Skip to main content
Premium Trial:

Request an Annual Quote

New Article Makes Case for EGFR Testing Before Using Iressa for NSCLC Treatment

Newly published research led by Massachusetts General Hospital Cancer Center suggests genetic screening of non-small cell lung cancer patients for certain epidermal growth factor receptor mutations may help identify the 10 percent of North American lung cancer patients who might benefit from AstraZeneca’s Iressa — a drug that currently has limited distribution in the US due to poor efficacy in the general lung cancer population.
Iressa, an EGFR tyrosine kinase inhibitor, “is much more effective in the genetically targeted population,” Lecia Sequist, lead author of the report, published in the May 20 issue of the Journal of Clinical Oncology, told Pharmacogenomics Reporter last week.
Only about one out of ten non-small cell cancer patients in the general population respond to the drug, also known as gefitinib, and show a median time-to-tumor growth of around two months. According to Sequist, chemotherapy is twice as effective as Iressa is in the general lung-cancer population, with a response rate between 20 percent and 30 percent and a median time-to-tumor growth of around four months.
“What we found is that gefitinib, in a targeted population, appears even more effective than chemotherapy, with a response rate of 55 percent and a time to tumor growth of nine months,” said Sequist, who is also a member of the clinical research faculty at the Massachusetts General Hospital Cancer Center and Harvard Medical School.
According to the study, genetic screening may identify those patients for whom Iressa can become a first-line treatment. “First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance,” the authors write in the JCO paper.
If the results of study are validated, it is conceivable that with the help of a companion diagnostic for Iressa, AstraZeneca may be able to make a case for the FDA to expand the drug’s indication in the US.
AstraZeneca provided funding for the trial, which the published article discusses. The company did not respond to requests for comment.
Small Target
The US Food and Drug Administration approved Iressa in 2003 for non-small cell lung cancer, but AstraZeneca informed the agency a year later that it would limit distribution of the drug in the US after the drug failed to show a survival advantage in the general NSCLC population in a randomized clinical trial.
In June 2005, the FDA approved new labeling for the drug that limited its indication only for patients who, in a physician’s opinion, are benefiting from it. Since then Iressa has been used as a third-line NSCLC treatment for patients who have failed to respond to at least two chemotherapeutic agents.
The demotion has forced AstraZeneca to lose its NSCLC market share in the US to Genentech’s EGFR tyrosine kinase inhibitor Tarceva.

"We think these results will also apply to other effective EGFR inhibitors, and we hope they can be duplicated for other types of cancer that involve these mutations.”

On the diagnostic front, Genzyme has seen the companion diagnostic opportunities in the EGFR expression market since at least 2005 when it began offering fluorescence in situ hybridization-based EGFR-expression testing services.
“Based on current literature, EGFR gene amplification and/or high polysomy, as measured by FISH testing, have shown statistical significance in association with better response, disease control rate, time to progression, and survival in patients with non-small cell lung carcinoma who are treated with tyrosine kinase inhibitors” such as Iressa and Tarceva, also known as erlotinib, Genzyme states on its website.
The company recommends that oncologists prescribe its EGFR test in conjunction with other clinical information. Turn-around time for results is between two and three days.
Laboratory Corporation of America offers a PCR-based “investigation-use-only” EGFR test to help determine how NSCLC patients respond to Iressa. And Monogram’s VeraTag technology, which is currently under development, is being designed to interrogate EGFR and other HER-receptor family members targeted by approved cancer therapies, which may be useful as a tool to gauge Iressa response.
The study published in JCO stands to boost these companies’ position in the EGFR-testing market, and could invite additional competition.
Dx Files
In the study, which began the same year that AstraZeneca said it would limit how it will sell Iressa in the US, the researchers began genetically screening 98 chemotherapy-naïve patients from 11 centers with advanced NSCLC and one or more clinical characteristic associated with EGFR mutations. The team used DNA sequencing to analyze tumor tissue at EGFR exons 18 to 21. The trial lasted two years.
Out of the 98 patients, 34 were found to have a sensitizing mutation, leaving 31 individuals to be enrolled in the trial to receive Iressa until tumor progression or until they experienced “unacceptable toxicity.”
The researchers identified 53 percent of EGFR mutations at exon 19 and 26 percent at L858R, while 21 percent of the mutation-positive cases had less common subtypes, including exon 20 insertions, and T790M/L858R, G719A, and L861Q mutations.
“Patients with the two most typical mutations had vigorous responses to Iressa, but the seven patients found to have atypical mutations had a more limited response,” Massachusetts General Hospital Cancer Center reported in a statement last week announcing the JCO findings. “None of the atypical cases had tumor shrinkage, but the majority had disease stabilization for a period of time.”
Meanwhile, two patients whose cancer relapsed were found to have additional mutations at T790M EGFR and had MET amplification, which earlier studies have suggested conferred resistance to Iressa.
“It has been theorized that those resistance mutations develop in response to treatment, but this is the first observation of the mutations being present before treatment began,” according to the JCO paper.
Ultimately, only two study participants did not benefit from treatment with Iressa. All other patients’ tumors shrunk “significantly” or ceased to grow for a month or longer. By the end of the two-year study, Iressa yielded a 55 percent response rate in the genetically-screened population and showed a median progression-free survival of 9.2 months. Fourteen patients died.
Approximately 13 percent of patients had grade 3 toxicities including one grade 3 pneumonitis. One participant dropped out due to side effects associated with Iressa.
"It's starting to look like the strategy of genomically directed cancer therapy will need to incorporate testing for multiple genotypes — screening for three, four, or even more genetic markers, some of which may indicate likelihood of response to treatment, and others the chance of resistance," Sequist said in a statement. "We think these results will also apply to other effective EGFR inhibitors, and we hope they can be duplicated for other types of cancer that involve these mutations.”
According to Sequist, a larger randomized trial is needed to directly compare chemotherapy and Iressa as first-line treatments for non-small cell lung cancer patients with these specific EGFR mutations. Such trials are currently underway in Asia and Europe.
According to Sequist, approximately 10 percent of NSCLC patients in North America, and more than 35 percent of NSCLC patients in East Asia display response mutations associated with Iressa. “It is not known why there is such a difference,” Sequist said.
At Mass General, researchers are continuing to investigate strategies to prevent, delay, and treat resistance to EGFR TKIs that develop in patients with mutations.
"This is a pivotal clinical trial that demonstrates the power of personalized medicine in lung cancer treatment," Sequist said.

Filed under

The Scan

Study Tracks Responses in Patients Pursuing Polygenic Risk Score Profiling

Using interviews, researchers in the European Journal of Human Genetics qualitatively assess individuals' motivations for, and experiences with, direct-to-consumer polygenic risk score testing.

EHR Quality Improvement Study Detects Demographic-Related Deficiencies in Cancer Family History Data

In a retrospective analysis in JAMA Network Open, researchers find that sex, ethnicity, language, and other features coincide with the quality of cancer family history information in a patient's record.

Inflammatory Bowel Disease Linked to Gut Microbiome Community Structure Gradient in Meta-Analysis

Bringing together data from prior studies, researchers in Genome Biology track down microbial taxa and a population structure gradient with ties to ulcerative colitis or Crohn's disease.

Ancient Greek Army Ancestry Highlights Mercenary Role in Historical Migrations

By profiling genomic patterns in 5th century samples from in and around Himera, researchers saw diverse ancestry in Greek army representatives in the region, as they report in PNAS.