SAN FRANCISCO – Adding bevacizumab to capecitabine for first-line therapy for elderly patients with metastatic colorectal cancer significantly delayed disease progression and improved treatment response rates compared with capecitabine alone in a study of 280 patients.
The study is the first prospective, phase III clinical trial of a biologic agent (bevacizumab) for metastatic colorectal cancer in patients aged 70 years or older, who comprise many patients with this disease and generally are underrepresented in clinical trials, Dr. David Cunningham said.
Courtesy the American Society of Clinical Oncology
The combination treatment was effective and well tolerated, said Dr. David Cunningham.
Median progression-free survival rates were 5.1 months with capecitabine (Xeloda, Roche) and 9.1 months with capecitabine plus bevacizumab (Avastin, Roche/Genentech), an intent-to-treat analysis showed. Patients were followed for a median of 22 months in the monotherapy arm and 25 months in the combination therapy arm.
Among secondary outcomes, overall response rates were significantly better with the combination regimen (19%) compared with monotherapy (10%), he and his associates reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.
The capecitabine/bevacizumab group also showed improved median overall survival (20.7 months) compared with the control group (16.8 months). This difference did not reach statistical significance, but the study was not powered to show a difference in overall survival. The primary outcome was progression-free survival, said Dr. Cunningham, head of the gastrointestinal unit at Royal Marsden Hospital, London.
The benefits were seen across all subgroups, he added.
The Avastin in the Elderly with Xeloda (AVEX) trial randomized elderly patients from 10 countries to first-line treatment with capecitabine 1,000 mg/m2 b.i.d. on days 1-4 with or without bevacizumab 7.5 mg/kg every 3 weeks. Patients had a median age of 76 years at enrollment and an Eastern Cooperative Oncology Group performance status of 0-2. The study recruited patients who were not considered optimal candidates for combination therapy including irinotecan or oxaliplatin. Baseline characteristics were similar between treatment groups.
Grade 3 or higher adverse events occurred in 59% of patients on the combination therapy, compared with 44% on capecitabine alone, a safety analysis on 270 patients found. Rates of any serious adverse events were 31% with combination therapy and 32% with monotherapy. Adverse events led to death in 8% of the combination group and 12% on monotherapy.
"As a clinician, I was impressed with how well tolerated this combination was," Dr. Cunningham said. No signals of unusual adverse events were seen in this older population.
Among grade 3 or higher adverse events of special interest with bevacizumab or related to chemotherapy, hypertension developed in 2.2% on the combination and 1.5% on monotherapy, venous thromboembolic events were seen in 8.2% on the combination and 4.4% on monotherapy, arterial thromboembolic events occurred in 3.7% on the combination and 1.5% on monotherapy, and proteinuria was seen in 1.5% on the combination and in no patients on monotherapy. Grade 3 or higher bleeding, pulmonary hemorrhage, or heart failure occurred in less than 1% on monotherapy and no patients on combination treatment.
Patients on the combination therapy were exposed to treatment for a longer duration (5.8 months) compared with those on monotherapy (4.2 months). The capecitabine-plus-bevacizumab group underwent a median of nine cycles of therapy compared with six cycles in the capecitabine group.
The combination treatment was "effective, generally well tolerated, and produced meaningful disease control and good survival," Dr. Cunningham said. Because the multicenter study included patients from around the world, "these results should be transferable" and generalizable to elderly patients with metastatic colorectal cancer, he added.
Thirty-seven percent of patients in each treatment group received subsequent therapy for metastatic colorectal cancer.
Bevacizumab is considered part of standard care for metastatic colorectal cancer in general, and prior studies had suggested that elderly patients would benefit from adding bevacizumab to chemotherapy, he said.
The meeting was cosponsored by ASCO, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Dr. Cunningham reported receiving research funding from Roche, which markets capecitabine and bevacizumab, and from AstraZeneca and Merck KGaA. Several of his associates in the study were employees, leaders, or stockholders in Roche.
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