Washington Editor

Genmab A/S began a pivotal survival study of HuMax-EGFr (zalutumumab) in otherwise incurable patients with head and neck cancer, an indication that could serve as a springboard for using the human antibody more broadly down the road.

"In a way, this is a strategy for us to look for a way through the regulatory pathway," CEO Lisa Drakeman told BioWorld Today. Starting with patients "who are very sick and don't have an alternative," the company eventually plans to expand the product's use into first-line head and neck cancer treatment and other diseases, she said. That allows for a quicker route to market with HuMax-EGFr to "help patients faster and help us build a business more rapidly."

The Phase III trial will recruit up to 273 patients, all of whom suffer from squamous cell carcinoma of the head and neck that is refractory or intolerant to standard platinum-based chemotherapy. "There's nothing left to treat them with that has the potential to cure them," Drakeman said, noting that their life expectancy is about three months from that point.

In the study, they will be randomized to receive the drug in combination with best supportive care or best supportive care alone. The patients represent an appropriate population for a product that targets the epidermal growth factor receptor, because about 90 percent of them have it on their tumors.

In the primary endpoint, overall survival from randomization until death, Drakeman expressed hope that treatment with HuMax-EGFr would extend the median by two to three months.

The Copenhagen, Denmark-based company will conduct the trial in the U.S. and Europe, with the majority of enrollees expected from the latter because they don't have the same treatment options there that American patients have. Here, Erbitux (cetuximab, ImClone Systems Inc. and Bristol-Myers Squibb Co.) is marketed in that population, but with a different label than Genmab would seek for HuMax-EGFr.

"Through our discussions with the FDA and the fast-track designation that we have [in this indication]," Drakeman said, "we seem to be in agreement that this is an unmet medical need."

Erbitux, which the FDA approved on objective response rates such as tumor response, has not been part of a survival study in head and neck cancer. Nevertheless, it generated $173 million in sales last quarter, so success in the trial of HuMax-EGFr could distinguish the potential competitors.

Drakeman is eyeballing a launch in 2009 in both the U.S. and Europe, as the study could support FDA clearance and possibly approval in Europe, too, under a new accelerated pathway there.

Patients in the study drug group will receive an initial dose of 8mg/kg of HuMax-EGFr, followed by weekly infusions of a maintenance dose until disease progression. The maintenance dose will be adjusted until patients develop a dose-limiting skin rash, up to a maximum of 16 mg/kg. That rash, which results from EGF treatment with antibodies and small molecules, "correlates with survival," Drakeman said, because it signals saturation of the receptors. "They're getting the drug where they need it to be for the tumors."

Disease status will be assessed every eight weeks until disease progression by computerized tomography or magnetic resonance imaging, and patients will be followed for survival.

Positive Phase I/II findings pushed Genmab toward the study design. In that previous trial, an open-label, dose-escalation study, 20 of 27 original patients completed both the single and multiple-dose portions, and clinical and metabolic response was demonstrated by two types of scanning.

Assessed by FDG-PET, which visualizes tumor metabolism, seven of 18 evaluable patients achieved partial metabolic response and four had stable metabolic disease one week after their fifth and final infusion. In the two highest dose groups, nine of 11 obtained partial metabolic response or stable metabolic disease. Those results were supported by computerized tomography scans, which showed that two of 19 evaluable patients achieved partial response and nine had stable disease. In the two highest dose groups, seven of 10 patients obtained partial responses or stable disease.

Drakeman indicated that Genmab would begin testing HuMax-EGFr in a first-line setting for head and neck cancer "very shortly," probably before the end of this year. The company owns all rights to the drug, although partnering discussions are under way.

That's also the case for HuMax-CD20 (ofatumumab), which is in two Phase III studies to treat chronic lymphocytic leukemia and follicular non-Hodgkin's lymphoma. Data are expected in the second half of next year. Another Phase III product in Genmab's portfolio is HuMax-CD4 (zanolimumab) for cutaneous T-cell lymphoma, and those findings are expected in the first half of next year. It's partnered with Serono SA, of Geneva. Both are accelerated approval candidates, and Drakeman said those later-stage antibodies are expected to enter the market in 2008.

On Thursday, shares in Genmab on the Copenhagen Stock Exchange (CSE:GEN) lost DKK2 to close at DKK224 (US$38.21).