By Randall Osborne

National Editor

With scandal-tainted but profit-making colorectal cancer drug Erbitux (cetuximab) near approval in Europe, the research firm Datamonitor is resurrecting an old concern about Erbitux, which is but one drug in the headline-making class of epidermal growth factor inhibitors.

Specifically, Erbitux is approved by the FDA for use with irinotecan for patients with EGFR-expressing metastatic disease that is refractory to irinotecan-based chemotherapy, as well as for use as a single agent in those patients who are intolerant to chemotherapy. It's not yet approved in Europe, but the European Union's Committee for Proprietary Medicinal Products has recommended the drug for approval.

Problem: It doesn't always work, even in patients with the "right" tumors. And sometimes it works when nobody expects results. And scientists aren't yet sure why, although the picture has begun to get clearer.

As London-based Datamonitor pointed out, EGFR-expression levels in patients seem unrelated to response to EGFR-inhibiting therapy. A "significant number" of EGFR-positive tumors resist Erbitux, while those widely considered EFGR-negative, in some instances, respond. Such was the word from an editorial in the April 1, 2004, issue of the Journal of Clinical Oncology, by Lee Ellis and Paulo Hoff.

Ellis and Hoff are physicians at the Houston-based M.D. Anderson Cancer Center, and Ellis has been a consultant for ImClone Systems Inc., of New York, which is developing Erbitux with Bristol-Myers Squibb Co., also of New York, and Darmstadt, Germany-based Merck KGaA.

JCO's editorial on the article put the finger on the "considerable challenge" pegged by Datamonitor, i.e., "the lack of a predictive marker that would allow us to select patients who are most likely to benefit from [Erbitux] therapy."

Presence of EGFR "would be the obvious choice, but it does not seem to be particularly helpful," the editorial remarked. "In fact, since all epithelial cells express the EGFR, it is unknown whether those tumors that are now considered EGFR-negative may respond to [Erbitux], especially if the tumor microenvironment is rich in the EGFR ligands transforming growth factor-alpha and epidermal growth factor. In addition, some EGFR activity may be mediated through heterodimerization with HER2/neu and cell-surface receptor cross talk."

Activation of EGFR might be an important signal for tumor-cell growth and survival, but other growth factor receptors - such as cMET (hepatocyte growth factor receptor), the platelet-derived growth factor receptor and the insulin-like growth factor receptor-1, among others - play roles, JCO pointed out. Such receptors might crank up downstream signaling pathways. What's more, activated signaling pathways such as Ras and Src can initiate downstream action that leads to cell proliferation and blocking of all-important cancer cell death.

"Therefore," the editorial said, "if a tumor cell possesses one or more of these receptors or activated signaling intermediates, targeting a single cell-surface protein tyrosine kinase such as EGFR may not be enough to inhibit growth or survival signals." Truths like that can render the laboratory weapon of immunohistochemistry (IHC) less than completely useful.

In IHC, a primary antibody to the specific protein that's being sought is applied to cells or tissue on a slide. Then a second antibody, coupled to an enzyme directed against the first, is introduced. In the final step, the slide is treated with a chromogenic substrate, and scientists look for staining, which gives away the presence of the protein. Thus IHC marks a patient's EGFR "positivity" on a scale. On the same day in mid-February of this year that the FDA approved Erbitux, it granted marketing clearance to Glostrup, Denmark-based DakoCytomation A/S's pharmDx EGFR kit for such testing.

Alas, the rise in IHC-positivity turns out to be no guarantee that Erbitux will beat down the tumor.

EGFR's already complicated picture became even more so late last month when revelatory data were disclosed on another EGFR drug - the approved Iressa (gefitinib), from London-based AstraZeneca plc for non-small-cell lung cancer. Researchers had been puzzled by Iressa's limited efficacy; only about 10 percent of those given the drug had their tumors shrink. It turned out that every one of the improved patients had a mutation of EGFR - a fact that could provide a way of learning how to more accurately aim other drugs in the class, including Erbitux. Harvard researchers published their findings in the New England Journal of Medicine online.

What else might be a clue to efficacy? The widely noted and still mysterious skin rash. None other than Leonard Saltz, father of the widely deployed Saltz regimen of cancer therapy, remarked upon the rash in 2001, commenting on a Phase II study of Erbitux. Patients who came up with the rash had a 29 percent response rate to the drug, while those without had only a 3 percent response rate. That's high statistical significance, even if its significance otherwise is uncertain.

The rash has continued to show up in Erbitux tests - and in experiments with yet another EGFR inhibitor, Tarceva (erlotinib HCl), the NSCLC therapy that widened investor eyes late last month with positive data from a Phase III trial. Tarceva is being developed by Melville, N.Y.-based OSI Pharmaceuticals Inc. and Genentech Inc., of South San Francisco, as well as F. Hoffmann-La Roche Ltd., of Basel, Switzerland, overseas. (See BioWorld Today, April 27, 2004.)

JCO's editorial called the rash a potential "poor man's test" of Erbitux efficacy. While the rash proves EGFR blocking in normal tissues, such as skin, it might not mean anything to the proliferating tumor. But if clinicians find no activity on the skin, they can at least be more confident about diseased tissue going untouched as well.

Such a diagnostic blunt instrument is hardly ideal, but oncologists agree the method will have to suffice until precision tools come down the pike.

The editorial offered qualified hope: "More sophisticated molecular markers, such as phosphorylation of downstream signaling molecules, are also being investigated as predictive markers for therapy. However, since the tumor microenvironment often expresses a wide range of growth stimulatory signals, it is unknown whether the signaling pathways analyzed in the primary tumor are representative of the signaling pathways in metastases, the common target of systemic therapy."

Efficacy puzzles aside, Erbitux is doing well on the market. The drug helped ImClone - once hobbled by the insider-trading controversy that sent its CEO to prison and put domestic maven Martha Stewart on the same course - achieve long-sought profitability. The company's first-quarter earnings saw revenues bounding to $109.6 million, up $90 million from a year earlier, thanks largely to milestone payments and Erbitux royalties from BMS. (See BioWorld Today, April 28, 2004.)