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Sloan Kettering Research May Help Eliminate Non-Responders from Iressa, Tarceva Patients

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Another small piece of the Iressa puzzle may have been fitted into place by Memorial Sloan Kettering Cancer Center researchers who seem to have found a way to identify some non-responding patients.

The study, which appears in the current issue of the online journal Public Library of Science Medicine, examines the effect of mutations in the KRAS or EGFR genes on non-small cell lung-cancer patient survival. The two genes produce proteins that function in the same signaling pathway.

“We sequenced the tyrosine kinase domain in EGFR, and then exon 2 in KRAS, in which most of the [KRAS] mutations in lung cancer are found, and correlated with response or lack of response,” lead researcher William Pao told Pharmacogenomics Reporter.

“As previously shown,” EGFR mutations were associated with sensitivity to Iressa and Tarceva, while “only the non-responders had KRAS mutations,” said Pao.

If a patient’s tumor shows an exon-2 mutation in KRAS, “our data would suggest that your tumor will not shrink,” said Pao. “Mechanistically, it might be because the KRAS is downstream, so if you block the EGFR signaling molecule with these drugs, it doesn’t really matter because the [KRAS] mutation downstream is going to bypass the effect anyway,” he said.

Pao and colleagues never found both mutations in the same sample. “You can either have mutations in EGFR or Kras, and that can account for maybe 30 to 40 percent of lung adenocarcinomas,” he said. Research published last spring by the same team indicates that “about 50 percent of never-smokers” and about 5 percent of current and former smokers with non-small cell lung cancer carry the tyrosine kinase EGFR mutation, said Pao.

The researchers suggest that a DNA-sequencing test looking at both genes would prove particularly useful. “The EGFR [sequencing] test is available at Memorial Sloan Kettering,” as well as in other academic centers, said Pao. “We’re also developing a [KRAS] test, so that you could basically test the tumor for both mutations at the same time,” he said.

Patients with a KRAS mutation would probably avoid taking Iressa or Tarceva as a front-line therapy, while those having only an EGFR mutation might use these drugs first, said Pao. He expects the Memorial Sloan Kettering pathology laboratory’s gene-sequencing KRAS test to be ready “soon.”

In light of the recent failure of Iressa to show a survival benefit during phase 3 trials, Pao’s study may prove very interesting to the drug’s maker, AstraZeneca. The pharmaceutical giant has not yet released the recent trial’s pharmacogenomic data, but it indicated that results pointed to a possible survival benefit among nonsmokers and Asians.

“I’d be really interested to see them break it down — especially the [KRAS] mutation data. It could be that maybe a higher percentage of [the sample population] had [KRAS] mutations, so they just didn’t see an advantage,” said Pao.

The Sloan Kettering group did not work with drug developers on the current study, but Iressa and Tarceva’s makers are probably aware of the results, Pao said. The group might be willing to collaborate on an interesting project, he added.

— CW

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