Editor

CHICAGO - "You name the diseases in medicine that we cure," said David Cunningham, lead investigator in Merck KGgA's clinical trial with Erbitux (cetuximab), which became one of the stars at this year's meeting of the American Society of Clinical Oncology.

Silence.

"What we do in coronary artery disease is control the disease," he said. "We put stents in, we operate on patients, we give blood pressure-lowering agents. We use a multi-modality approach."

And that's turning out to be the approach most likely to work not only in colorectal cancer - the illness at which Erbitux and another ASCO star, Genentech Inc.'s Avastin (bevacizumab) are aimed - but in other cancers as well.

It's working for colorectal cancer, Cunningham said a week ago Sunday. Other efforts are making inroads as well.

"The crucial message that I can see, listening to today's presentation at ASCO and a summary of what we've achieved in 10 years, is that people have gone from living an average of six months to nearly two years now, 20 to 21 months," he said.

Due partly to the scandal involving U.S. developer (and Merck partner) ImClone Systems Inc., and due at least as much to hopes of efficacy in a difficult-to-treat disease, Erbitux has become one the world's most-watched drugs.

Cunningham, head of the gastrointestinal and lymphoma units at the Royal Marsden Hospital in London and Surrey, UK, disclosed the Erbitux data Sunday to a crowded ASCO hall, and spoke to BioWorld Financial Watch later, saying "everything that happened with ImClone" would "have no bearing on how we interpret the clinical results."

He was the lead investigator in the 329-patient study known as BOND, which stands for "bowel oncology with cetuximab antibody."

Results from the European trial in metastatic colorectal cancer that expressed the epidermal growth factor receptor, or EGFR, which usually indicates the disease will advance quickly, showed Erbitux in combination with irinotecan slowed progression of the cancer 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.

Long-silent ImClone, with U.S. partner Bristol-Myers Squibb Co., also of New York, issued a joint statement Monday saying they were "encouraged" by the Merck results. Late Thursday, the U.S. companies said they had met with the FDA and would use the Merck data in filing a biologics license application in the second half of this year.

As for any caution that remains in the market, Cunningham said there is "a degree of skepticism and healthy cynicism, and long may that continue. But I think we've got a real drug here."

Avastin, too, redeemed itself in the eyes of doubters at ASCO. And how.

Data from the Phase III trial in more than 900 patients with previously untreated metastatic colorectal cancer 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 - so the study's results went even beyond what the company had hoped for.

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 represents 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 said it is in talks with the FDA regarding the filing of a biologics license application for the drug. Was the company surprised by the good data, given the rumblings about trouble?

"No," said Neil Cohen, associate director of corporate relations for Genentech. "If you look at the Phase II data we had, the colorectal and the renal data, they were positive. We did have adverse events in lung [cancer trials]," he acknowledged, and the missed endpoint in a breast cancer trial - but the company always believed the drug would work differently in each tumor type, Cohen told BioWorld Financial Watch.

The third major newsmaker at ASCO was, like Erbitux, an EGFR drug. And, like Avastin, it's from Genentech.

That drug is Tarceva (erlotinib), being developed in Phase III trials against non-small-cell lung cancer (and in other trials for other indications) in a three-way deal with OSI Pharmaceuticals Inc. and Roche Holdings Inc.

Especially impressive - though early - were data from a Phase I study against brain cancer. Colin Goddard, CEO of OSI, allowed that the dose-ranging study was "not necessarily designed to maximize a search for activity," but noted the results were satisfying enough for Genentech to commit to a Phase II study with OSI.

The approval in May of Iressa (gefitinib), AstraZeneca plc's tyrosine kinase inhibitor pill for advanced NSCLC, shone a spotlight on EGFRs, but Genentech's Cohen said there's room for more than one.

"The drugs are different and we think the results will bear that out," he said.

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.

Another key in cancer is a way to manage side effects of chemotherapy, and ASCO highlighted advances there, too. MGI Pharma Inc. offered data from a Phase III program showing its 5-HT3 antagonist palonosetron (for which a new drug application was submitted last year) beat GlaxoSmithKline plc's market leader Zofran (ondansetron) for chemo-induced nausea and vomiting.

MGI wants to nudge Zofran aside, along with the anti-nausea drugs Anzemet (dolasetron mesylate) from Aventis Pharmaceuticals Inc. and Kytril (granisetron) from Hoffmann-La Roche Inc.

Mucositis, another chemo side effect and one for which there is no approved treatment, is the target of Amgen Inc.'s recombinant keratinocyte growth factor palifermin, for which pivotal Phase III data were disclosed at ASCO.

Compared to placebo, the drug reduced the duration and incidence of severe oral mucositis three times better in patients with hematologic malignancies undergoing high-dose chemotherapy, radiotherapy and total body irradiation followed by hematopoietic stem cell support.

Such drugs will provide valuable backing for chemotherapy and for the likes of Erbitux, Avastin and Tarceva, as the "multi-modality" approach marches ahead, Cunningham predicted.

"We'll see fine-tuning of the management of advanced disease and the very rapid development of these [new anticancer] agents into the adjuvant setting," he said. "Progress is slow, but progress is real."