Bevacizumab Plus Cisplatin/Gemcitabine Extends Progression-Free Survival in Advanced NSCLC

ASCO—A global phase III study is the second to show that adding bevacizumab (Avastin) to chemotherapy extends progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC). The results add momentum to the move toward considering bevacizumab/chemotherapy as the standard of care for first-line treatment of NSCLC. Lead author Christian Manegold, MD, professor of medicine, University of Heidelberg, Germany, presented the findings of the study, known as the Avastin in Lung (AVAiL) trial, at the 43rd Annual Meeting of the American Society of Clinical Oncology (LBA-7514).

The study combined bevacizumab with cisplatin and gemcitabine (Gemzar). Last year, the Eastern Cooperative Oncology Group reported similar gains from adding bevacizumab to carboplatin and paclitaxel (E4599). The carboplatin/paclitaxel regimen is more commonly used in the United States, while cisplatin/gemcitabine is more often used in Europe.

The investigators randomized 1,043 patients with previously untreated non-squamous-cell advanced or recurrent NSCLC and no brain metastases to receive either chemotherapy alone (cisplatin 80 mg/m² on day 1 and gemcitabine 1,250 mg/m² on days 1 and 8 every 3 weeks for up to six cycles) or the same chemotherapy with one of two doses of bevacizumab (7.5 mg/kg or 15 mg/kg). Bevacizumab or placebo was continued to progression after completion of chemotherapy. The primary endpoint was progression-free survival (PFS). "The secondary endpoint, overall survival, requires further follow-up," he said.

Median PFS was 6.1 months with placebo, 6.7 months with bevacizumab 7.5 mg/kg (HR 0.75, P = .0026), and 6.5 months with bevacizumab 15.0 mg/kg (HR 0.82, P = .0301). "At 3, 6, 9, and 12 months, PFS rates were about 5% to 10% increased in patients receiving bevacizumab," Dr. Manegold said. He also pointed out that the ECOG study, which used the 15 mg/kg bevacizumab dose, found a very similar median PFS of 6.2 months at that dose vs 4.5 months for the placebo control arm.

Dr. Manegold described the bevacizumab regimen as being "well tolerated." Serious adverse events did not differ significantly with the addition of bevacizumab, including adverse events leading to death. However, there was more grade 3 or higher bleeding, hypertension, and proteinuria on the bevacizumab combination arm.

Pulmonary hemorrhage was uncommon, he said: 4.9% for controls, 7% for low-dose bevacizumab, and 9.7% for high-dose bevacizumab. These included fatal hemorrhages in 1.2% of patients on low-dose bevacizumab and 0.9% on high-dose bevacizumab vs 0.3% for controls.

In response to a question from the audience about the efficacy of the two bevacizumab regimens, Dr. Manegold responded, "There were clear hints from our study that there is no difference in efficacy between these two doses, but the study was not powered to compare dose."

'Small Step Forward'

Questions were also raised about the clinical significance of the PFS finding, with one attendee noting that "the extra 2 weeks of progression-free survival were purchased at the cost of more bleeding and hypertension." During an earlier press briefing, Roy S. Herbst, MD, PhD, of M.D. Anderson Cancer Center, said that the increase in PFS was clinically meaningful, although it is "only a small step forward in a killer disease."