Say "Erbitux" to biotechnology investors and you're likely to get a reaction that is definitely . . . ambivalent.

Center of an exhaustively publicized trading scandal that sent ImClone Systems Inc.'s top man to prison and put home décor guru Martha Stewart on the same route, the epidermal growth factor receptor inhibitor Erbitux (cetuximab) still charmed the scientific world.

It's doing good things for ImClone's balance sheet, too. In April, the company reported first-time profitability, with some $650 million in aggregate milestone payments chalked up so far from Erbitux partner Bristol-Myers Squibb Co. In detailing first-quarter results, ImClone officials said sales were recorded from the beginning of distribution on Feb. 24, just after Erbitux won FDA approval for late-stage colorectal cancer.

Specifically, the drug is for use in combination with irinotecan to treat patients with EGFR-expressing, metastatic disease who are refractory to irinotecan-based chemotherapy and for use as a single agent in those patients who are intolerant to the chemotherapy.

Weirdness around the company persisted right up to approval. ImClone's stock nose-dived 21 percent in the hours before the disclosure of Erbitux's approval by the FDA. Jittery investors apparently believed rumors that the agency would reject Erbitux. That didn't happen, and the day after approval ImClone gained back the loss and more, rising almost 29 percent.

EGFRs, in any case, have steadily gained favor. They rocked the 2003 meeting of the American Society of Clinical Oncology in Chicago, at which overseas partner Merck KGaA offered Erbitux data and Genentech Inc. did the same for Tarceva (erlotinib HCl), another EGFR drug.

Tarceva's bigger news came late last month, when positive Phase III results in non-small-cell lung cancer boosted Genentech's stock as well as the shares of partner OSI Pharmaceuticals Inc. (Swiss firm Roche Holdings Inc. also is part of the Tarceva project.)

The EGFR marketplace pioneer, of course, is Iressa (gefitinib), AstraZeneca plc's tyrosine kinase inhibitor pill for advanced NSCLC, approved in May 2003 - although Erbitux for various reasons has gained more press.

Approved by the Swiss and U.S. regulatory authorities, Erbitux has been recommended for approval by the European Union's Committee For Proprietary Medicinal Products, so Europe-wide marketing seems like a sure thing.

Rash Is Important Clue, But Not The Whole Story

But there's a problem, points out industry research organization Datamonitor - and it's one clinicians have wrestled with: The level of an individual's EGFR expression seems to be unrelated to response to EGFR-inhibiting therapy.

Immunohistochemistry (IHC) testing can establish a patient's EGFR "positivity" on a scale ranging from minus-one to plus-two. 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 primary one, is introduced. At the end, the slide is treated with a chromogenic substrate, and scientists look for staining, which gives away the presence of the protein.

A rise in IHC positivity, though, is hardly a sure-fire way to figure increased response to anti-EGFR therapy. What's more, a significant number of EGFR-positive tumors have been found to be resistant to Erbitux. Even worse (or better, for the lucky patient), certain tumors widely considered EGFR-negative might respond to the drug.

Downstream signaling could be implicated in all this, but no one knows yet. The point is, Erbitux evokes a highly individualized response, and the challenge for researchers is to devise tests to predict which patients can best reap the benefit of Erbitux's magic - and the magic of the other EGFRs, for that matter. They're working on it.

At the 2003 ASCO meeting, OSI's Tarceva data from a Phase II trial pointed to a possible crystal ball for response - the company cliamed it saw a "very strong correlations of [skin] rash to survival outcome in lung, ovarian and head and neck cancer. In essence, those patients [who developed the skin rash side effect] did markedly better from a survival outcome perspective than those who didn't." Erbitux researchers already noted this, although OSI's were the first to find it, in late 2002, said CEO Colin Goddard. (See BioWorld Financial Watch, June 9, 2003.)

It wasn't the first time skin rashes and Erbitux found themselves in the same room at ASCO. In 2001, Leonard Saltz - developer of the tripartite Saltz regimen of cancer therapy - remarked upon the rash in a Phase II study with Erbitux. Patients who came up with the rash had a 29 percent response rate, while those who did not had only a 3 percent response rate, which amounts to a result with high statistical significance.

It has continued to show up in trials. As a forecasting method, skin rash is far from foolproof, Datamonitor pointed out, since it might be an indicator of EGFR inhibition in normal tissues but not in the tumor. But on the other hand, if the rash fails to show up, the drug's efficacy is less likely than otherwise. So the method is better than nothing, Datamonitor said.

Roman Perez-Soler, physician and director of medical oncology at Albert Einstein College of Medicine, has been involved with EGFRs since about 1992.

"I've been there when nobody really paid attention," he told BioWorld Financial Watch. Perez-Soler has taken part to some degree in research on Iressa and Erbitux, but has done the most with Tarceva, with which he conducted a Phase II trial.

He said he is "convinced that the patients who develop rash are those who live longer," although "the Iressa/AstraZeneca group has been skeptical, not willing to accept that. In all the trials, when investigators looked at the relationship between rash and survival, it's been positive. The problem has been that the two key trials for Iressa were about 250 patients total, and it's being said that all the responders had rash, but [researchers at AstraZeneca] have not shown the data" matching rash with survival.

Mutation Marks Exquisite Responders,' But Who Resists?

Perez-Soler, who will present a number of papers on EGFRs at the ASCO meeting in June, is so confident about his theory that some in the industry have nicknamed him "Dr. Rash" (and officials at Genentech once gave him a tee shirt bearing a slogan that played upon the advertising pitch, "Got milk?"). But he allowed that patients who develop rash might simply have better immune systems to begin with, since if the drug dosage is pushed high enough, most patients will get the rash.

Complicating the situation (or perhaps ultimately simplifying it) is the Iressa news disclosed late last month, when researchers at the Dana Farber Cancer Institute found a specific EGFR mutation directly linked to efficacy of the drug, which works only in about 10 percent of patients.

Perez-Soler said AstraZeneca might be shy about the rash-to-survival data because "there has been a philosophy from the beginning that these therapies would be tumor specific, so you would not have to push the dose up to the limit as we have done with chemotherapy. That's probably true with people with [EGFR] mutations, but there may be another group of patients in which that margin between the therapeutic and toxic levels are very close."

Those pinpointed with EGFR mutations, he added, are in a class of "exquisite responders. These may not be all the group of people you want to treat. Other people may not respond as well, or they may have stable disease [as a result of treatment] and live longer."

The mutation assay, Perez-Soler said, "probably is a way to identify people who respond so well that, if you had that information, the drug would be the first choice. But what we need is an assay of resistance. That's what we don't have."

Could resistance be due to a different EGFR mutation?

"I don't think it is, but it could be," he said, noting that the more common event is that the tumor "gets smart" and begins to resist the drug. "That's what happens with Gleevec [imatinib, the cancer drug from Novartis AG]," he said.

Finding a way to test patients likely to be the best responders, along with patients who won't respond at all - that is, being able to determine which tumors need the EGFR pathway (mutated or not) to thrive and which will grow to kill without it - would be a major advance, Perez-Soler said.

"If we do what we want to do, which is to tailor therapies to people, we need both sides," he said.