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About seven months after the Phase II trial of the monoclonal antibody Avastin (bevacizumab) reached its efficacy endpoint and was stopped, Genentech Inc. unveiled the study's positive results in kidney cancer at the annual meeting of the American Society of Clinical Oncology in Orlando, Fla.

"We don't have a [Phase III kidney cancer] program yet, but we're in discussions" with the FDA and the National Cancer Institute, which ran the Phase II trial, said Colleen Sweeney, manager of corporate communications, from the ASCO meeting.

"We're going to find out how we should structure the program," she added. "I don't have a definitive time line."

The Phase II study of 116 patients showed that patients with metastatic kidney cancer treated with 10mg/kg of Avastin every two weeks showed a statistically significant increase in the primary endpoint - time to disease progression - compared to placebo patients.

Also, cancer in Avastin patients took two and a half times longer to manifest measurable growth than the cancer in those given the placebo, adding more credibility to Avastin's anti-angiogenesis approach, which has gained support through positive data in Phase II studies in colorectal and breast cancers. Phase III studies in those indications are under way. (See BioWorld Today, May 23, 2000.)

"The first Phase III trial we'll get data back on is the breast cancer trial, sometime this year," Sweeney told BioWorld Today. That trial has an endpoint of time to disease progression.

"It's not a survival trial, so it's a little different, and the FDA hasn't given us any sort of range [of data required for filing a new drug application]," Sweeney said. "They have said that, for the data to be file-able, it would have to be very significant. They've never said it would be definitely file-able, and they haven't said it wouldn't be."

Either way, the company "will definitely learn a lot" from the study of 450 patients, which is testing Avastin with Xeloda (capecitabine) vs. Xeloda alone for refractory metastatic breast cancer.

"We'll see, in terms of filing," Sweeney said. "These patients are refractory, and some have failed a couple of regimens. These are pretty sick women. Even looking at time to progression, we'll still learn a lot. If we didn't file for [breast cancer], the next one would be colorectal cancer."

Data from that Phase III study, with 900 patients and survival as an endpoint, are due next year, she said. The study is comparing Avastin plus CPT-11/5-FU/Leucovorin - the well-known Saltz regimen - to the Saltz regimen alone.

In the meantime, ASCO attention was on the kidney cancer results. A third arm of the trial studied patients given low-dose Avastin therapy (3mg/kg every two weeks), who also showed a trend toward improvement in time to disease progression compared to placebo. Avastin patients' disease took 1.3 times longer to grow measurably.

Adverse events that appeared more often in patients given Avastin included nosebleeds, fever, hypertension and asymptomatic proteinuria.

Genentech offered long-term Avastin data, too, from 35 cancer patients with advanced cancer (17 colorectal, 12 non-small-cell lung, five breast and one prostate) who had received single-agent Avastin therapy or Avastin plus chemotherapy for at least a year.

"It's a small group of patients who had been enrolled in either the Phase I or Phase II Avastin trial," Sweeney said. "These are folks who, when they reached the end of the study, were still taking Avastin and doing well, and they elected to continue. It's not really a study, but a subset of patients we pooled in this poster to look at."

Especially encouraging, she said, was that "some patients treated with Avastin stopped, and their disease progressed. They went back on Avastin and saw response the second time. There are some patients still continuing on the therapy, and some [have survived] 40-some months," though the advanced stage of their disease would have suggested only a year or so.

Specifically, 23 patients given Avastin for more than a year had an off-treatment observation period and resumed treatment with Avastin when their disease progressed. Twenty-two (96 percent) achieved a response or disease stabilization on their first course of Avastin, and 13 of the patients (57 percent) showed a response or disease stabilization on their second course of the drug.

Seventy-one percent (25 out of 35) patients who received more than one year of Avastin were still alive. The median survival of those patients has not been reached, but is at least 27.5 months.

In the long-term study, adverse events that appeared more often in the Avastin patients were bleeding, thrombosis, hypertension and proteinuria. While the rate of hypertension was lower in patients treated for one year than in the overall Phase I/II treatment population, the rate of bleeding, thrombosis and proteinuria matched in both groups.

The apparent lack of thromboembolitic problems was a relief to some analysts, Sweeney acknowledged.

"We did see, in our Phase II trials in other cancers, there were some incidents of thrombosis or bleeding," she said. "Since we're working on blood vessels, that's a common question that people ask."

Patients treated for a year or more who developed bleeding or thrombosis (known to be a complication of cancer treatment) while on Avastin were able to restart with the drug after they were treated for those problems.

In the Phase II studies, most adverse events with Avastin in combination with chemotherapy were consistent with those of chemotherapy alone. Most often observed in the combination arms were headache, fever, chills, bleeding, rash, hypertension, diarrhea and stomatitis, proteinuria and thrombosis.

Genentech's stock (NASDAQ:DNA) closed Monday at $38, down 25 cents.

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