National Editor

CHICAGO - After a wet, blustery start to the weekend, Lake Michigan sparkled under a clear sky Sunday, dotted with sailboats pushed along by lighter breezes. It was a day the likes of which many cancer patients are privileged to enjoy too few.

At the American Society of Clinical Oncology's annual meeting, held at McCormick Place on the lakeshore, scientists gathered to explore ways medicine might change that.

The world's largest cancer meeting with about 26,000 expected registrants, ASCO offered an avalanche of data. More than 900 pages of abstracts are summarized in the book of proceedings.

A clear ASCO show stealer was South San Francisco-based Genentech Inc.'s Avastin (bevacizumab), which shut down the skeptics as it proved positive in a Phase III study with previously untreated metastatic colorectal cancer patients.

But anxious investors also finally got a peek into Merck KGaA's progress with Erbitux (cetuximab) - which in the U.S. became stalled by regulators and then embroiled in the financial scandal involving Merck partner ImClone Systems Inc., of New York.

"When people saw the failed Phase III [Avastin] trial in breast cancer, they took a step back," said Neil Cohen, associate director of corporate relations for Genentech. "But we've been saying it would work differently in every tumor." (See BioWorld Today, Sept. 11, 2002.)

Avastin is a humanized therapeutic antibody designed to inhibit tumor growth by binding to and inhibiting vascular endothelial growth factor, which plays a role in tumor angiogenesis.

"There is a theory that once you get too late in a disease, there's not just VEGF working; other angiogenic factors are at play," Cohen told BioWorld Today, moments before Herbert Hurwitz, of Duke University Medical Center, presented the data.

"We have a first-line breast cancer trial [under way]," Cohen added. "That will answer more questions. If that works, it could have been we were treating people too late in their disease" in the first trial.

Avastin Presentation Draws A Crowd

Hundreds of listeners crowded into the vast lecture hall for Hurwitz's presentation. The image of the man, a tiny figure standing at the distant lectern, was projected onto four huge projection screens. Lights went down. His paper was introduced.

"There it is," whispered one attendee to the man sitting beside him.

There it was. Data from the Avastin Phase III trial in more than 900 patients showed the study met its primary endpoint of improving overall survival, with patients getting the drug plus chemotherapy increasing their chance of survival by 50 percent compared to those given chemo alone. The hazard ratio was 0.65 (p=0.00003).

Genentech designed the study to detect a hazard ratio of 0.75, which would correspond to a 33 percent increase in survival.

As Cohen put it, "The study met and exceeded what we were looking to study" - and it was the first time an anti-angiogenesis drug had emerged from a Phase III trial so impressively.

Patients were randomized to get either Avastin plus the standard-of-care chemo - 5-FU/leuvocorin/CPT-11, also known as IFL - or the IFL regimen plus placebo.

Specifically, the benefit represented an extension in the median survival of patients treated with Avastin plus chemotherapy by about five months, compared to patients treated with chemo alone, 20.3 months vs. 15.6 months.

Median time to progression increased 71 percent, from 6.24 months in the chemo arm to 10.6 months in the Avastin plus chemo arm (p<0.00001). Avastin plus chemo improved overall response rates from 35 percent in the group receiving chemo alone to 45 percent with Avastin plus chemo (p=0.0029). Duration of response jumped to 10.4 months with Avastin plus chemo from 7.1 months with chemo alone (p=0.0014).

Genentech is in talks with the FDA regarding the filing of a biologics license application for the drug.

"Avastin Rules, And [Genentech] Owns ASCO!" enthused analyst Michael King of Banc of America Securities, who had once been among the drug's doubters, in the title of a research report issued Monday.

"We expect Genentech to file its [Avastin] application with the FDA sometime in the next few months," King wrote. "In our opinion, Avastin is the prototypical drug that the FDA would like to see on the market in the minimum amount of time possible." King estimated that could come as early as the end of the year.

When Hurwitz's talk was finished, throngs of audience members trooped out of the hall, leaving the next speaker to discuss the pharmacogenomics of cancer to their backs.

Erbitux Data Help Put Scandal In Background

Somewhat muted but equally deserved excitement greeted the metastatic colorectal cancer data on Erbitux, presented in the same hall by David Cunningham, on behalf of Darmstadt, Germany-based Merck.

Cunningham, head of the gastrointestinal and lymphoma units at the Royal Marsden Hospital in London and Surrey, UK, was the lead investigator in the study known as BOND, which stands for "bowel oncology with cetuximab antibody."

Given the FDA's refusal of ImClone's rolling BLA for Erbitux in irinotecan-refractory colorectal cancer and the ensuing disgrace from an investigation into the company's management, observers had begun to lose the distinction between the drug and its developers. (See BioWorld Today, Jan. 3, 2002.)

Whether Erbitux - a monoclonal antibody that targets the epidermal growth factor receptor - works had become a question of long standing, at least in the minds of some. But after Cunningham spoke, the compound tested in the BOND study was no longer a secret agent.

Results from the European trial in 329 patients with metastatic colorectal cancer that expressed EGFR (usually a marker of fast advance) showed Erbitux in combination with irinotecan slowed progression of the disease by more than four months, shrinking tumors by 50 percent or more in 22.9 percent of patients.

Two-thirds of the patients were given Erbitux and irinotecan, with the rest getting only Erbitux. Overall response rate was 11 percent for Erbitux alone. With irinotecan, the number jumped to 23 percent, proving that the combination works even when patients have stopped responding to irinotecan.

Merck, which licensed rights outside the U.S. and Canada from ImClone in 1998, plans to submit an application for approval of Erbitux to European and Swiss regulators this summer, and could be marketing the drug in Switzerland late this year and in the European Union next year.

ImClone, with U.S. partner Bristol-Myers Squibb Co., also of New York, issued a joint statement Monday saying they are "encouraged" by the Merck results.

ImClone's stock (NASDAQ:IMCLE) gained encouragement, too, ending at $33.50, up $5, or 17.5 percent - on top of a run-up already this year - on a day that generally favored the sector, but generally not that much.

"I think everything that happened with ImClone, and I'm not aware of all the details, should have no bearing on how we interpret the clinical results," Cunningham told BioWorld Today. "This is a resoundingly positive trial, and that will be the main determinant of what we do in clinical practice. Everybody wants this agent to receive a license as soon as possible so that our patients can get the treatment."

He acknowledged that Erbitux "is not a big quantum leap - bang, this is the cure - but the study shows an incremental benefit. Move this to the adjuvant setting, move [Tarceva] to the adjuvant setting and who knows? We could begin to see more cures up front."

Added Cunningham: "I think we've got a real drug here. I've used it personally on 20 patients as part of this trial and it's good. It's good."

Tarceva Takes Place On Center Stage

Genentech's Tarceva, another EGFR drug, is being developed in Phase III trials against non-small-cell lung cancer in a three-way deal with OSI Pharmaceuticals Inc., of Melville, N.Y., and Roche Holdings Inc., of Basel, Switzerland. Among OSI's offerings at ASCO was data in a poster session from a Phase I/II trial of Tarceva with Avastin in recurrent NSCLC.

Colin Goddard, CEO of OSI, said the "real news" was elsewhere. He pointed to Phase I results with Tarceva against malignant glioma (brain cancer).

"It's a remarkable piece of work," he told BioWorld Today. "This is a very tough setting." The trial was a "dose-ranging study, not necessarily designed to maximize a search for activity," but results were good enough for Genentech to commit to a Phase II study with OSI.

Monday morning, OSI disclosed also-positive numbers from a Phase I/II trial of Tarceva in bronchioloalveolar cell carcinoma - a 26 percent response rate in 50 patients.

"It's a remarkable set of data," Goddard said, noting this type of cancer "and its variants probably make up 20 percent of all [NSCLC]," and the results show cause for optimism with the drug as a monotherapy.

"Our approach has been more aggressive in a dosing sense than the folks at AstraZeneca," he added. "Getting the dose right is going to be very important."

EGFRs gained credibility with the approval in May of London-based AstraZeneca plc's tyrosine kinase inhibitor pill for advanced NSCLC, Iressa (gefitinib).

An OSI presentation was slated for today to include a "retrospective analysis of all Phase II data, showing very strong correlations of 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."

In the Erbitux study with colorectal cancer, Cunningham noted similar results. "We were pleased [to see that]," Goddard said. "We were first to point this out last November."

OSI's stock (NASDAQ:OSIP) closed Monday at $28.25, up $1.89. Genentech's shares (NYSE:DNA) gained $4.12 to close at $66.73.

Given all this, Genentech's Cohen said, Tarceva is hardly a "me-too" tablet.

"The drugs are different and we think the results will bear that out," he said. "We haven't seen our Phase III results. That will answer more questions."

Final data from a pair of Phase III studies of Tarceva in combination with paclitaxel and carboplatin against NSCLC as a front-line therapy are expected in July. At ASCO, Genentech disclosed favorable results in a Phase I trial against malignant glioma (brain cancer).

Merck has more in the pipeline, CEO Bernhard Scheuble said, adding that the company is not "an oncology player only." The company's main focus is cardiovascular disease and diabetes, although several projects in the latter area recently were discontinued - due partly to "positive oncology news," an apparent reference to Erbitux but also a possible reference to Theratope, the vaccine for metastatic breast cancer, which Scheuble mentioned three times.

Mixed news on Theratope, partnered with Biomira Inc., of Edmonton, Alberta, came last fall when a Data Safety Monitoring Board conducted an interim analysis of the companies' 1,030-patient trial of Theratope vaccine and recommended it continue to conclusion. (See BioWorld Today, Sept. 20, 2002.)

But the board also said data that it reviewed did not meet the predetermined statistical significance required for either endpoint - survival and time to disease progression - possibly due to the built-in attempt at getting strong, early results through the interim board review.

Final results likely will be disclosed later this month, Scheuble said.

"If the data are positive, then of course we will be very happy and we'll be struggling to get sufficient support for the project," he said. "That will be a very pleasant situation to be in."

Merck also has, through its U.S. subsidiary EMD Pharmaceuticals Inc., of Durham, N.C., EMD 72000. In Phase II trials, EMD 72000 is another EGFR drug being tested in gastric, cervical and ovarian cancers as well as NSCLC.

Unlike Erbitux, which is a chimeric antibody, EMD 72000 is fully humanized, and Merck owns the worldwide rights to it, although the product is much further back in the pipeline and likely to launch no sooner than 2007.

That, of course, is a rather long time away. Words often heard at ASCO were "time" and "incremental advance." Speaking of Erbitux, Cunningham said, "Progress is slow, but progress is real."

Many audience members at the ASCO meeting, which continues through today, likely were believers. Like someone at a religious revival, one man seemed unable to contain himself when he stood at a session Sunday afternoon to ask a question of the presenting scientist.

"It's a great day for medicine!" he began.

During the breaks, some attendees stood on McCormick Place's upper deck, feeling the breeze and gazing out at Lake Michigan, where the sailboats drifted across on the bright water like messengers of hope.