Iressa/Gefitinib Gets Second Chance

[Barb73]

http://www.sciencedaily.com/releases/20 ... 202508.htm

ARTICLE:

. . . . . . . . .

Iressa Proves Just As Effective As Chemotherapy For Lung Cancer

ScienceDaily (Nov. 20, 2008) — Gefitinib, also known as Iressa, the once-promising targeted therapy for the treatment of non-small cell lung cancer, has proven as effective as chemotherapy as a second-line therapy for the disease with far fewer side effects, according to an international Phase III clinical trial, led by researchers at The University of Texas M. D. Anderson Cancer Center.

However, in contrast to earlier Iressa findings, the study showed that there was no additional survival benefit for patients who expressed an elevated level of the epidermal growth factor receptor (EGFR) mutation.

The Iressa in Non-small cell lung cancer Trial Evaluating REsponse and Survival versus Taxotere (INTERST) study, published today in The Lancet, represents a paradigm shift for the treatment of the disease, according to lead author Edward S. Kim, M.D., assistant professor in M. D. Anderson's Department of Thoracic Head and Neck Medical Oncology. It marks the first time in lung cancer that an oral pill has proven as effective as chemotherapy in a head-to-head trial.

"This is the largest study in lung cancer comparing an oral biologic therapy to chemotherapy, and shows, for the first time, that an oral biologic therapy is just as effective as chemotherapy," said Kim, the study's corresponding author. "Based on our findings, I'm hopeful that Iressa can return as a treatment for lung cancer in the United States, offering this some patients a therapy with far fewer side effects."

The study also should offer both physicians and patients some confidence in another biological oral therapy, erlotinib, commercially known as Tarceva, that hits similar targets as Iressa and is commercially available for the treatment of lung cancer in the second line setting, explained Kim.

To best appreciate these findings, it's important to remember Iressa's history, said Kim. Iressa, a once-daily, oral tablet, was the first in a new class of anti-cancer drugs known as EGFR tyrosine kinase inhibitors (TKI) to become commercially available after two Phase II trials found the drug to be efficacious. Iressa was fast-tracked to the FDA and received approval May 5, 2003 as a single agent treatment for patients whose advanced lung cancer had continued to progress despite treatment with platinum-based and docetaxel chemotherapy.

However, in 2005, a large randomized lung cancer study reported that Iressa failed to significantly improve survival in patients with non-small cell lung cancer when compared to placebo. Ultimately, the drug's labeling was altered by the FDA; only cancer patients who had already taken the medicine and whose physicians believed it was helping them were allowed to receive the drug. No new lung cancer patients in the United States were given the drug after this time. However, Iressa remained an available therapy in other countries around the world.

Just prior to these negative findings, the INTEREST study began to enroll patients in 2004. Because of the negative data, INTEREST, an FDA-mandated study, was halted in the United States but continued in other parts of the world.

The Phase III international study enrolled 1,466 lung cancer patients from 149 centers in 24 countries. Of those enrolled, 1,433 were evaluable. All had either locally advanced or metastatic disease and had been previously treated for their cancer. Patients were randomized to receive either Iressa (250 milligrams daily) or docetaxel (75 mg/m2) every three weeks. The study had two primary survival endpoints: in all treated patients and in those whose tumors had high EGFR gene copy number, explained Kim.

When comparing all treated patients, median overall survival for those receiving Iressa was 7.6 months and one-year survival was 32 percent, compared to 8 months and a 34 percent one-year survival for those taking chemotherapy. In an assessment of quality of life, Iressa patients experienced far fewer side effects, with the most common being a rash and diarrhea. In contrast, patients taking docetaxel experienced low blood count, infection, and hair loss.

In the subgroup of 174 patients with a high EGFR gene copy number, median overall survival in the Iressa arm was 8.4 months and one-year survival was 32 percent, versus 7.5 months overall survival and a one-year survival rate of 35 percent for those taking chemotherapy.

Tissue samples were evaluable for at least one biomarker in 453 patients. In an additional analysis of the biomarkers EGFR and K-ras mutations, the study indicates that both mutations are overall prognostic survival markers for lung cancer, but not predictive to treatment with either therapy.

"Our study found that patients who received Iressa and whose tumors had EGFR mutations will have an improved response rate and progression-free survival compared to docetaxel, but overall survival was similar in both treatment groups. In contrast, the K-ras gene mutation proved to be an overall poor prognostic marker, with both treatment arms doing poorly," said Kim.

"As lung cancer researchers, our mandate is to focus on finding appropriate biomarkers for the disease so ultimately, we can begin to tailor therapies for lung cancer patients based on their individual tumor characteristics."

Lung cancer is the leading cause of cancer death in the United States, according to the American Cancer Society. In 2008, approximately 215,000 people will be diagnosed with lung cancer and approximately 114,000 people will die from the disease.

The study was funded by AstraZeneca, makers of Iressa. Dr. Kim has received research funding from, and served as a consultant for, both AstraZeneca and Sanofi-Aventis, the makers of docetaxel.

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 39 Comprehensive Cancer Centers designated by the National Cancer Institute. For five of the past eight years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.

. . . . . . . . .

(Science Daily, Research News, November 20, 2008)

[Ry]

I am so glad to read this. Iressa worked wonders for John and I regretted switching to Tarceva. I always wondered if we should have stayed on the Iressa until it stopped working instead of switching due to one study (which appears to be flawed).

[Barb73]

Ry,

I always wondered why they were so quick to shelve Iressa.

Hopefully, in the future, they will do more intense research before eliminating drugs as viable.

Barbara

[gpawelski]

The cancer drug Iressa actually does work miracles, in some patients. Cell function analysis has been able to find the cellular signal for response to the drug and can identify clinical responders - prospectively.

The Iressa situation is a great argument for pre-screening an individual's tumor. Iressa has been shown to benefit those that are benefitting from it. If the drug is working for some people, then obviously there are others out there who would also benefit. Who are those that benefit from its use? All the more reason to test the tumor first.

Assay-directed therapy is an individualized approach to killing cancer. The bio-marker method is used to determine what precise medications would kill the particular cancer. Doctors have assumed that stopping cell division would stop cancer, because most cancer cells divide and grow rapidly. But the approach didn't always kill the malignant cells. Cancer isn't a case of cells growing out of control, but of cells refusing to die on schedule.

By inhibiting anti-apoptosis with Iressa (small molecule inhibitor of tyrosine kinase, a key intermediary in the EGF cascade pathway), the cells undergo apoptosis and die. This can be detected at the whole cell level and reported out prospectively. It is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.

The EGF system is a target for a number of newer anti-cancer drugs. However, EGF-targeted drugs like Iressa are poorly-predicted by measuring the ostensible target (EGFR), but can be well-predicted by measuring the effect of the drugs on the "function" of live cells. It is an area of cancer research which has been abandoned by the entire cancer research establishment. A bioengineering problem overcomed by a band of private-lab cell biologists.

More and more physicians and patients are turning to individualized therapies to treat cancers. Under this approach, scientists study how an individual's cancerous cells respond to several drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs. Without individualized testing, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.

There are over numerous different therapeutic drug regimens out there. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them. What's needed is to make extensive use of bio-marker tests in treatment decisions.

Literature Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117