Genentech, Inc. and Roche announced that a Phase II study of the investigational drug Avastin (bevacizumab) plus 5-FU/Leucovorin chemotherapy in 209 previously-untreated metastatic colorectal cancer patients showed a 29 per cent improvement in median survival, the primary endpoint, which did not achieve statistical significance. The study also showed a 67 per cent prolongation in median progression-free survival, which was highly statistically significant, in patients treated with Avastin plus 5-FU/Leucovorin compared to 5-FU/Leucovorin alone.

"We're encouraged that a survival trend was observed and that patients also experienced a statistically significant improvement in progression-free survival, which is clinically meaningful for patients with metastatic cancer and consistent with the results of our Phase III trial," said Susan D. Hellmann, MD, MPH, Genentech's executive vice president, development and product operations, and chief medical officer. "We filed the Biologics License Application for Avastin in September, and we continue to expect FDA approval no later than the end of the first quarter of 2004."

This randomized, controlled, multi-center study enrolled patients who were not optimal candidates to receive first-line CPT-11. In this Phase II study, the addition of Avastin to 5-FU/Leucovorin was well tolerated and the safety profile was consistent with that seen in previous Avastin clinical trials in colorectal cancer. Only Grade 3 hypertension, easily managed with oral medications, and asymptomatic proteinuria were increased in this trial. As in the pivotal Phase III study, although uncommon, the incidence of gastrointestinal perforation may be increased by the addition of Avastin to chemotherapy (two cases, 2 per cent).

Results of the 900-patient pivotal study of Avastin plus the IFL chemotherapy regimen (5-FU/Leucovorin/CPT-11) were announced earlier this year and showed that Avastin plus the IFL regimen improved median survival by approximately five months, compared to patients treated with chemotherapy alone (20.3 months versus 15.6 months). These data were the basis for the Biologics License Application (BLA) for Avastin in metastatic colorectal cancer, which was submitted to the US Food and Drug Administration (FDA) in September.

Many researchers have discussed the link between angiogenesis and cancer growth for decades, but it wasn't until 1989 that Napoleone Ferrara, MD, a staff scientist at Genentech, discovered a key growth factor influencing the process, Vascular Endothelial Growth Factor (VEGF). Dr Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. This research was published in the journal Science in 1989. Dr Ferrara then created a mouse antibody to this protein. In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumour growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumour growth. Clinical studies with a humanized version of the antibody, Avastin, began in 1997.

Avastin is an investigational therapeutic antibody designed to inhibit VEGF, a protein that plays an important role in tumour angiogenesis and maintenance of existing tumour vessels. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to tumours, a process that is critical to tumour growth and metastasis.

Based on preclinical and clinical studies showing that VEGF plays a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in metastatic colorectal, renal cell (kidney), breast and non-small cell lung cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in pancreatic, prostate, ovarian, melanoma and several types of solid tumour cancers and hematologic malignancies. To date, more than 2,000 patients have been treated with Avastin in clinical studies.