Adding Aflibercept to FOLFIRI Resulted in Persistent Improvement in Overall Survival Over Time in Patients With Metastatic Disease

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Patients with metastatic colorectal cancer showed a continued and persistent improvement in overall survival over time when they received the VEGF inhibitor aflibercept in addition to FOLFIRI (leucovorin, fluorouracil, irinotecan), according to a study reporting on the overall survival benefit and safety of aflibercept over the course of the VELOUR trial. Survival was improved by 50% at 24 months and almost doubled at 30 months.

A large, international, randomized trial, VELOUR found a statistically significant and meaningful benefit in median overall and progression-free survival and response rates among patients with metastatic colorectal cancer previously treated with oxaliplatin who then received FOLFIRI plus aflibercept vs FOLFIRI alone. The median overall survival, the primary endpoint of the VELOUR trial, was 13.5 months for patients randomized to receive aflibercept vs 12 months for those receiving placebo, representing an 18.3% reduction in the risk of death for those receiving aflibercept (also called ziv-aflibercept [Zaltrap] in the United States).

“However, the increase in median overall survival underestimates the clinical benefit gained for the overall patient population as the Kaplan-Meier survival curves continue to separate past the median time point, indicating that the magnitude of the aflibercept treatment effect is increasing over time,” Paul Ruff, MD, Director of Medical Oncology, University of Witwatersrand, Johannesburg, and colleagues noted in the European Journal of Cancer.

The analysis of the time course of the efficacy and safety results was based on data from the VELOUR intent-to-treat patient population of 1,226 patients, 612 randomized to receive aflibercept and 614, placebo. “The estimated probabilities of survival were 38.5% vs 30.9% at 18 months, 28.0% vs 18.7% at 24 months, and 22.3% vs 12.0% at 30 months for the aflibercept- and placebo-treated arms, respectively,” the investigators stated.

“The absolute percent increase in the probability of survival in the aflibercept arm over the placebo arm at 12, 18, 24, and 30 months is 5.8%, 7.6%, 9.3%, and 10.3%, respectively. Correspondingly, the proportional increase in the probability of survival at 12, 18, 24, and 30 months is 11.5%, 24.6%, 49.3%, and 85.8% in the aflibercept arm over the placebo arm,” the authors added. 

Severe adverse events (grade 3 to 4) occurred among 83.5% of patients receiving aflibercept vs 62.5% of patients receiving placebo, but the adverse event “profile did not affect patients’ abilities to continue to receive treatment,” the researchers reported. The most common adverse events, including diarrhea, stomatitis, infection, and hypertension, occurred only once. Adverse events “were generally reversible, and the vast majority of patients recovered from grade 3/4 events, with the exception of those patients who developed proteinuria,” the investigators noted. Most of the grade 3/4 adverse events associated with aflibercept occurred in early treatment cycles and then decreased sharply.     

Time Course Analysis

“The time course analysis of adverse events in VELOUR provides health-care practitioners with the ability to anticipate expected treatment toxicities and manage them accordingly. The anticipation and appropriate management of adverse events are all the more important in light of an on-treatment progression-free survival analysis of VELOUR, which supports the continuation of aflibercept treatment as close to tumor progression as is reasonably possible. This on-treatment progression-free survival analysis, within 28 days of the end of treatment, demonstrated a significantly improved treatment effect for the addition of aflibercept to FOLFIRI in metastatic colorectal cancer (hazard ratio [HR] = 0.55 [95% confidence interval (CI): 0.46–0.66], P < .00001) over the primary VELOUR analysis (HR = 0.76 [95% CI: 0.66–0.87], P = .00007),” the researchers wrote.

“This integrated analysis of the time course of both the efficacy and safety of the aflibercept plus FOLFIRI regimen complements and expands the original results of the VELOUR study, making this regimen an effective and manageable therapeutic option for patients with metastatic colorectal cancer previously treated with an oxaliplatin regimen and demonstrates a meaningful clinical benefit, which is sustained over a significant time period,” the authors concluded. ■

Ruff P, et al: Eur J Cancer 51:18-26, 2015.