SAN FRANCISCO – The antiangiogenic agent bevacizumab is not efficacious when added to standard adjuvant chemotherapy for stage III colon cancer, despite its proven efficacy in the metastatic setting, a second randomized trial has reported.
Dr. Aimery de Gramont
Among 2,867 patients, the addition of bevacizumab (Avastin) to the adjuvant FOLFOX4 regimen or XELOX regimen did not improve the rate of disease-free survival, compared with FOLFOX4 alone, in the AVANT trial. Indeed, outcomes were slightly worse with the added bevacizumab.
"This study is negative," lead investigator Dr. Aimery de Gramont told attendees of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. "It’s very disappointing to say that bevacizumab is the third agent, after irinotecan and cetuximab, to fail in the adjuvant setting" despite showing efficacy in the metastatic setting.
The AVANT findings echo results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) C-08 trial, which reported that about three-fourths of early colon cancer patients were disease free at 3 years, whether they had adjuvant bevacizumab or not after FOLFOX6. Roche had announced in September 2010 that AVANT failed to meet its primary end point of improving disease-free survival.
The AVANT data suggest that the poorer outcomes with bevacizumab were not a result of decreased treatment duration, increased toxicity, or a rebound effect after discontinuing the agent. Instead, Dr. de Gramont hypothesized, bevacizumab may have pushed the cancer into a dormant state.
"Cetuximab, irinotecan, and bevacizumab inhibit VEGF [vascular endothelial growth factor] signaling via HIF [hypoxia-inducible factor–1] alpha, and this can induce tumor dormancy," he elaborated. "We know that arrested angiogenesis is a component of cell dormancy. ... And cell dormancy, it has been shown by preclinical work, can protect tumor cells from chemotherapy."
AVANT enrolled 3,451 patients from 34 countries who had undergone resection of their high-risk, stage II or stage III colon cancer. The patients were randomized in nearly equal numbers to receive FOLFOX4 alone for 24 weeks followed by observation for 24 weeks; FOLFOX4 plus bevacizumab (5 mg/kg every 2 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks); or XELOX plus bevacizumab (7.5 mg/kg every 3 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks).
Bevacizumab, a monoclonal antibody to VEGF, is approved by the U.S. Food and Drug Administration for use in combination therapy to treat metastatic colorectal cancer, as well as some other cancers. It is manufactured by Genentech and Roche.
The primary end point was disease-free survival among the 83% of patients who had stage III cancer, according to Dr. de Gramont, head of the department of internal medicine/oncology at the Saint-Antoine Hospital in Paris. These patients were predominantly men (54%) and white (84%). The median duration of follow-up was slightly more than 4 years.
In intention-to-treat analysis conducted after a minimum follow-up of 3 years, the rate of disease-free survival did not differ significantly among groups. If anything, patients tended to fare worse if they were given FOLFOX4-bevacizumab (hazard ratio, 1.17; P = .07) or XELOX-bevacizumab (HR, 1.07; P = .44), compared with FOLFOX4 alone.
More-detailed analysis showed that the effect of added bevacizumab varied over time; that is, there was a transient early benefit in the first year with the combinations (HRs, 0.63 and 0.61) that was lost in subsequent years, a pattern similar to that seen in the NSABP C-08 trial.
Dr. de Gramont hypothesized that this may relate to a benefit of bevacizumab among patients who already have vascularized but undetectable micrometastases. "So these patients could have a [disease-free survival] effect during the first year," he said. "But after the first year, the treatment is not favorable, and this is even worse than in the C08 trial."
The 3-year rate of disease-free survival was 76% with FOLFOX4 alone, 73% with FOLFOX4-bevacizumab, and 75% with XELOX-bevacizumab.
An interim analysis of overall survival yielded similar findings. The risk of death was somewhat higher with FOLFOX4-bevacizumab (HR, 1.31) and with XELOX-bevacizumab (HR, 1.27) than with FOLFOX4 alone.
"Immature overall survival data suggest a possible detriment, but continued follow-up is needed to confirm [this]," cautioned Dr. de Gramont.
In the entire study population, the leading grade 3-5 adverse events were venous thromboembolism (seen in 5% of patients) and hypertension (1%) with FOLFOX4 alone; hypertension (11%) and venous thromboembolism (8%) with FOLFOX4-bevacizumab; and hypertension (10%) and venous thromboembolism (5%) with XELOX-bevacizumab.
Among the patients with stage III disease, the patterns of recurrence – including involvement of multiple sites – and the time from recurrence to death were similar across treatment arms.