By Karen Pihl-Carey

Five months after announcing it would move forward into pivotal Phase III trials with its recombinant humanized monoclonal antibody to vascular endothelial cell growth factor (rhuMAb-VEGF), Genentech Inc. presented the data responsible for its decision - positive Phase II results in advanced metastatic colorectal cancer.

The results, presented Sunday at the 36th annual meeting of the American Society of Clinical Oncology in New Orleans, showed rhuMAb-VEGF achieved its primary endpoints of response rates and time to disease progression. Genentech, of South San Francisco, plans to initiate a Phase III trial by the end of the third quarter. It still is working with investigators and the FDA regarding the study's design.

"What we were very pleased with was that all the efficacy endpoints, response rate and time for progression, were improved in both anti-VEGF-treated arms," said Gwen Fyfe, senior director of oncology at Genentech. "In addition, survival was improved in both arms as well, and remarkably, more in the low-dose arm than in the high-dose arm."

In the open-label Phase II study in 104 patients previously untreated for advanced metastatic disease, patients were randomized into one of three treatment arms: those receiving anti-VEGF at 5 mg/kg in combination with 5-FU/leucovorin; those receiving anti-VEGF at 10 mg/kg in combination with 5-FU/leucovorin; and those receiving 5-FU/leucovorin alone.

Response rates were 40 percent in the low-dose arm, 24 percent in the high-dose arm, and 17 percent in the 5-FU/leucovorin arm. Time to disease progression was 9 months, 7.2 months and 5.2 months, respectively. Median survival has not yet been reached at 17.3 months in the low-dose arm. It was 16.1 months in the high-dose arm and 13.6 months in the 5-FU/leucovorin arm.

Anti-VEGF was well tolerated, with some mild to moderate adverse events, such as fever, chills, headache, hypertension, infection and rash. About 16 of 35 patients in the low-dose arm and 17 of 30 patients in the high-dose arm experienced nose bleeds.

Also, there were 13 incidents of thrombosis. "There were more problems with clotting on anti-VEGF-treated arms, but the patients were on trial longer so some of that may be expected," Fyfe told BioWorld Today. "And secondly, all cancer patients do have somewhat of an increased risk for clotting."

Genentech also announced in December its plans to start a Phase III trial of rhuMAb-VEGF in patients with metastatic non-small-cell lung cancer. Phase II results from that program will be presented today at ASCO. (See BioWorld Today, Dec. 17, 1999, p. 1.)

Analysts have said that the non-small-cell lung cancer results may not be as promising as the colorectal cancer results. Anti-VEGF was associated with six cases of hemoptysis, including four that proved fatal to the patient, said analyst Peter Ginsberg, of Minneapolis-based U.S. Bancorp Piper Jaffray, in a research note. Hemoptysis is the spitting of blood from a pulmonary hemmorhage.

Fyfe confirmed that bleeding in the lung was seen in the trial, but that after reviewing the data the National Cancer Institute and the company still intend to move forward with a pivotal Phase III study for the indication.

Genentech's stock (NYSE:DNA) closed Monday at $108.50, down $17.50, or 14 percent. The downswing is not reflective of Genentech news coming out of ASCO, said analyst Jay Silverman, of San Francisco-based Robertson Stephens.

"Genentech's having a very, very positive meeting, absolutely, on all fronts," Silverman told BioWorld Today. "Herceptin monotherapy with this new FISH assay looks incredibly strong." Rituxan, he said, appears to have potential in higher grades of lymphoma. "And anti-VEGF, I think, looks a lot better than people thought when they read the abstract."

Data on the approved drug Herceptin for breast cancer shows it may have a benefit when used in combination with Navelbine. The combination therapy produced an overall response rate of 75 percent among 40 patients. Also, the use of FISH - a method of detecting HER2 overexpression - seems to enhance response rates to Herceptin by better enabling clinicians to choose the right patients for the drug, according to Ginsberg's research note.

Also, Idec Pharmaceuticals Inc., of San Diego, presented at ASCO results of a study using Rituxan in combination with chemotherapy to treat 35 previously untreated chronic lymphocytic leukemia (CLL) patients. Rituxan, which is marketed by Genentech, already is approved to treat relapsed/refractory low-grade non-Hodgkin's lymphoma. Preliminary results showed that nine of 15 patients experienced a complete response and five more experienced a partial response for an overall response rate of 93 percent, Ginsberg said.

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