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Adding Ziv-Aflibercept to FOLFIRI Results in Persistent Improvement in Overall Survival in Patients With Metastatic Colorectal Cancer

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Key Points

  • Patients with metastatic colorectal cancer previously treated with oxaliplatin showed a continued and persistent improvement in overall survival when they received ziv-aflibercept in addition to FOLFIRI.
  • Survival was improved by 50% at 24 months and almost doubled at 30 months.
  • Most adverse events occurred early, were reversible, and did not affect the ability of patients to continue to receive treatment.

Patients with metastatic colorectal cancer showed a continued and persistent improvement over time in overall survival when they received ziv-aflibercept (Zaltrap) in addition to FOLFIRI (irinotecan, fluorouracil, leucovorin), reported by Ruff et al in the European Journal of Cancer. Survival was improved by 50% at 24 months and almost doubled at 30 months.

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

“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 [ziv-]aflibercept treatment effect is increasing over time,” Paul Ruff, MD, Director of Medical Oncology, University of Witwatersrand, Johannesburg, and colleagues noted.

Increases in Probability of Survival

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 randomly assigned to ziv-aflibercept and 614 to placebo. “The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the [ziv-]aflibercept- and placebo-treated arms, respectively,” the investigators stated.

“The absolute percent increase in the probability of survival in the [ziv-]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 [ziv-]aflibercept arm over the placebo arm,” the authors added.  

Most Grade 3/4 Adverse Events Occurred Early

Grade 3 to 4 adverse events occurred among 83.5% of patients receiving ziv-aflibercept arm vs 62.5% of patients receiving placebo, but did not affect patients’ abilities to continue 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 ziv-aflibercept occurred in early treatment cycles and then decreased sharply.

“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] is all the more important in light of an on-treatment [progression-free survival] analysis of VELOUR which supports the continuation of [ziv-]aflibercept treatment as close to progression as is reasonably possible,” the researchers wrote. The on-treatment progression-free survival analysis demonstrated that the addition of ziv-aflibercept to FOLFIRI resulted in a significantly improved treatment effect 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).

Complements and Expands VELOUR Results

“This integrated analysis of the time course of both the efficacy and safety of the ziv-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 mCRC previously treated with an oxaliplatin regimen and demonstrates a meaningful clinical benefit, which is sustained over a significant time period,” the authors concluded.

Dr. Ruff is the corresponding author for the European Journal of Cancer article.

The study was funded by Sanofi in collaboration with Regeneron Pharmaceuticals. Several of the authors reported honoraria and/or research funding from Sanofi and/or consultant advisory roles with Sanofi. Three of the authors are employees of Sanofi.

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®.


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