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Clinical Trial Suggests Genetic Signatures Could Guide Non-Small Cell Lung Cancer Drug Response

NEW YORK (GenomeWeb News) – New research suggests that advanced lung cancer patients with certain genetic signatures respond to an experimental cancer drug as a first line of defense.
In a paper published in yesterday’s issue of the Journal of Clinical Oncology, American researchers used a prospective, multi-center clinical trial to test genotype-directed treatment with AstaZeneca’s cancer drug Iressa (gefitinib), an epidermal growth factor receptor inhibitor, for advanced non-small cell lung cancer. The team found that, overall, those with EGFR mutations responded to the drug, though this effect was heavily dependant on specific mutations.
“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,” lead author Lecia Sequist, a clinical researcher at the Massachusetts General Hospital Cancer Center, said in a statement. 
Non-small cell lung cancer, the most common form of lung cancer, reportedly causes more deaths in the US each year than colon, breast, pancreatic, and prostate cancer combined. Drugs that inhibit the EGFR tyrosine kinase, such as Iressa and Genentech’s Tarceva (erlotinib), have been tested as potential non-small cell lung cancer treatments, particularly for those who don’t respond to chemotherapy.
But the drugs don’t work for everyone — less than 15 percent of patients with non-small cell lung cancer respond to gefitinib. The US Food and Drug Administration changed the drug’s label in 2005, limiting its use to a small subset of patients.
In 2004, researchers at the Massachusetts General Hospital and the Dana-Farber Cancer Institute reported that certain EGFR mutations that drove tumor development were also associated with better response to EGFR tyrosine kinase inhibitors. Even so, not all EGFR mutations are the same — and some patients with EGFR mutations develop resistance to the drugs relatively quickly.
The latest study, a phase II prospective clinical trial funded by an AstraZeneca, was conducted at 11 different centers over two years and involved 98 individuals with advanced non-small cell lung cancer. Of these, 34 individuals had the EGFR mutations and 31 participated in the trial, taking gefitinib daily instead of getting standard chemotherapy treatment.
More than half — 55 percent — of the 31 patients responded to gefitinib. Overall, one patient had a complete treatment response, 16 had a partial response, 12 had stable disease, and two had progressive disease. The median progression-free survival was 9.2 months and, after a median follow-up time of 12.3 months, 17 patients were alive and 14 had died. One patient left the study due to pneumonitis after 12 days on gefitinib.
The researchers found that the two patients with rapid tumor re-growth had so-called classic EGFR mutations along with additional EGFR mutations, suggesting gefitinib response is stratified by EGFR mutation type.
Even so, there are limitations to the study. For instance, the trial is relatively small, the authors noted, and was designed before the researchers knew that gefitinib would not be widely used in the US.
The authors also noted that “without randomization we could not know whether a genotype-directed treatment strategy provides a survival advantage. EGFR mutations likely portend a more favorable biology and natural history regardless of therapy.” In the future, the authors suggested that the gefitinib therapy should be compared with combination chemotherapy.

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