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Iressa Beats Erbitux in EGFR-Mutant NSCLC; Combination Therapy May Be Way to Go

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In the Aug. 17 issue of the Journal of the National Cancer Institute, a team of researchers reports that non-small cell lung cancer tumor cells with common mutations respond much better to AstraZeneca's Iressa than to Erbitux, which is manufactured by ImClone Systems and Bristol-Myers Squibb.

The study's results are not entirely surprising, since Iressa binds to the intracellular tyrosine-kinase domain of EGFR, where the mutations are expressed, while Erbitux binds the receptor's extracellular ligand-binding site.

Nevertheless, the results add to the growing body of knowledge about the molecular behavior of EGFR inhibitors. Around 85 percent of NSCLC patients who respond to small-molecule EGFR inhibitors like Iressa and Tarceva have mutations in the EGFR gene, but little was known about the efficacy of the antibody Erbitux — currently indicated as a second-line stand-alone therapy for colorectal cancer — in EGFR-mutant NSCLC. The drug is currently undergoing clinical trials as a second-line therapy for lung cancer in combination with chemotherapeutics.

"Our question was, 'Are [Iressa and Erbitux] equal methods of targeting the mutant [EGF] receptor?'" said Pasi Jänne, an author of the paper and an assistant professor of medicine at the Dana-Farber Cancer Institute. "And basically, the data from the cell lines would suggest that [Erbitux] is ineffective in causing growth inhibition of the mutant cell lines," he said.

In two wild-type cell lines, Iressa and Erbitux behaved very similarly, with little to no response. A third wild-type cell line showed response to both drugs, while four EGFR-mutant cell lines responded only to Iressa, Jänne said.

Four patients whose tumors carried the mutation, and who had taken the two drugs at different times, also experienced no radiographic tumor regression with Erbitux, but did with Iressa, he said. The patient population was far too small for significant conclusions.

"It looks like the mutation can help us predict which [type of drug] will be of benefit, and which one will not," Jänne said.

While the results suggest that Iressa would be a better choice for most NSCLC patients, an editorial accompanying the paper notes that Erbitux still offers hope as a combination therapy alongside small-molecule EGFR inhibitors.

In the editorial, University of Texas Southwestern Medical Center researchers John Minna, Michael Peyton, and Adi Gazdar briefly discuss their own unpublished research, which indicates that Erbitux "consistently lowers the concentration of [Iressa] required for 50 percent inhibition of cell growth by up to 10-fold in both EGFR mutant and wild-type lung cancer cells."

Erbitux "may still have an effective punch," they write, although they note that details must still be worked out, such as the best schedules and the best way to stratify patient subpopulations.

It is still not known exactly why tyrosine-kinase inhibitors seem to be more effective in EGFR-mutant tumor cells than in wild-type cells. "The mutant receptor probably binds the small-molecule [drugs] much better than the wild-type receptor" since it takes less Iressa to inhibit mutant-EGFR tumor cells than it does wild-type cells, although that reasoning remains speculative, Jänne said. Tarceva — a product of Genentech, OSI Pharmaceuticals, and Roche Pharmaceuticals — should produce results similar to those his group demonstrated with Iressa, he said.

The evidence for all molecular markers of response to the tyrosine-kinase inhibitors remains decidedly mixed, especially the evidence for this specific EGFR mutation. "The mutations predict for response to not only Iressa, but also Tarceva," in research conducted by scientists at the Memorial Sloan-Kettering Hospital, and in as-yet unpublished work Jänne has seen, he said.

But in a clinical trial led by researchers at the Toronto Princess Margaret Hospital, the EGFR mutation was recently found to be an insignificant factor in predicting patient response to Tarceva. The researchers conducting the clinical trial "were unable to do a complete mutation analysis in the vast majority of patients, so that may contribute to some of those findings," said Jänne.

There is not yet a molecular marker to predict response to Erbitux, Jänne said.

About 10 percent to 15 percent of all patients with [NSC] lung cancer have tumors with the EGFR mutation, Jänne said. "It's much more commonly found in patients who are non-smokers, it's more common in women, patients who have adenocarcinoma histology," he said. "It is also more common in patients of East Asian origin."

Perhaps fortuitously for clinicians — depending on whether EGFR mutations turn out to identify Iressa or Tarceva responders — Genzyme will release a diagnostic intended to identify the mutation in cancer cells. The test will be available in "several months," according to a Genzyme spokesperson.

— Chris Womack ([email protected])

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