Extended Survival Benefit With Zaltrap Seen in Metastatic Colorectal Cancer

Paul Ruff, MD

Patients with metastatic colorectal cancer (mCRC) whose disease had progressed despite treatment with oxaliplatin experienced an improvement in survival by switching to a regimen of ziv-aflibercept (Zaltrap) plus FOLFIRI (fluorouracil, leucovorin, and irinitecan) compared with FOLFIRI alone, according to the results of a large randomized international trial.

Median overall survival, the primary endpoint of the study, was extended by 1.4 months with the addition of ziv-aflibercept to FOLFIRI, said Paul Ruff, MD, director of Medical Oncology at the University of Witwatersrand, Johannesburg, South Africa, who presented data from the phase III VELOUR study at the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, held from January 24—26 in San Francisco, California.

Ziv-aflibercept is a fusion protein that consists of the key domains of the vascular endothelial growth factor (VEGF) receptor-1 and VEGF receptor-2, joined at the Fc portion of human IgG, “to make a very potent agent for binding to VEGF, making it a very potent antiangiogenic agent,” said Ruff. “The potential benefit of this is that it binds not only to human VEGF-A isoforms as bevacizumab does, but also VEGF-B and placental growth factor.”

The FDA approved the drug in August for use in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen.

The VELOUR trial included 1226 patients with mCRC who received prior oxaliplatin-based treatment and whose disease had progressed during or following the last administration of the oxaliplatin regimen. Patients who relapsed within 6 months of completing oxaliplatin-based chemotherapy were also eligible. About 30% of patients had prior bevacizumab treatment. They were randomized to receive aflibercept, 4 mg/kg intravenously or placebo every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS).

The intent-to-treat analysis showed an OS advantage with ziv-aflibercept. Median OS was 13.5 months in the ziv-aflibercept/FOLFIRI group compared with 12.06 months in the placebo/FOLFIRI group (HR=0.817, P=.032).

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Dr. Paul Ruff Analyzes Overall Survival in the VELOUR Trial

A time-course analysis showed that “the [survival] curves continue to separate as time goes on. At 18 months, the benefit of ziv-aflibercept was increased to 2.6 months, and by 24 months, it was 4.4 months, so the benefit seems to continue with time,” Ruff said. The improvement in survival was almost double for ziv-aflibercept at 30 months vs. placebo (22.3% vs. 12.0%, respectively).

Median progression-free survival was also significantly longer with ziv-aflibercept by 2.2 months (HR, 0.758; P=.00007).

“The adverse events were those generally expected from anti-angiogenic agents, such as hypertension and proteinuria, but that tended to be early and usually fairly manageable,” Ruff said. There were more grade 3/4 adverse events with ziv-aflibercept compared with placebo. Most occurred during the first four cycles of treatment, and the vast majority (76.3%) were single episodes in nature. Grade 3/4 hypertension occurred in 3.6% of the treatment cycles and grade 3/4 diarrhea occurred in 2.8% of the cycles “but diarrhea was probably more due to the chemotherapy background than the actual treatment,” he sad.

Adverse events with ziv-aflibercept did not influence the ability of the patients to receive chemotherapy. Sixteen patients (2.3%) discontinued ziv-aflibercept prematurely due to hypertension and continued with an additional 7.4 cycles of FOLFIRI alone. Another 29 (4.7%) discontinued ziv-aflibercept prematurely due to proteinuria; they received an additional eight cycles of FOLFIRI alone.

“Ziv-aflibercept does seem to give a benefit in a second-line setting, including some patients who have had prior bevacizumab,” said Ruff. “We have seen a number of new agents that have come in the last 10 or 15 years. We are slowly but surely getting better and better in the management of patients with mCRC.”

Ruff P, Lakomy R, Prausová J, et al. Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and aflibercept or placebo in patients with mCRC that progressed on prior oxaplatin treatment. J Clin Oncol. 2012:30(suppl 34; abstract 451).

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