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New Studies Look Beyond EGFR Mutations for Clues to Sensitivity to Erlotinib

Rabiya S. Tuma

The approval of erlotinib (Tarceva) in November 2004 was based on the results of a randomized, placebo-controlled trial called BR.21, in which the drug improved overall survival for patients with non–small-cell lung cancer who had already been treated with one or two chemotherapy regimens. Despite the survival benefit, only a small percentage of patients showed substantial tumor shrinkage in response to the drug.

When data from BR.21 were released in May 2004, it appeared that erlotinib would follow in the path of another epidermal growth factor receptor (EGFR) inhibitor, gefitinib (Iressa)—that researchers would find that patients with EGFR mutations would be the best responders. However, a retrospective analysis of the trial, presented this May at the annual meeting of the American Society of Clinical Oncology, shows that's not likely to be the case. Those data leave open the question of why only a subset of patients show strong responses to erlotinib and, perhaps more important, what defining characteristics that patient group has.

In BR.21, patients on erlotinib had a median survival of 6.7 months compared with the 4.7 months for the patients in the control arm who received best supportive care. The overall response rate, by RECIST criteria, which reflects tumor shrinkage, was 9% in the erlotinib arm and less than 1% in the placebo arm.

In the new retrospective analysis of BR.21 data, Ming S. Tsao, M.D., and colleagues from the Ontario Cancer Institute and Princess Margaret Hospital in Toronto and OSI Pharmaceuticals looked for correlates of response to erlotinib. Researchers were able to perform mutation analysis on tumor samples from 197 of the 731 patients enrolled in the study. Of those, they successfully sequenced the exons encoding the kinase domain of EGFR from 177 samples. Forty patients had mutations in the EGFR gene.



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Ming S. Tsao

 
The presence of a mutation nearly doubled the response rate between the two groups (7.4% in the wild-type group compared with 15.8% in the mutation group), but the difference was not statistically significant. Furthermore, there was no difference in survival associated with the presence or absence of the mutations. "Patients with mutations did not derive greater benefit from erlotinib than wild type," concluded Tsao.

Although the numbers are small in the retrospective analysis compared with the study as a whole, OSI scientists are satisfied that mutations are not the key to determining sensitivity, said Gabriel Leung, M.S., president of OSI Oncology, which markets erlotinib. As such, the company does not plan to perform any prospective trials addressing the question.

Bruce Johnson, M.D., one of the scientists who first discovered the link between EGFR mutations and gefitinib response, isn't so quick to dismiss the role of mutations in erlotinib sensitivity. "We believe the mutations define a biologically important subset of patients," said Johnson. "There is a lot of information about the interaction between mutations and gefitinib treatment. The studies with erlotinib are less mature, and Ming Tsao's data suggests that it is not as straightforward as we see with gefitinib." The fact that the two drugs behave differently may be a dose effect or a real effect, but that won't be known until the studies are done, said Johnson, director of the Thoracic Oncology Program at the Dana-Farber Cancer Institute in Boston.



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Bruce Johnson

 
Tsao's group also looked at the prognostic value of EGFR expression and gene amplification and found that gene copy number may be an important predictor of response to erlotinib. When researchers compared the response rates in patients with high copy number (20% of 25 evaluable patients) versus low copy number of the EGFR gene (2.4% of 41 patients), the comparison was statistically significant but did not hold up in terms of overall survival.

Fred Hirsch, M.D., and colleagues at the University of Colorado Health Sciences Center found a strong correlation between clinical response to gefitinib and gene copy number (see article, Vol. 97, No. 9, p. 643). They are now planning two prospective trials to test the relationship between erlotinib and gene copy number, including one with the Southwest Oncology Group cooperative group.

The fact that researchers are now considering copy number and expression level is important, according to Alan Sandler, M.D., a thoracic oncologist at Vanderbilt Medical School in Nashville, Tenn. "When you discover one thing, like the mutations, everything else sort of gets pushed aside," he said. With the presentation of Tsao's results, he said, the field is ready to look more broadly for correlates of response. (Sandler has received honoraria and research support from and served as a consultant for Genentech, makers of gefitinib, and OSI Pharmaceuticals.)



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Alan Sandler

 
In fact, Daphne Haas-Kogan, M.D, of the University of California, San Francisco, and colleagues recently explored the relationship between response to erlotinib and EGFR expression or phosphorylated PKB/Akt, an enzyme, in patients with malignant glioma (see article, Vol. 97, No. 12, p. 880). They found that patients with high levels of EGFR expression and low levels of phosphorylated PKB/Akt had a better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.

Scientists at OSI think the reason some tumors respond and others don't has to do with the relative maturity of the tumor. Epithelial-derived cancer cells take on a more mesenchymal phenotype as they separate from one another and start to invade. During this epithelial-to-mesenchymal transition, the cells alter expression of extracellular matrix proteins, turning off E-cadherin and turning on vimentin, for example. Cells early in this process are sensitive to erlotinib, but those that have switched to vimentin expression are resistant, said Neil Gibson, Ph.D., vice president of research at OSI. The correlation holds for patient samples from both lung cancer and pancreatic cancer, according to work the group presented at the American Association for Cancer Research annual meeting earlier this year. Gibson also noted that other groups have shown an interaction between E-cadherin and EGFR expression.

His team is working on a retrospective analysis of samples from BR.21 and other large randomized erlotinib trials to see how well the epithelial-to-mesenchymal correlation holds up. "If it looks good, then we will think about prospective trials," said Gibson.

Meanwhile, other researchers think that looking at the top of a signaling pathway doesn't make sense when what really counts is whether the cell is proliferating or not. For that reason, Naoto T. Ueno, M.D., Ph.D., of the Breast Cancer Research Program at the University of Texas M. D. Anderson Cancer Center in Houston, has looked at the activity of a key cell cycle regulator, CDK2, in sensitive and resistant tumor cell lines. They found a correlation between increasing resistance and increasing CDK2 kinase activity, which promotes cell cycling. The amount of protein or activity of proteins in the pathway steps between EGFR and CDK2 do not seem to be related to erlotinib sensitivity, according to Ueno's data. "If you don't suppress CDK2, then erlotinib doesn't work regardless of phospho-AKT status," said Ueno, referring to one of those intervening proteins. "If you want to arrest the cell growth, then CDK2 has to be turned off."

Leung, however, doesn't envision that erlotinib works through just one pathway. "The drug goes down at least two different pathways that we know of," said Leung. "One is more closely linked to apoptosis, so by blocking that one, we trigger cell death and tumor shrinkage. But the pathway we originally thought it would block is more of a growth pathway, and if you inhibit it, you drive the cell into stasis," said Leung.

Regardless of the current lack of agreement on what the likely correlates of response are for erlotinib, everyone agrees the flurry of activity can only benefit the field. "Trying to sort this out is good," said Johnson. "We just have to have the discipline to ask the questions to figure out what is important here. I think at the end of the day we will make a lot of progress figuring out the relationship between mutations, copy number, immunohistochemistry, or whatever technique is required for figuring out who is going to benefit it from this."

From his view, however, Sandler noted the irony of the current emphasis on trying to distinguish the strong responders from those who just achieve stable disease. "It is funny to me that people are so concerned that we find the right subset of patients for erlotinib because of its response rate. Its response rate in a randomized trial was higher than docetaxel's was, and yet we're not looking to find the 8% or 6% that respond to docetaxel."



             
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