses for Gefitinib

Currently gefitinib is approved by the FDA as a third-line treatment for lung cancer patients who have not responded to conventional therapy.

Studies are currently underway to test whether gefitinib can prevent the cancer from coming back in patients who have been through surgery. Other trials are testing gefitinib in combination with radiotherapy or conventional chemotherapy drugs.

While gefitinib does not offer a cure for lung cancer, it keeps the cancer’s growth and spread in check.

“The response is not permanent,” Haber points out. Conceivably, patients would take gefitinib once a day for however long it continued to work, whether that is a month or years.

Clinical trials are also looking into gefitinib’s effectives against other solid tumors such as breast, colon, and pancreatic cancers, and gliomas. But Haber says the EGFR mutations that signaled gefitinib’s effectives in non-small-cell lung cancer have yet to be found in these other tumors.

• New England Journal of Medicine 2004, May 20 early release.
•  Science 2004, www.sciencexpress.org/ 29 April 2004 / 10.1126/science.1099314
• Cancerpage.com telephone interview with Dr. Daniel Haber, April 28, 2004.