Elderly patients are often underrepresented in clinical trials of metastatic colorectal cancer. In the phase III AVEX trial reported in The Lancet Oncology,1 David Cunningham, MD, of Royal Marsden Hospital in London and colleagues assessed the addition of bevacizumab (Avastin) to capecitabine in patients aged ≥ 70 years with previously untreated metastatic colorectal cancer who were not considered candidates for oxaliplatin- or irinotecan-based chemotherapy. The bevacizumab/capecitabine combination significantly improved progression-free survival and was associated with more frequent adverse events than capecitabine alone.
In this international open-label trial, 280 patients were randomly assigned to receive capecitabine at 1,000 mg/m2 orally twice a day on days 1 to 14 alone (n = 140) or with bevacizumab at 7.5 mg/kg intravenously on day 1 (n = 140) given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival.
Median ages were 76 years in the combination group (61% ≥ 75 years) and 77 years in the capecitabine-alone group (67% ≥ 75 years), and 60% of patients in both groups were male. The groups were generally well matched for other baseline characteristics, including Eastern Cooperative Oncology Group (ECOG) performance status, site of metastatic disease, synchronous metastatic disease, primary tumor location, time since diagnosis of primary and metastatic disease, history of other medical conditions, and use of any concomitant drugs. However, more patients in the combination group had undergone surgical resection of the primary tumor, received previous adjuvant treatment, and had been treated with radiotherapy.
Prolonged Progression-Free Survival
Median follow-up was 24.8 months for the combination group and 21.6 months for the capecitabine-alone group. Progression-free survival was significantly longer with bevacizumab/capecitabine (median, 9.1 vs 5.1 months, hazard ratio [HR] = 0.53, P < .0001). Progression-free survival was 66.7% vs 44.2% at 6 months, 34.8% vs 10.3% at 12 months, and 16.2% vs 3.6% at 18 months.
Exploratory subgroup analyses of progression-free survival were consistent with the overall findings. Analysis by age suggested improved outcomes with the combination in patients aged 70 to 74 years (HR = 0.52, 95% confidence interval [CI] = 0.32–0.83), 75 to 79 years (HR = 0.60, 95% CI = 0.40–0.89), and ≥ 80 years (HR = 0.36, 95% CI = 0.19–0.71).
More patients in the combination group achieved response (19% vs 10%, P = .04) and disease control (74% vs 58%, P = .01), with duration of response being similar in the two groups (median, 9.0 vs 9.4 months).
Overall Survival Outcomes
Median overall survival did not differ significantly in the combination vs capecitabine-alone groups (20.7 vs 16.8 months, HR = 0.79, P = .18). Overall survival was 73.6% vs 60.0% at 1 year and 44.3% vs 35.1% at 2 years. The proportions of patients who had subsequent treatment after progression were similar in the two groups, including treatment with fluoropyrimidine monotherapy (17% vs 18%), bevacizumab (6% vs 8%), irinotecan doublets (6% vs 3%), oxaliplatin doublets (2% vs 1%), cetuximab (Erbitux; 3% vs 1%), and panitumumab (Vectibix; 1% vs 4%).
Treatment-related adverse events of grade 3 or higher occurred in 40% of patients in the combination group and 22% of patients in the capecitabine-alone group, and treatment-related serious adverse events occurred in 14% and 8%, respectively. The most common grade 3 or higher adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (16% vs 7%), diarrhea (7% vs 7%), and venous thromboembolic events (8% vs 4%). Treatment-related deaths occurred in 3.7% of patients in the combination group and 2.9% in the capecitabine-alone group. The most common adverse event of any grade of special interest for bevacizumab was hemorrhage (25% vs 7%). Adverse events led to dose interruption or modification in 55% of combination patients vs 43% of capecitabine patients and to discontinuation in 25% vs 15%.
The investigators concluded, “[O]ur data suggest that bevacizumab plus capecitabine represents an additional therapeutic option in elderly patients with metastatic colorectal cancer, particularly in those who are unsuitable for upfront oxaliplatin-based or irinotecan-based combination regimens.” ■
Disclosure: The study was funded by F Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com/journals/lanonc.
1. Cunningham D, Lang I, Marcuello E, et al: Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 14:1077-1085, 2013.
As reported in The Lancet Oncology by Cunningham and colleagues and reviewed in this issue of The ASCO Post, the AVEX trial was an open-label randomized phase III trial limited to patients over the age of 70 years with previously untreated, unresectable metastatic colorectal cancer who were not...