National Editor

Genentech Inc.'s much-praised cancer drug Avastin, awaiting approval at the FDA, missed the primary endpoint in a Phase II trial, but the company said it expects no delay in getting the product cleared for marketing.

Wall Street seemed unshaken by the news. Genentech's stock (NYSE:DNA) dipped 59 cents Wednesday to close at $83.78.

"Not hitting an endpoint per se is not meaningful in a Phase II trial," said Winton Gibbons, analyst with William Blair & Co. in Chicago. "And it wasn't that they didn't get the results they expected, they just weren't statistically significant."

He also told BioWorld Today that "with the data they have here, if I were a physician, I would be inclined to use the drug." Statistical significance, he added, is "a confidence-interval game, depending on what happens if you are right and what happens if you are wrong. A lot of people mix this up."

The Phase II study was designed to investigate Avastin (bevacizumab) plus 5-FU/Leucovorin chemotherapy in 209 previously untreated metastatic colorectal cancer patients.

Median survival, the primary endpoint, was 29 percent - not statistically significant. But the study also showed a 67 percent longer median progression-free survival, which was highly statistically significant, in patients treated with Avastin plus 5-FU/Leucovorin, compared to 5-FU/Leucovorin alone.

5-FU and Leucovorin make up two-thirds of the Saltz regimen, used in the widely hailed, much larger pivotal Phase III trial of Avastin in 900 patients, positive data from which were disclosed in May at the American Society of Clinical Oncology's annual meeting. (See BioWorld Today, June 3, 2003.)

The third part of the Saltz regimen is irinotecan (also known as CPT-11), and the Phase II study enrolled patients considered nonoptimal for irinotecan as a first-line therapy.

Although possibly disappointing to some investors, the Phase II trial results are similar to the Phase III data, but on a smaller scale that turned out to be not statistically significant with regard to median survival.

In the Phase III trial testing Avastin with the Saltz regimen, median survival increased by 30 percent - from 15.6 months to 20.3 months - and the median time to disease progression was 71 percent.

Avastin in the latest reported Phase II was well tolerated, and the safety profile was consistent with earlier trials testing the drug in colorectal cancer. Only Grade 3 hypertension, managed with oral medications, and asymptomatic proteinuria were increased.

As in the pivotal Phase III study, a few patients in the Phase II trial had incidents of gastrointestinal perforation, although that was uncommon (two cases, 2 percent).

Gibbons noted that South San Francisco-based Genentech's stock took a sharp dip on first word of the Phase II news but then seemed to recover "as people started realizing what was going on."