Avastin (bevacizumab) - Angiogenesis Inhibitor and Cancer Therapy

The product of a joint development programme between Genentech and Roche, Avastin (bevacizumab) is a humanised monoclonal antibody (MAb) directed against vascular endothelial growth factor (VEGF), a pro-angiogenesis factor.

Avastin broke new ground in becoming the first angiogenesis inhibitor to market, when it secured US FDA approval at the end of February 2004 and in Europe in early 2005. It is used as a first-line treatment with 5-FU for patients with metastatic colorectal cancer.

The EMEA has since given approval for Avastin to be used in combination with any chemotherapy for colorectal cancer. This new, broader label will allow Avastin to be used with Roche's Xeloda (capecitabine), an oral chemotherapeutic agent.

Building on the successful results in colorectal cancer, Avastin has since been explored as a potential treatment in a range of other solid tumours. It is now a licensed treatment not only for colorectal cancer but also for breast and lung cancer, where it has similarly demonstrated a progression-free or overall survival benefit.

Most recently, European approval was granted for the use of Avastin in combination with interferon for the treatment of renal cell carcinoma, for which a significant improvement in progression-free survival was also observed.

AVASTIN BLOCKS VEGF RECEPTOR BINDING

Angiogenesis inhibitors are drugs which are designed to stop tumours from developing a blood supply, a pre-requisite for tumour growth and metastasis (tumour spreading).

Avastin works by inhibiting the action of VEGF, a specific angiogenesis growth factor that binds to receptors on blood vessels and stimulates the formation of new blood vessels. By binding to VEGF, Avastin blocks VEGF receptor binding.

The idea of attacking tumours by cutting off their blood supply was first described in the early 1970s. It has been hailed as one of the most exciting approaches to the treatment of solid tumours.

Over 50 angiogenesis inhibitors are in development for cancer, reflecting the level of interest in this new class of anti-cancer agents.

These findings suggest that the addition of Avastin to standard chemotherapy as first-line therapy confers survival benefit in patients with advanced breast cancer. Avastin was generally well tolerated by patients in this study, where it was administered at the recommended dose of 10mg/kg every two weeks.

SURVIVAL BENEFIT IN LUNG CANCER PATIENTS

After colorectal and breast cancer, lung cancer was the third major cancer in which Avastin demonstrated a survival benefit. Evidence for its efficacy in one of the most difficult-to-treat cancers was seen in results from the pivotal E4599 trial.

Involving 878 patients with locally advanced, metastatic or recurrent NSCLC, the study showed that patients receiving Avastin plus chemotherapy (paclitaxel and caroboplatin) had a 20% reduction in risk of death compared with those receiving chemotherapy alone. Median survival was 12.3 months in the Avastin treatment arm, compared with 10.3 months in the control arm.

Improvement in overall survival among Avastin-treated patients was accompanied by improvement in progression-free survival (35% reduction in risk of progression) when compared with chemotherapy alone. More patients in the Avastin treatment arm also responded to therapy compared with those on chemotherapy alone (29% vs. 13% respectively).

Positive results also emerged from the recently completed European AVAiL trial. In this phase III trial involving over 1,000 patients with previously untreated advanced NSCLC, two doses of Avastin in combination with gemcitabine and cisplatin were compared with platinum-based therapy alone. Again, results showed a significant improvement in progression-free survival in the Avastin treatment arm as well as higher and more durable response rates.

SURVIVAL BENEFIT IN KIDNEY CANCER PATIENTS

Evidence is accumulating to suggest that the survival benefit first seen in patients with metastatic colorectal cancer also extends to patients with other solid tumours, most notably breast and lung cancer and, now, kidney cancer.

Trials in patients with renal cell carcinoma, in which Avastin was added to interferon, suggest that it can make a significant improvement in progression-free survival. In the randomised, double-blind, placebo-controlled AVOREN trial, the addition of Avastin to interferon in patients with advanced kidney cancer resulted in a significantly longer median duration of progression-free survival compared with interferon alone (10.2 months vs. 5.4 months; HR 0.63, 95% CI 0.52–0.75; p=0.0001).

Patients who had received previous systemic treatment for metastatic renal cell carcinoma were excluded from the study, thus all patients were treatment naïve at study entry.

Until relatively recently, there were few treatment options for patients with renal cell carcinoma. Now four new drugs are available for renal cell carcinoma, which in addition to Avastin, include sunitinib, sorafenib and temsirolimus. It is anticipated that future studies will likely compare Avastin as single-agent, first-lint therapy with these new therapies as well as in combination with these new agents.

The UK, National Institute of Clinical Excellence (NICE) is due to issue guidance on the use of Avastin, sunitinib, sorafenib and temsirolimus for renal cell carcinoma in early 2009.

MARKETING COMMENTARY

Early enthusiasm for angiogenesis inhibitors waned after several promising drugs failed to meet increased survival endpoints in pivotal phase III trials in cancer patients. The survival benefit first seen with Avastin in the colorectal cancer trials was important in demonstrating proof of principle, as well as increasing treatment options for patients with metastatic colorectal cancer. Evidence is accumulating to suggest that this survival benefit extends to patients with other solid tumours, most notably breast and lung cancer.

Avastin is now seen as having the potential to be incorporated into a range of treatment regimens for patients with a variety of solid tumours. In addition to colorectal, breast and lung cancer, it is also being evaluated in pancreatic, ovarian, and kidney cancer. It is anticipated that as the global development programme for Avastin expands, there will eventually be data on over 40,000 patients.