Study Compares Maintenance Strategies After First-Line Oxaliplatin/Fluoropyrimidine/Bevacizumab in Patients With Metastatic Colorectal Cancer
In a German noninferiority phase III trial (AIO 0207) reported in The Lancet Oncology, Hegewisch-Becker et al found that maintenance treatment with bevacizumab (Avastin) was noninferior to a fluoropyrimidine plus bevacizumab in time to maintenance strategy failure following first-line treatment with oxaliplatin, fluoropyrimidine, and bevacizumab in patients with metastatic colorectal cancer. The primary endpoint of time to strategy failure was defined as time to second progression after maintenance, and reinduction if applicable, death, or initiation of further treatment including a new drug. Progression-free survival was significantly longer with fluoropyrimidine/bevacizumab maintenance.
Study Details
In this open-label trial, 472 patients without disease progression after 24 weeks of treatment with either fluorouracil/leucovorin/oxaliplatin or capecitabine/oxaliplatin, both with bevacizumab, were randomly assigned between September 2009 and February 2013 to receive a fluoropyrimidine plus bevacizumab (n = 158), bevacizumab alone (n = 156), or no maintenance (n = 158). The protocol called for reinduction with at least part of the first-line regimen at first progression.
Time to strategy failure was equivalent to time to first progression in patients who did not receive reinduction treatment. The noninferiority boundary was the upper limit of the one-sided 98.8% confidence interval [CI] = 1.43 for the hazard ratio (HR) for time to strategy failure. Analyses were performed in the intent-to-treat population. Follow-up is ongoing.
Time to Strategy Failure
Median follow-up was 17.0 months. Median time to strategy failure was 6.9 months in the fluoropyrimidine/bevacizumab group, 6.1 months in the bevacizumab-alone group, and 6.4 months in the no-treatment group.
Bevacizumab alone was noninferior to fluoropyrimidine/bevacizumab (HR = 1.08, 95% CI = 0.85–1.37, P = .53; upper limit of one-sided 99.8% CI = 1.42); no treatment was not noninferior to fluoropyrimidine/bevacizumab (HR = 1.26, 95% CI = 0.99–1.60, P = .056; upper limit of one-sided 99.8% CI = 1.65). Overall, reinduction after first progression was performed in only 36% of patients, including 19% of the fluoropyrimidine/bevacizumab group, 43% of the bevacizumab-alone group, and 46% of the no-treatment group.
Progression-Free Survival
Median time to first progression was 11.7 months in the fluoropyrimidine/bevacizumab group, 10.0 months in the bevacizumab-alone group, and 9.0 months in the no-treatment group. Median progression-free survival was 6.3 months in the fluoropyrimidine/bevacizumab group, 4.6 months in the bevacizumab-alone group, and 3.5 months in the no-treatment group (P < .0001). Hazard ratios for progression-free survival were 1.34 (P = .015) for bevacizumab alone and 2.09 (P < .0001) for no treatment vs fluoropyrimidine/bevacizumab and 1.45 (P = .0018) for no treatment vs bevacizumab alone.
Adverse Events
The most common adverse events of any grade were sensory neuropathy (44% in fluoropyrimidine/bevacizumab group, 72% in bevacizumab-alone group, 71% in no-treatment group) and fatigue (28%, 18%, and 20%). The most common grade 3 or 4 adverse event was sensory neuropathy (13%, 14%, and 8%; all grade 3), with no other grade 3 or 4 event occurring in > 3% of any group.
The investigators concluded: “Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.”
Susanna Hegewisch-Becker, MD, of HOPE–Practice for Oncology, Hamburg, is the corresponding author for the Lancet Oncology article.
The study was funded by RochePharma AG and AIO Studien gGmbH. For full disclosures of the study authors, visit www.thelancet.com/journals/lanonc/.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
