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Upcoming EGFR Inhibitor May Take Erbitux Route, Embrace PGx Later

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WASHINGTON, DC — An epidermal growth factor receptor inhibitor under development at Amgen and Abgenix may enable physicians to treat colorectal cancer in patients who have failed standard chemotherapy, and it may require a pharmacogenomic test, according to data presented at the American Association for Cancer Research meeting, held here this week.

A phase III trial of the drug, a human monoclonal antibody called panitumumab, showed clear advantages in progression-free survival over best supportive care. Since it was developed in the mould of preceding EGFR inhibitors, such as ImClone's Erbitux, only patients testing positive for EGFR staining by immunohistochemistry were enrolled in the trial.

And like with Erbitux, panitumumab's manufacturer may seek to take steps to ensure that the drug is not limited to patients who only test positive for EGFR by IHC.

If the US Food and Drug Administration approves Amgen and Abgenix's biologic license application, filed last week, the drug's label may recommend an EGFR staining test. However, a recent study has shown that individuals who test negative for EGFR by IHC respond to Erbitux. And because Erbitux and panitumumab work in the same way, it could mean that the Amgen drug might not require EGFR testing.

"For the moment, in the literature, we know that some patients with EGFR-negative tumors also have an effect of inhibition with … panitumumab," Marc Peeters, director of gastrointestinal oncology research at the University Hospital of Ghent, Belgium, told Pharmacogenomics Reporter this week. "Probably in the future, it would not be necessary to have this staining done."


"Probably in the future, it would not be necessary to have this staining done."

There is reason to think that tumors that test negative for EGFR IHC staining might sometimes respond to panitumumab. Small datasets published for Erbitux, which has the same molecular target as panitumumab, show nearly the same response rate in patients with tumors staining negative for EGFR as in patients whose tumors stain positive, said Peeters. "I think immunohistochemistry to determine EGFR status is not the right way to do it," he said.

Instead, other molecular markers might prove useful to identify patients responding to panitumumab. Peeters points to FISH as a possible method, although work in the area is "very preliminary."

A May 2005 study in The Lancet by an Italian group searching for Erbitux response biomarkers in colon cancer identified gene amplification of EGFR as the best correlate, William Pao, a researcher at Memorial Sloan-Kettering Cancer Center, who has worked extensively on the EGFR pathway, said in June. The test "could be a readily available test, because we do that testing in breast cancer — for Her2, you look for gene amplification," he said.

About 25 percent of patients with EGFR IHC-undetectable disease in lung cancer and in colon cancer respond to Erbitux, Eric Rowinsky, ImClone's chief medical officer, said in a June interview with Pharmacogenomics Reporter. "Immunohistochemistry as a test is a terrible test — every laboratory has its own procedure," said Rowinsky. "As a test it just doesn't stand up — it can't be quantitated very well, nor qualified," he said. "We need to look for other predictors, and we're doing that in several trials with our partner Bristol-Myers [Squibb]."

In one of the trials with BMS, researchers explored approximately 40 genes as candidates for biomarkers of Erbitux response using gene-expression microarrays, said Rowinsky.

The phase III panitumumab trial involved 463 patients split between a group receiving only best supportive care, and an arm receiving the compound and best supportive care. Following a median time of 19 weeks, patients receiving the compound showed a significant advantage in progression-free survival, with a progression rate approximately 46 percent that of the best supportive-care group.

Forty-nine percent of patients on panitumumab survived to the eight-week checkpoint, as compared to 30 percent of the best supportive care group, and a difference between the two groups persisted through week 32.

The drug improved "progression-free survival, the hazard ratio was substantial, and particularly in the early phases of the trial, the patients on best supportive care were either failing or dying very quickly, and the effect of panitumumab was obvious and fairly impressive," said James Abbruzzese, professor of medicine and chairman of the department of gastrointestinal oncology at the University of Texas MD Anderson Cancer Center, during a press briefing at the AACR meeting. "As the patients in the study dwindled, it was a little bit more difficult to be sure what was happening — there may be some issues later on in terms of resistance," he said.

Current first-line treatment for colorectal cancer includes fluoropyrimidine, oxaliplatin, and irinotecan. In Europe, panitumumab can quickly take a place in the sequence of treatments, said Abbruzzese. In the United States, Erbitux is available as a second- or third-line treatment.

There is a need for panitumumab to "continue to work hard to figure out where it's going to end up in the overall medical practice" for treating colorectal cancer patients in the United States, said Abbruzzese. "Those trials are in progress, and I think we'll know more in the next year or 18 months," he said.

— Chris Womack ([email protected])

 

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